Report of The External Review Committee for
The Institute of Medical Science
The University of Tokyo
March 2021

Contents
Prologue(1) Goals and aim for External Review of IMSUT ...............................................................................6(2) Period of Review .............................................................................................................................6(3) External Review Method.................................................................................................................6(4) List of External Review of IMSUT Committee Members ..............................................................7
I. General Statement: Current Status of IMSUT(1) Mission and Features.......................................................................................................................9(2) Organization ..................................................................................................................................10(3) Status of Current Research Activities ............................................................................................ 111) Implementation System and Support/Promotion System for Research ...................................... 112) Initiatives and quality improvement in research activities .........................................................173) Academic Papers/Patents/Conference Presentations etc.............................................................27
4) Research Funds ...........................................................................................................................31
5) Research Activities through International Collaboration............................................................35
6) Contribution to Academic Community.......................................................................................36(4) Status of Research Results ............................................................................................................39(5) Status of Education Activity ..........................................................................................................43(6) Status of Social Cooperation .........................................................................................................43(7) Issues and Future Prospects...........................................................................................................46
II. Detailed Exposition
Department of Microbiology and Immunology ..................................................................................49
Division of Virology .......................................................................................................................51
Division of Infectious Genetics ......................................................................................................55
Division of Molecular Virology ......................................................................................................57
Division of Vaccine Science ...........................................................................................................60
Division of Malaria Immunology ...................................................................................................63
Department of Cancer Biology ...........................................................................................................66
Division of Molecular Pathology ....................................................................................................69
Division of Cellular and Molecular Biology (-2020.3) ...................................................................73
Division of Genetics .......................................................................................................................76
Division of Cancer Cell Biology.....................................................................................................79
Department of Basic Medical Sciences ..............................................................................................821

Division of Molecular Cell Signaling (-2017.3) .............................................................................84
Division of Neuronal Network........................................................................................................86
Division of Cell Signaling and Molecular Medicine ......................................................................88
Human Genome Center.......................................................................................................................90
Laboratory of DNA Information Analysis (-2020.3) ......................................................................93
Laboratory of Genome Technology ................................................................................................93
Laboratory of Genome Database ....................................................................................................93
Laboratory of Sequence Analysis ...................................................................................................93
Division of Computational Science (Health Intelligence Center) (-2020.3) ...................................93
Laboratory of Molecular Medicine .................................................................................................96
Laboratory of Functional Analysis in Silico ...................................................................................99
Department of Public Policy ......................................................................................................... 102
Division of Medical Data Informatics .......................................................................................... 104
Division of Health Medical Intelligence ....................................................................................... 106
Division of Metagenome Medicine............................................................................................... 110
Center for Experimental Medicine and Systems Biology ................................................................. 112
Laboratory of Developmental Genetics (-2018.3) ........................................................................ 115
Division of Stem Cell Pathology .................................................................................................. 117
Laboratory of Innate Immunity ..................................................................................................... 120
Laboratory of Reproductive Systems Biology .............................................................................. 122
Laboratory of Systems Biology (-2019.3) .................................................................................... 124
Division of Genome Engineering ................................................................................................. 126
Advanced Clinical Research Center ................................................................................................. 128
Division of Molecular Therapy ..................................................................................................... 130
Division of Cellular Therapy ........................................................................................................ 133
Division of Infectious Diseases .................................................................................................... 136
Division of Clinical Genome Research......................................................................................... 139
Division of Innovative Cancer Therapy ........................................................................................ 142
Division of Advanced Medicine Promotion.................................................................................. 144
Division of Advanced Genome Medicine ..................................................................................... 146
Division of Genetic Therapeutics (-2018.3).................................................................................. 148
Division of Bioethics .................................................................................................................... 150
Center for Stem Cell Biology and Regenerative Medicine ............................................................... 153
Division of Stem Cell and Molecular Medicine ........................................................................... 156
Division of Regenerative Medicine .............................................................................................. 158
Division of Stem Cell Transplantation .......................................................................................... 161
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Division of Stem Cell Processing/Stem Cell Bank ....................................................................... 163
Division of Stem Cell Signaling ................................................................................................... 165
Division of Stem Cell Dynamics (-2019.3) .................................................................................. 168
Division of Stem Cell Cellomics (-2019.5) .................................................................................. 171
Division of Experimental Pathology ............................................................................................. 173
Division of Stem Cell Biology ...................................................................................................... 175
International Research Center for Infectious Diseases ..................................................................... 177
Division of Viral Infection ............................................................................................................ 180
Division of Bacteriology (-2019.3) ............................................................................................... 183
Division of Systems Virology ....................................................................................................... 185
International Research and Development Center for Mucosal Vaccines .......................................... 188
Division of Mucosal Barriology ................................................................................................... 191
Division of Innate Immune Regulation......................................................................................... 194
Division of Clinical Vaccinology .................................................................................................. 197
Division of Mucosal Vaccine ........................................................................................................ 199
Division of Mucosal Symbiosis .................................................................................................... 201
Health Intelligence Center ................................................................................................................ 203
Division of Health Medical Data Science ..................................................................................... 205
Center for Gene and Cell Therapy .................................................................................................... 208
Division of Molecular and Medical Genetics ............................................................................... 211
Laboratory Animal Research Center ................................................................................................. 214
Laboratory Animal Research Center (Kai Laboratory) (-2019.3) ................................................. 216
Division of Animal Genetics ......................................................................................................... 218
Animal Center (-FY2018) ............................................................................................................. 220
Animal Center (FY2019-) ............................................................................................................. 222
Amami Laboratory of Injurious Animals (-FY2018) ........................................................................ 224
Amami Laboratory of Injurious Animals (FY2019-) ........................................................................ 226
Medical Proteomics Laboratory ........................................................................................................ 228
Research Center for Asian Infectious Diseases................................................................................. 230
Laboratory of Molecular Genetics (-FY2016) .................................................................................. 235
Laboratory of Molecular Genetics (Frontier Research Unit) ............................................................ 237
IMSUT Hospital................................................................................................................................ 239
Department of Hematology/ Oncology ......................................................................................... 243
Department of Infectious Diseases and Applied Immunology...................................................... 246
Department of Rheumatology and Allergy ................................................................................... 249
Department of General Medicine.................................................................................................. 251
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Department of Applied Genomics................................................................................................. 253
Department of Radiology.............................................................................................................. 255
Department of Palliative Medicine ............................................................................................... 257
Department of Diagnostic Pathology/Department of Pathology................................................... 260
Department of Surgery .................................................................................................................. 262
Department of Anesthesia ............................................................................................................. 265
Department of Joint Surgery ......................................................................................................... 269
Department of Surgical Neuro-Oncology ..................................................................................... 271
Department of Medical Informatics .............................................................................................. 274
Department of Radiological Technology ...................................................................................... 276
Department of Cell Processing and Transfusion ........................................................................... 278
Surgical Center.............................................................................................................................. 282
Department of Medical Supply Center ......................................................................................... 284
Department of Laboratory Medicine............................................................................................. 286
Regional Medical Liaison Office .................................................................................................. 288
Center for Clinical Safety and Infection Control .......................................................................... 290
Center for Translational Research ................................................................................................. 292
Center for Antibody and Vaccine Therapy .................................................................................... 295
Therapeutic Vector Development Center ...................................................................................... 298
IMSUT CORD .............................................................................................................................. 300
Department of Nursing ................................................................................................................. 302
Department of Pharmacy .............................................................................................................. 305
IMSUT Distinguished Professor Unit ............................................................................................... 307
Division of Stem Cell Therapy ..................................................................................................... 307
Division of Mucosal Immunology ................................................................................................ 309
Corporate Sponsored Research Program .......................................................................................... 313
Project Division of Molecular and Developmental Biology ......................................................... 313
Project Division of Fundamental Study on Cutting Edge of Genome Medicine .......................... 316
Social Cooperation Research Programs ............................................................................................ 319
Project Division of RNA Medical Science ................................................................................... 319
Project Division of Systems Immunology Research (-2019.9) ..................................................... 321
Project Division of Advanced Regenerative Medicine (-2017.9) ................................................. 324
Project Division of International Advanced Medical Research .................................................... 326
Project Division of ALA Advanced Medical Research (-2020.3) ................................................. 328
Project Division of Advanced Biopharmaceutical Science ........................................................... 330
Project Division of Cancer Biomolecular Therapy ....................................................................... 332
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Project Division of Genetic Medicine and Disease Prevention .................................................... 334
External Review Meeting ................................................................................................................. 336
Report of the External Review Committee ....................................................................................... 337
Postscript........................................................................................................................................... 343

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Prologue(1) Goals and aim for External Review of IMSUTThe Institute of Medical Science, the University of Tokyo (hereafter IMSUT) is one of Japan’slargest national institutes in the life science field with its own affiliated hospital. The missions of
IMSUT are to implement translational research promoting basic and clinical research to apply its
findings in medical practice, and to integrate a genome-based precision medicine into clinical practice.
Furthermore, IMSUT enhances postgraduate education in association with many graduate schools of
the University of Tokyo. We believe that it is important to create the environment in which researchersand students can focus on their studies, so as to deliver world-leading, high quality research along withan education system fit for the next generation of researchers.
With these in mind, aiming to improve research and education standards in accordance with the
emerging trend, IMSUT formed the IMSUT Self-Inspection and Evaluation Committee (hereafter“Self-Inspection and Evaluation Committee”) and scrutinized the vision of our research and education
evaluation. In this context, the Committee played the central role in making an evaluation of IMSUT
research and education activities as well as its administrative performance. Following this, IMSUT
raised its sights to advancing research and education activities by developing our strengths andclarifying areas for improvement. In addition, IMSUT commissioned researchers who are active inJapan and overseas to objectively re-evaluate the self-inspection and evaluation results from a
professional perspective, and IMSUT will reflect their evaluation in its future activity policies.

(2) Period of Review
April 1, 2016 – June 30, 2020

(3) External Review Method
External Review of IMSUT is to be conducted according to the following procedure.
(1) Implementation of the self-inspection and evaluation(2) Compilation of Materials for External Review of IMSUT based on the self-inspection andevaluation results(3) Prior review in writing by the external review committee members(4) Holding an external review meeting(5) Summary of external review results(6) Publication of Report of External Review of IMSUT

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(4) List of External Review of IMSUT Committee Members(alphabetically)
Mary Collins (Okinawa Institute of Science and Technology Graduate University)
Rudolf Jaenisch (Whitehead Institute, Massachusetts Institute of Technology)
Aikichi Iwamoto (Japan Agency for Medical Research and Development)
Minoru Kanehisa (Institute for Chemical Research, Kyoto University)
Thirumala-Devi Kanneganti (Immunology Department, St. Jude Children's Research Hospital)
Hiroaki Mitsuya (National Cancer Institute, National Institute of Health)Takuro Nakamura (The Cancer Institute of JFCR)
Masato Okada (Research Institute for Microbial Diseases, Osaka University)
Emmanuelle Passegué (Columbia Stem Cell Initiative, Colombia University Irving Medical Center)Toshio Suda (International Research Center for Medical Sciences, Kumamoto University)
Takaji Wakita (National Institute of Infectious Diseases)
Limsoon Wong (School of Computing, National University of Singapore)7

I. General Statement: Current Status of IMSUT

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General Statement: Current Status of IMSUT(1) Mission and Features
IMSUT is the only national university-affiliated research institute of Japan with its own hospital.
IMSUT explores the universal truth of biological phenomena and the principles underlying diseases
through basic research, with the results gained promptly applied for medical practice. Our clinicalinformation is then to be reflected forthwith on basic research, which leads to the establishment of ourleading medical research system. Under this virtuous-cycle system, we set our minds to making acontribution to society through advanced medical treatment, drug discovery and translational researchsuch as vaccine development. In addition to diseases research including emerging and re-emerging
infections, immune disorders, and cancer, IMSUT has been advancing basic medical research focusing
on stem cells, regenerative medicine, and clinical genome sequencing. Along with this, with the aimof applying research results to medical practice, we are conducting advanced medical treatment bypromoting next generation vaccine development, gene and cell therapy, and translational research suchas personalized medicine with AI (Artificial Intelligence). Following our university’s third mid-term
goal, “pursuing excellence and diversity in every academic area, and based on which, vigorously
creating new academic fields”, IMSUT continuously implements its organizational reformation tocreate project-oriented research centers which satisfy the needs of the present generation as bases forleading research open to Japan and the rest of the world (Material 1).
Furthermore, in FY2010, IMSUT was authorized as a Joint Usage/Research Center by the Ministryof Education, Culture, Sports, Science and Technology, Japan (hereafter MEXT). On top of that, whenre-authorized in FY2018, IMSUT became the only International Joint Usage/Research Center among
the national university-affiliated research institutes of Japan serving the field of medical science andbiology. While widely calling upon expertise of researchers from Japan and abroad, we have been
providing the public with research materials, technology platforms, and medical information, such asa supercomputer supporting research in the life science field across the nation; banks of DNA, serum,
and tissue essential for the personalized medicine; a disease-specific iPS cell bank supporting
regenerative medicine research; and a pathogenic microbes repository indispensable to infectious
disease research. Through developing and offering these research resources and environment which
an individual university cannot provide on its own, IMSUT executes its commitment to efficientpromotion of medical research throughout Japan.

Yuji Yamanashi, Ph.D.
Dean
The Institute of Medical Science, The University of Tokyo

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General Statement: Current Status of IMSUT(2) Organization【Material 1】Organization chart of IMSUT
Department of Microbiology and Immunology
Research Departments

Department of Cancer Biology

Department of Basic Medical Sciences
Dean
IMSUT hospital
Vice Dean
Laboratory Animal Research Center

Amami Laboratory of Injurious Animals

Laboratory of Molecular Genetics

Human Genome Center

Center for Experimental Medicine and Systems Biology

Steering Committee Meeting

Research Facilities

Advanced Clinical Research Center

Department Heads' Meeting

Center for Stem Cell Biology and Regenerative Medicine

Senior Faculty Meeting

International Research Center for Infectious Diseases

Medical Proteomics Laboratory
International Research and Development Center for
Mucosal Vaccines
Center for Gene & Cell Therapy
Health Intelligence Center(Integrated into Human Genpme Center in April, 2020）
Research Center for Asian Infectious Diseases
Corporate Sponsored Research Programs/ Social Cooperation Research Programs
Technical Office

Dean's Office

Common Research Facilities

Administration Office10

General Statement: Current Status of IMSUT(3) Status of Current Research Activities
1) Implementation System and Support/Promotion System for Research
In the MEXT Budget Request, our new five proposed programs satisfying societal needs have been
approved since FY2013, which led to the reinforcement of IMSUT organizational structures, during
the third mid-term target period (hereafter “the third period”) (Material 2). Among these fiveprograms, “Global Promotion of Strategic Research and Development for Mucosal Vaccines” and“Establishment of a Collaborative Platform for Research and Human Resources for the Control of
Infectious Diseases” were approved in FY2016 or later, each of which is currently being implemented
principally by the International Research and Development Center for Mucosal Vaccines, and theInternational Research Center for Infectious Diseases, respectively. Meanwhile, “Core Research for
Creating New Dimension Genomic Medicine by Integrating Human Intelligence and AI” launched
in FY2020, and we plan to open up a new dimension of

genomic medical treatment (in line withsociety 5.0, our new society in which cyberspace and our real space are fused by AI) with the HealthIntelligence Center’s effective integration into the Human Genome Center (Material 2). Along with
this, the Center for Antibody and Vaccine Therapy, the Center for Gene & Cell Therapy, and theCenter for Translational Research play the central roles in our system promoting the development ofadvanced medical treatment and translational research.
【Material 2】MEXT Budget request within the third mid-term target period
Projects

PeriodProject outline and its related centers

Cultivation of Human
Resources for Global
Leaders and Coordinators
Conducting Clinical Trials
of Innovative Antibody
and Vaccine Therapy at
First in Man (FIM)

FY2013～
FY2017（for 5years）●Center for Antibody and Vaccine Therapy
The aim of this project is to build a medical/educational system to enablesystematic and continuous clinical practice of exploratory advanced medicine.
Through On-the-Job Training (OJT), the center develops leading professionals
who can conduct the world's first "clinical trial" using antibodies/vaccines
developed by IMSUT.

Organization ofInternational Genomic
Medicine Research
Initiative for Innovative
Therapies and Prevention

FY2015～FY2019（for 5years）●Health Intelligence CenterWith the view that the development of genomic medical science is an urgent issue
in health care, this project works to establish an International Genomic Medicine
Research Initiative by gathering all efforts of the University of Tokyo aiming toenhance its capabilities. Also, it seeks to create and promote an academic field
called “medical informatics” that integrates genomic information andclinical/health information so that patients will be able to receive personalized
medicine and disease prevention.

11

General Statement: Current Status of IMSUT

Global Promotion ofStrategic Research andDevelopment for Mucosal
Vaccines

FY2016～FY2020（for 5years）●International Research and Development Center for Mucosal Vaccines
This project aims to establish a collaborative research system with university
research institutions both in Japan and overseas based around IMSUT. The
center forms an international joint research center and accumulates academic
fundamental research seeds to develop a safe and effective "prospective mucosal
vaccine" against infectious diseases, allergies, cancers, etc. from the perspectiveof mucosal immunology. By doing this, it is expected to create a new academicarea, "mucosal vaccinology", to develop a "prospective mucosal vaccine that does
not require syringes and needles" to contribute to global medical care, and tonurture global human resources in related fields. The center works to contributeto enhancement of university functions and globalization throughleading/international research and human resource development based on"mucosal vaccinology", and "next generation mucosal vaccines".

Establishment of a
Collaborative Platform for
Research and Human
Resources for the Control
of Infectious Diseases

FY2016～FY2021（for 6
years）●International Research Center for Infectious Diseases
Hokkaido University, The University of Tokyo, Osaka University, and Nagasaki
University form the Alliance in Research and Education for the Control of
Infectious Diseases, and by utilizing the characteristics that each center has built
to date, establish an organic collaboration base for research and human resource
development between each base. By doing this, the center aims to establish an allJapan system for control of infectious diseases.

Core Research for
Creating New Dimension
Genomic Medicine byIntegrating HumanIntelligence and AI

FY2020～
FY2024（for 5years）●Progressive integration of a Health Intelligence Center into the Human Genome
CenterBased on the integrated genome information of "the human genome" (20,000
genes) and "the symbiotic and virus plexus genome" (20 million genes), and vast
literature information, this project focuses on advancing genome research thatgenerates medical value with a uniquely developed AI and on creating a new
dimension of genomic medicine for Society 5.0 that fuses human intelligence andAI.

More than 11 of our large-scale research projects have been adopted during this third period, which
includes the four approved or renewed in FY2016 or later. IMSUT has taken a lead role in promoting
each project (Material 3). Through the National Bioresource Project, the Tailor-made Medical
Treatment Program, and the BioBank Japan Project for Genomic and Clinical Research, one of theworld's largest sets of data and samples acquired from 267,000 patients with 51 diseases including
DNA, serum, and medical records has been stored and offered to researchers at home and abroad.
【Material 3】Leading research projects implemented within the third mid-term target period
Projects

PeriodTranslational Research Network Program (AMED)"Advanced Center for the Establishment and Coordination of Biomedical Innovation Development
Assistance"

FY2012-FY2016

National Bioresource Project (NBRP) (AMED)"Collection, cryopreservation and distribution of human umbilical cord blood stem cells for basic
researches"
Tailor-Made Medical Treatment with the BioBank Japan Project (BBJ) (AMED)"Establishment of a Biobank and Creation of a Database of Clinical Information"

12

FY2012-FY2016

FY2013-FY2017

General Statement: Current Status of IMSUT

Advanced Research and Development Programs for Medical Innovation, Leading Advanced
Projects for medical innovation (LEAP)（AMED）

FY2014-FY2018"Research and development of innovative treatment and prevention methods aimed at controllinginfluenza"
Advanced Research and Development Programs for Medical Innovation, Leading Advanced
Projects for medical innovation (LEAP) (AMED)FY2015-FY2019"Generation of Functional Organs using Developmental Niche"
Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) (AMED)"China-Japan Research Collaboration on Defense against Emerging and Reemerging Infections"Post-K Supercomputer Development Project (Flagship2020) (MEXT)"Integrated computational life science to support personalized and preventive medicine"

FY2015-FY2019
FY2015-FY2019

The Translational Research Program; Strategic Promotion for Practical Application of Innovative
Medical Technology (TR-SPRINT)
FY2017-FY2021"Strategic Promotion and Expansion of a Translational Research to Establish a Global Base forKnowledge Collaboration"
National Bioresource Project (NBRP) (AMED)"Collection, cryopreservation and distribution of human umbilical cord blood stem cells for basic
researches"

FY2017-FY2021

BioBank Japan Project for Genomic and Clinical Research (AMED)"Management of BioBank Japan (BBJ) for utilization of the human materials and medical
information"

FY2018-FY2022

Japan Program for Infectious Diseases Research and Infrastructure"Studies to control emerging, re-emerging and imported infectious diseases to be conducted ininternational collaboration sites in China"

FY2020-FY2024

With support from the program for promoting the enhancement of research universities and theWorld-leading Innovative Graduate Study Program for Life Science and Technology in FY2018,
IMSUT has enhanced its research support system with the expansion of common research facilities
and core laboratories. To cite a case, a high-speed confocal microscopy analysis system has been
installed in the Imaging Core Laboratory and so have the most advanced cell metabolism
measurement devices in our common facility spaces (Material 4).
【Material 4】Outline of common-use facilities and core laboratories
Name

Overview

Animal Center

Services offered by the Laboratory Animal Research Center include the provision ofanimal breeding spaces and a complete set of mouse-and-rat sterilization gauges. Support
for embryo/sperm freezing/thawing. Storage and supply in embryo bank. Provision of anexperimental laboratory for conducting animal infection experiments (P2A/P3A). Support
for experimental animals with X-ray irradiator, biological imaging system, MRI, andirradiation system.

Medical Proteomics
Laboratory（Proteome Information Analysis）
Comprehensive identification and analysis support for protein complexes using nanoLCMS/MS-type mass spectrometer system. Precise identification analysis support for posttranslational modification of proteins such as phosphorylation and ubiquitination.
High-precision relative quantitative analysis support based on mass spectrometry
spectrum data.

13

General Statement: Current Status of IMSUT（Micromorphological Analysis）
Support for micromorphological analysis using transmission/scanning electron
microscope.
（Culture Media Section）
Cleaning of laboratory glassware. Drying heat sterilization. Pure water supply.

Pathology Core Laboratory
Gene Manipulated Mouse
Section
FACS Core Laboratory

Manufacture of histopathological specimens. Pathological consultations/morphologic
diagnoses and analyses.
Generating genetically modified mice.
Supporting cell sorting and analysis using flowcytometry equipment.

Imaging Core Laboratory

Providing a basic research environment with state-of-the-art microscopes and imagingrelated equipment. Instruction and support for imaging operation.

IMSUT Clinical Flow
Cytometry Laboratory

Analysis of clinical samples using flowcytometry equipment and its result report, and cellsorting.

Photographic Laboratory

Printing figures for academic papers and posters for scientific meetings. Photography at
various events within IMSUT such as symposiums and seminars.

IT Service Room

Maintenance and management of webserver and IMSUT website. Setting and registrationof DNS/mail hosting. Maintenance and management of the institute’s local area network.
Handling security and information ethics issues. Technical consultation (network related).

Radioisotope Center

Facilities for radioisotope (RI) analysis and X-ray irradiation.

Office of Health and Safety

Planning and implementation regarding health and safety management. Safety educationand notification.

Genetically Modified
Microorganisms Support
OfficeEducation on genetic recombination experiments and experiments using research
microorganisms. Support with the application forms required for experiments.
Implementation of preliminary examinations.

Office of Research Ethics

Management of the Research Ethics Committee (REC) at IMSUT. Research ethics
support. Planning/conducting/management of research ethics seminar at IMSUT.

In IMSUT Joint Usage/Research projects, there are a “Core Center” with three research areas anda “Functional Enhancement Center” with three projects. We have been promoting core activities byclose collaboration across the entire institute with each of three areas/projects as stated below.
Namely, the Core Center is composed of three research areas: (1) Development of Cutting-Edge
Medical Therapies,(2)

Genome/Cancer/Disease

Systems

Biology,and(3)

Infectious

Diseases/Immunology. For its part, the Functional Enhancement Center is composed of threeprojects: (1) Establishment of an International Genomic Medicine Research Organization Towards
Innovative Medicine and Prevention of Diseases, (2) Establishment of a Cooperative Platform for
Research and Human Resource Development in Infection Control, and (3) Vaccine Research andDevelopment for Infection, Allergy, Cancer and Immunological Disorders. On 13 November 2018,
IMSUT was re-authorized as the only International Joint Usage/Research Center among the national
university-affiliated research institutes of Japan in the fields of medical science and biology. Thus,
we are making a new start by serving as a contact point for partnership/cooperation in Japan and the14General Statement: Current Status of IMSUT

rest of the world, as well as by leading research development in the designated areas as Japan’s
foremost medical science institute (Material 5).

15General Statement: Current Status of IMSUT【Material 5】International Joint Usage/Research Center

Regarding the operation system of the Joint Usage/Research Center, a Steering Council is being set
up to deliberate important items in response to the consultation from the Dean. Notable features arethat more than half of the board members are from outside the institute, and that international advisors
are assigned to provide advice from a global perspective at the request of the Dean. Furthermore, as
its research support system, IMSUT boasts Common Research Facilities, Core Laboratories, theTechnical Office, and the Administration Office, as well as the Clinical Trial/TR (translational
research) Implementation Unit for Joint Research (Material 6).

16General Statement: Current Status of IMSUT【Material 6】Operation/support system for the International Joint Usage/Research Center2) Initiatives and quality improvement in research activities
IMSUT boasts an Office of Health and Safety as the system to manage and provides information
on its internal environment, health, and safety management. The office conducts activities such as
safety education through safety training courses, workplace patrol, voluntary inspection ofresearch equipment, and the control of chemical substances (Material 7-(a)).

17General Statement: Current Status of IMSUT【Material 7】 Efforts to address compliance and research ethics(a) Environment, health and safety management(b) Compliance, research ethics

18

General Statement: Current Status of IMSUT(c) Number of research ethics seminars held and attendees in each fiscal year
Number of seminars
Number of attendees

FY20108446

FY2011
4161

FY20124397

FY20136410

FY20143261

FY201510734

FY201610689

FY20174184※1

FY20185366※2FY20197525※3(For reference 1) Number of attendees for events not included above:※1 Those who took e-learning as renewal training in fiscal 2017 / 451persons※2 Those who took e-learning as renewal training in fiscal 2018 / 200 persons※3 Those who took e-learning as renewal training in fiscal 2019 / 38 persons(For reference 2）Regarding number of seminars held
Even if held on the same day, first and second sessions were counted separately.

In 2008, IMSUT set up the Office of Research Ethics, which was a pioneering effort in Japan tomaintain research ethics. The office conducts mandatory and unique ethics seminars for all members
involved in medical research, and a total of 1,764 attended the seminars between FY2016 to FY2019.
On top of this, the office appoints one research ethics leader to each laboratory and conducts anannual training workshop for the leaders, which enables them to share information with otherlaboratories.
Furthermore, 26 training sessions/workshops for new members on prevention of research fraudand conflicts of interest were conducted between FY2016 to FY2019, while the total number ofparticipants in e-learning training sessions for the members after their second year amounted to 689
between FY2017 and FY2019 (Material 7-(b), 7-(c)).
After the enactment of IMSUT internal rules in FY2016, evaluation of the full-time faculty
members who have been employed for more than one year is implemented every fiscal year. In
FY2017, rules on self-inspection and evaluation as well as on external review were enacted to form
the system examining research/education activities, operation, social contributions, and other
involvement. The results of self-inspection and evaluation implemented in FY2019 are available on
the IMSUT website (Material 8-(a), 8-(b)).

19

General Statement: Current Status of IMSUT【Material 8】Systematization of the verification of research activities, and method used(a) Evaluation of faculty members(b) Self-inspection and evaluation

Integrated Research Systems, the University of Tokyo enables multiple departments to carry out
collaborative academic research within a specified period. Under this scheme, the Anti-infective
Research Consortium, the University of Tokyo (ARC-UT) was launched in FY2017. By collaborating,a total of nine departments centered at IMSUT, ARC-UT commenced collaborative research aiming
to control emerging and re-emerging infectious diseases. In FY2017, the Institute for Life Science
Research Education and the One Health Collaboration Research Organization were launched.
Subsequently, the Collaborative Research Institute for Innovative Microbiology (CRIIM) was
launched in FY2018, where IMSUT faculty members are currently participating and promoting thecreation of new academic fields and the development of highly skilled young scientists (Material 9).
20

General Statement: Current Status of IMSUT【Material 9】Participation in Integrated Research Systems of the wider university
Outline of Integrated Research Systems<Institute for Life Science Research and Education>
Establishment: April 1, 2017
Established for the purpose of setting up a global education and research basefor bio-evolution research aiming to elucidate the principles of life systems
developing over time.
(1) Elucidation of the principle of bio-evolution. Clarification of thefundamental principles of evolution of life systems over time.
(2) Bio-evolution analysis by new technology. Promotion of research by new
dynamic system analysis technology.
(3) Investigating the failure of bio-evolution and diseases. Social contribution
based on creation of new disease concepts and development of preventive
treatments.
Through these three research issues, the institute works to develop
professional human resources (high-level knowledge professionals) whileforming a global research base that aims to elucidate the principle of life as adynamic system and how it can fail.
< Anti-infective Research Consortium,
the University of Tokyo (ARC-UT) >Establishment: October 1, 2017
Composed of altogether nine collaborating departments centered at IMSUT,
ARC-UT carries out the development of innovative methods for prevention,
diagnosis and treatment, and nurtures young scientists who will lead
infectious disease research in the next-generation.
ARC-UT also collects and analyzes data on the situation of infectious disease
outbreaks in Japan and overseas and transmits accurate information tosociety. Furthermore, ARC-UT aims to control emerging and re-emerging
infectious diseases by promoting collaborative research that integrates
research resources, technological bases, and human resources.

Participating Departments(◎: Responsible Dept.)◎Graduate Schoolof Medicine〇Graduate School of
Science〇Graduate School of
Pharmaceutical Sciences〇IMSUT〇Institute forQuantitative Biosciences※4 IMSUT faculty members are
participating.

◎IMSUT〇Graduate School of
Medicine〇Graduate School of
Agricultural and Life Sciences〇Institute of Industrial Science〇Graduate School ofEngineering〇Graduate School of Frontier
Sciences〇Graduate School of
Pharmaceutical Sciences〇Graduate School of
Science〇Graduate School of Arts andSciences※10 IMSUT faculty members are
participating.

< One Health Collaboration Research Organization >Establishment: October 1, 2017
One Health is an internationally recognized concept that human and animal
health are similar and closely related to each other. Hence, there is a need todevelop these two comprehensively and cooperatively as a single academicarea, rather than to promote medicine, veterinary medicine, agriculture, andenvironmental studies individually as has been customary. By establishing an
academic foundation, One Health aims to form the first academic base inJapan, to advance this academic field in cooperation with related universities
and research institutes as a central base in Japan and Asia, and to play a rolein leading this field internationally in cooperation with bases in otheradvanced nations.

21◎Graduate School of
Agricultural and Life Sciences〇IMSUT〇Graduate School of
Medicine〇Graduate School of Frontier
Sciences※3 IMSUT faculty members are
participating.

General Statement: Current Status of IMSUT< Collaborative Research Institute forInnovative Microbiology (CRIIM)>
Establishment: April 1, 2018
CRIIM is Japan's first integrated microbial research base consisting ofresearchers from various fields related to microbial science.
It is working to develop cutting-edge innovative microbial science researchin the four fields of "manufacturing", "environment/energy", "agricultural
production/ecosystem" and "basic/fundamental technologies".
"Basic/fundamental technologies" can support and connect the other three.
Furthermore, it creates new academic value that transcends specific fields ofstudy. Under industry-government-academia collaboration, CRIIM works toaccelerate applied research for the social implementation of knowledge, tocreate new industries, and to train and produce internationally minded
innovative young scientists who will be responsible for the next-generationof academic and industrial development in this field.

◎Graduate School of
Agricultural and Life Sciences〇Graduate School ofEngineering〇Graduate School of
Science〇Graduate School of
Pharmaceutical Sciences〇Graduate School of Frontier
Sciences〇IMSUT〇Institute forQuantitative Biosciences〇Atmosphere and Ocean
Research Institute〇Biotechnology Research Center〇Environmental Science
Center※2 IMSUT faculty members are
participating.

Some IMSUT faculty members are currently participating in four of the research organizations
which were set up by the Committee for Presidential Initiatives at the University of Tokyo with theaim of promoting university-wide key projects and cross-disciplinary education research projects(Material 10).
【Material 10】Participation in research organizations established by the Committee for Presidential
Initiatives
Outline of Research Organization＜Medical Genome Research Initiative, The University of Tokyo＞
By inviting outstanding researchers in the fields of “genomic science”,“medical science”, and “information science” from our university andcollaborating with related departments, this initiative promotes innovative
genomic medical science research, which is conducted with advanced genomic
and information analysis technology. Its aim is to contribute broadly to society
as an educational research organization, which creates interdisciplinary areas
and fosters human resources by integrating genomic science/medical scienceand information science, as well as returning its research findings to society as
genomic medicine.

Participating Departments
Administration Office: IMSUT＜Translational Research Initiative, The University of Tokyo＞
As one of Japan’s leading academic institutions, TR Initiative believes its
responsibility and foremost duty is to contribute to the medical field bytranslating our academic research achievements to medical innovations swiftly,
and in their optimal form.
As its key values, the TR Initiative strives to:• Ensure that patients, their families, and medical professionals receive themaximum benefit from medical innovations.

Director of TR Initiative:
Director of the University ofTokyo Hospital

22

IMSUT and
Other 18 Departments are
participating.

IMSUT and
Other 12 Departments are
participating.

General Statement: Current Status of IMSUT••

Deliver maximum results through an equal, cooperative partnership
between academia and corporations
Create an environment in which the University’s researchers fully
understand and appreciate the value of TR and can work proactively
towards goals of the TR Initiative.

＜Life Science Network, The University of Tokyo＞
This is a network-type cross-sectional organization in which 17 departments
within the university participate, which was created by combining the former
Life Science Research Network and the former Life Science Education Support
Network. In order to work on university-wide projects related to life sciences
and the further development of the field itself, the organization supports
education through the creation and revision of textbooks. It also holds
symposiums aiming to exchange researchers within the university and to
introduce its research to those outside the university.

Director of the network:
Dean of Graduate School ofArts and Sciences＜The University of Tokyo Sports Science Initiative＞
With the advent of a "super-aged society", it is feared that problems such as
skyrocketing medical costs, rising needs for nursing care, and a decrease in theworking-age population will all become apparent. Under such circumstances,the challenge of how to sustain the energy of society is recognized as a global
issue. With the aim of promoting cross-disciplinary research related to sports
and health sciences, the Initiative works on returning the academic results tostudent education and society, as well as on playing a key role in coordinating
between universities and research institutions in Japan and overseas.

Main Department:
Graduate School of Arts andSciences

IMSUT and other 16
Departments are participating.

IMSUT and other 15
departments are participating.

As part of the efforts to strengthen the network in the field of infectious diseases, IMSUT has heldinternational symposia supported by the “Japan Initiative for Global Research Network on Infectious
Diseases” from the Japan Agency for Medical Research and Development (hereafter AMED) threetimes since FY2016, together with Osaka University, Nagasaki University and Hokkaido University,
all of which have overseas bases. Also, in the field of immunology, IMSUT has successfullyenhanced cooperation and cultivated young scientists at home and abroad. One example is theInternational Symposium on Membrane Traffic in Awajishima, where IMSUT plays a leading roleand has sent six lecturers since FY2016.
Since FY2016, IMSUT has contracted with ten principal investigators (nine professors and one
associate professor) who have significant experience and expertise at other national universities,
together with two project professors with excellent research performance who had reached the
mandatory retirement age, and one professor with a cross-appointment at the University of Wisconsin.
Meanwhile, under “the University of Tokyo Excellent Young Researcher” system, one associate
professor and one assistant professor in FY2016, and one Senior Assistant Professor in FY2019 wereappointed to be provided with start-up support for the research environment of young researchers.
Along with this, IMSUT has promoted researcher diversity with respect to their background, age,and gender identity and the development of its research organization, such as by appointing one
23

General Statement: Current Status of IMSUT

female associate professor in FY2016 with a support system for female researchers.
At the Core Center in the Joint Usage/Research Project, IMSUT calls for proposals for joint
research projects from both domestic and overseas research institutes and provides its internal humanand material resources to promote open recruitment joint research. In preparation for the interim
evaluation it was decided that the grant would be allocated in instalments, which led to a 25%
reduction from the initial budget. Although the number of adopted proposals in this project decreased
in FY2018, it maintained at a high level throughout the third period compare to the second period.
Notably in FY2019, IMSUT began to call for international joint research proposals as an International
Joint/Usage Research Center, which has resulted in 84 proposals being adopted, the largest number
since the launch of the projects (Material 11).
Regarding the Functional Enhancement Center in the Joint Usage/Research Project, IMSUT
conducts advanced joint research projects by non-open recruitment together with other research
institutes in Japan and abroad. Although the number of adopted proposals for non-open recruitment
joint research decreased in FY2018 due to a 26% reduction in the project budget under legislative
and administrative measures in the field of science, 85 proposals, the highest figure since the launchof the projects, were adopted in FY2017. In FY2019, the number of adopted proposals remained thesame as in FY2018 despite the impact of COVID-19 (Material 11).

【Material 11】Fluctuation in the number of joint research projects

Both the numbers of participating research institutes and accepted researchers at the Core Centerand the Functional Enhancement Center were also affected by legislative and administrative
measures in the field of science. However, when comparing FY2015, which was the last fiscal year
24General Statement: Current Status of IMSUTof the first period of the Joint Usage/Research Center Project, and FY2017, both participating
institutes and accepted researchers significantly increased from 97 to 146, and from 136 to 224,
respectively. Likewise, the total number of visitors to IMSUT increased from 2,708 in FY2016 to
7,582 in FY2018, which indicates that joint research projects were carried out continuously andvigorously. Due to the impact of COVID-19, the number of visitors in FY2019 decreased to 5,517,
yet the total number of visitors from abroad soared roughly 15-fold owing to the launch ofinternational joint research proposals at the Core Center (Material 12).
【Material 12】Acceptance status involving joint research
Number of people accepted

Cumulative total number of people

NonJapaneseYoungResearchers(35 andunder)

Graduate
Students

NonJapaneseYoungResearchers(35 andunder)

Graduate
Students

232

3

ND

131

9

251

5

ND

20

ND

9

190

3

ND

17

3

15

16

414

7

70

40

127

10

13

12

711

13

114

53

97

136

4

26

16

501

10

84

42

2016

137

183

7

39

29

2,708

15

950

508

2017

146

224

11

37

30

3,698

17

1,206

1,343

2018

85

153

6

22

23

7,582

16

2,069

2,035

2019

102

168

25

38

22

5,517

244

1,858

1,017

FY

Number ofOrganizations

2010

38

78

1

ND

11

2011

50

81

1

ND

2012

50

70

1

2013

85

107

2014

98

2015

Upon the call for joint research projects by open recruitment, IMSUT encourages participation ofyoung researchers, postgraduates, or undergraduates (fourth year, or fifth/sixth year in six-year
undergraduate programs). Adopted research collaborators are to be conferred the title of "IMSUT
Joint Research Project Researcher (JRP Researcher)" and to be allowed the same access to thefacilities and academic samples as IMSUT researchers, which promotes their joint use (Material 13
and 14).

25

General Statement: Current Status of IMSUT【Material 13】Usage status of facilities and equipment
Name of Main
Facilities/Equipment
Medical Proteomics
Laboratory,
Mass Spectrometer

Outline and Purpose of Facilities/Equipment
Supports post-translational modification analysis such as protein identification andphosphorylation using a mass spectrometer that enables highly sensitive and accurate
shotgun measurement, and relative quantitative analysis between different samples.

FY

2015

2016

2017

2018

2019

Total numberof users since
FY2016

Number of users(of which related joint research)

27(27)

32(32)

30(30)

27(27)6(0)95(89)

Human Genome Center,
Supercomputer System

In response to the explosive increase in the amount of data in genome research and thediversification of data types and analysis methods, we have introduced one of the largest
supercomputer systems in Japan and also made it widely available to researchers who
engage in genome-related research. The registered external users are from universities,
independent administrative agencies, private companies, etc. It is widely used byresearchers.

FY

2015

2016

2017

2018

2019

Total numberof users since
FY2016

Number of users(of which related joint research)

630
(630)

716
(716)

941
(941)

1,103
(1,103)

1,408(1,408)4,168(4,168)

Imaging Core Laboratory

Installed Zeiss Multiphoton Microscopy LSM710NLO.
Technical guidance and analysis support.

FY

2015

2016

2017

2018

2019

Total numberof users since
FY2016

Number of users(of which related joint research)

68(5)

88(1)

137(13)59(5)40(13)

324(32)

Imaging Core Laboratory

Installed Nikon confocal microscope A1.
Technical guidance and analysis support.

FY

2015

2016

2017

2018

2019

Total numberof users since
FY2016

Number of users(of which related joint research)289(51)

192(42)156(81)200(70)221(87)769(280)

FACS Core Laboratory

Support for stem cells or immunocompetent cell sorting and analysis using Flow
Cytometry.

FY

2015

2016

2017

2018

2019

Total numberof users since
FY2016

Number of users(of which related joint research)

2,592
(386)

3,026
(349)

3,394
(347)

3,342
(252)

3,129
(294)

12,891(1,242)26

General Statement: Current Status of IMSUT【Material 14】 Status of usage/provision/collection of research resources
Research Resources

Outline and Provision Method of Research Resources

Pathogenic Bacteria

The Pathogenic Microbes Repository Unit, International Research Center for Infectious
Diseases stores 1,440 pathogenic bacterial strains, and provides them to research andeducational institutions.
Cryopreservation and maintenance of pathogenic bacterial strains are carried out. Checkand maintain the properties of the strains regularly. Cultivate and distribute pathogenic
bacteria upon request.

FY

2015

2016

2017

2018

2019

Number of strains

1,440

1,440

1,440

1,800

1,800

Total numberof uses since
FY2016

Number of uses(of which related joint research)

20(5)

27（3）

14（0）

14(0)

11（0）

66（3）

DNA (BioBank Japan, BBJ)DNA Bank (DNA storage facility) is playing a central role in BBJ and strictly stores andmanages the DNA provided by cooperating medical institutions in Japan.
Contingent on an ethics review, DNAs are provided to researchers for enabling
personalized medicine.

FY

2015

2016

2017

2018

2019

Number of samples

744,991

800,406

829,878805,285

805,279

Total numberof uses since
FY2016

Number of uses(of which related joint research)

11(11）

22（18）

11（3）20（13）

16（10）

69（44）

Genetically Modified Mice

Preparation of genetically modified model mice for human diseases on request.
Analysis of human disease development mechanism in model mouse, cryopreservation ofembryos, and provision of technology.

FY

2015

2016

2017

2018

2019

Number produced

52

41

16

20

20

Total number
provided since
FY2016

Number provided(of which related to joint
research)

52(1）

1（0）

16（0）

20（0）

20（4）

57（4）

3) Academic Papers/Patents/Conference Presentations etc.
Since the second period, IMSUT has continuously published approximately 500 papers every year.
For the four years from FY2016 through FY019, 1,933 English peer-reviewed papers were published,
and of these, 300 papers were in journals with an impact factor of ten or above. The ratio of these
papers to the total number of English peer-reviewed papers released by IMSUT increased to reach
16.76 % in FY 2018, the highest throughout the second period and the third period, which indicatesthat IMSUT is producing high-quality papers (Material 15). The number of papers per faculty
member also increased to 3.7 papers published from FY2016 through FY2018, compared to 3.3
papers published from FY2010 through FY2012 and 3.5 papers published from FY2013 throughFY2015 (Material 16).
27

General Statement: Current Status of IMSUT【Material 15】Number of English peer-reviewed papers

FY2013
FY2014FY2015FY2016FY2017FY2018FY2019Number of papers%

IF20
or more
25
5.19

IF10
Total number of English
or morepeer-reviewed papers
62
482
12.86

Number of papers

28

93

%

4.79

15.92

Number of papers

27

80

%

5.13

15.21

Number of papers

28

75

%

5.76

15.43

Number of papers

20

63
13.82

%

4.39

Number of papers

27

87

%

5.2

16.76

Number of papers

21

75

%

4.45

15.89

584
526
486
456
519
472

【Material 16】Comparison of the number of papers per core faculty member

The total number of papers published through joint research at the Joint Usage/Research Center
28

General Statement: Current Status of IMSUT

reached 721 for the period FY2016 to FY2019, a 1.56-fold increase compared with 462 from FY2012
through FY2015 (Material 17). 82% (588 papers) of them were co-authored papers with researchcollaborators (Material 18), while 236 joint papers were produced by principal authors or main
authors belonging to the Center. Furthermore, 33 papers with an impact factor of 20 or above were
published over the four years from FY2016 to FY2019 (Material 19).
【Material 17】Number of published papers at the Joint Usage/Research Center
FY

2012

2013

2014

2015

2016

2017

2018

2019

Total number of papers
since FY2016

Number of
papers

94

115

145

108

142

227

187

165

721

【Material 18】Affiliation of the authors of the papers (total of 721) published FY 2016-FY2019 at
the joint research center【Material 19】Number of papers with high impact factors (IF>20) published FY2016-2019 at thejoint research center
Name of journal

Number of papers

Name of journal

Number of papers

Nature6

Nature Immunology

4

Science1

Immunity

3

Cell

4

Lancet Oncology

1Nature Biotechnology

3

Annual Review of Immunology

1Nature Genetics

3

Journal of Clinical Oncology

2Nature Medicine

4

JAMA Oncology

1

The number of national patents steadily increased to 67 at the end of FY2019 from 50 at the endof the second period, while the number of foreign patents has drastically increased to 178 from 43,
respectively (Material 20).

29

General Statement: Current Status of IMSUT【Material 20】Number of unexpired patents
FY

2013

2014

2015

2016

2017

2018

2019

Number of National

21

36

50

51

56

62

67

Patents

(8)

(14)

(22)

(21)

(21)

(22)

(23)

Number of International

25

31

43

71

111

152

178

Patens

(13)

(17)

(17)

(34)

(40)

(52)

(64)

＊The numbers in parentheses are cumulative total of joint application by the end of each fiscal year.
＊The number for FY2019 is the preliminary results as of June 4, 2020.

The number of patent applications at the Joint Usage/Research Center for the four years from
FY2016 through FY2019 stood at three (Material 21). All of them were patents relating to medical
diagnosis which embody the Center’s mission to promote medical science based on translational
research.
【Material 21】Patent application and registration at the joint research center

1

2

3

Application Date

Aug. 18, 2017

Inventor

Naohiko Koshikawa, Motoharu Seiki

Patent Application

EphA2 N-Terminus Fragment Antibody(Publication No. PCT/JP2017/029596)

Application Date

Sep. 20, 2019

Inventor

Makoto Nakanishi, Yoshikazu Johmura, Tomohiko Ohta

Patent Application

Method for Determining Prognosis of Cancer(Patent Application No. PCT/JP2019/036949)

Application Date

Feb. 4, 2019

Inventor

Shinichi Yachida and others

International Application

Method for Detecting Early Colon Cancer(Patent Application No. PCT/JP2019/003825)

Since the second period, IMSUT has vigorously given presentations at academic conferences.
The average annual number of presentations given at international conferences from FY2016
through FY2019 was 168, while this number was 586 for presentation given in Japan. Notably, thenumber of IMSUT members who were invited to give lectures both inside and outside Japan
continued to increase, reaching 429 in FY2019 compared to 357 in FY2015 (Material 22).

30

General Statement: Current Status of IMSUT【Material 22】Lectures and oral presentations at academic conferences

FY2013
International
Domestic
Invited/Invited/
Oral
Oral
KeynoteKeynotePresentations
Presentations
Lectures
Lectures
97
112
174
320

FY2014
International
Domestic
Invited/Invited/
Oral
Oral
KeynoteKeynotePresentations
Presentations
Lectures
Lectures
105
130
204
347

FY2015International
Domestic
Invited/Invited/
Oral
Oral
KeynoteKeynotePresentations
Presentations
Lectures
Lectures
107
88
250
300

FY2016
International
Domestic
Invited/Invited/
Oral
Oral
KeynoteKeynotePresentations
Presentations
Lectures
Lectures
81
80
262
286

FY2017
International
Domestic
Invited/Invited/
Oral
Oral
KeynoteKeynotePresentations
Presentations
Lectures
Lectures
112
78
306
289

FY2018International
Domestic
Invited/Invited/
Oral
Oral
KeynoteKeynotePresentations
Presentations
Lectures
Lectures
115
57
299
295

FY2019International
Domestic
Invited/Invited/
Oral
Oral
KeynoteKeynotePresentations
Presentations
Lectures
Lectures
98
49
331
276

4) Research Funds
Regarding income from external sources, IMSUT has secured approximately five billion yen in
total as was the case for the second period. Notably, the amount of funds for contract andcollaborative research between FY2015 to FY2019 significantly increased, from 1,983 million yen
to 2,893 million yen and from 598 million yen to 929 million yen, respectively (Material 23).
Also, both the number of cases and amount of income from external sources acquired per faculty
member have remained high since the second period, 5.5 cases and 46 million yen respectively in
31

General Statement: Current Status of IMSUTFY2019 (Material 24).
【Material 23】Amount of income obtained from external sources (per faculty member)➢

The decline in the acquisition amount of Health and Labor Sciences Research Grant after fiscal 2016 was due tothe establishment of AMED in 2015. The amount acquired through the public offering of AMED is included in
the amount of the contract.
Unit: Million of yen
FY

FY2013

FY2014FY2015FY2016FY2017FY2018FY2019Number of Faculty members

127

128

125

124

119

114

113

Amount

180

164

202

274

167

159

242

Amount per faculty member

1.42

1.28

1.62

2.21

1.40

1.39

2.14

Amount

1,483

1,970

1,983

2,932

3,016

2,826

2,893

Amount per faculty member

11.68

15.39

15.86

23.65

25.34

24.79

25.60

Amount

440

372

598

562

816

913

929

DonationsContract

Collaborative➢➢

Amount per faculty member

3.46

2.91

4.78

4.53

6.86

8.01

8.22

Grant-in-Aid forAmountScientific Research
Amount per faculty member(MEXT)

1,357

1,015

820

985

822

839

1023

10.69

7.93

6.56

7.94

6.91

7.36

9.05

Health and Labor
Sciences Research
Grant

Amount

1,385

1,764

826

18

34

68

105

Amount per faculty member

10.91

13.78

6.61

0.15

0.29

0.60

0.93

Total Acquisition
amountAmount

4,845

5,285

4,429

4,771

4,855

4,805

5,192

Amount per faculty member

38.15

41.29

35.43

38.48

40.80

42.15

45.95

The amount column shows the amount of income from external sources acquired by all faculty members(including Project related faculty members) of IMSUT. (Includes acceptance by other than principle investigator.)
The number of faculty members shows the number of full-time faculty members, not including project related
faculty members at the end of each fiscal year.

32General Statement: Current Status of IMSUT➢"Contract" includes contract research expenses, which are competitive income from external sources funded by
the government such as AMED.

【Material 24】Number of cases of income obtained from external sources (per faculty member)

FY

FY2013

FY2014FY2015FY2016FY2017FY2018FY2019Number of Faculty members

127

128

125

124

119

114

113

Number of cases

107

129

105

122

125

104

101

Number of cases per faculty member

0.84

1.01

0.84

0.98

1.05

0.91

0.89

63

61

91

112

115

134

149

Number of cases per faculty member

0.50

0.48

0.73

0.90

0.97

1.18

1.32

Number of cases

101

110

120

107

111

122

140

Number of cases per faculty member

0.80

0.86

0.96

0.86

0.93

1.07

1.24

Grant-in-Aid for
Number of cases
Scientific Research
Number of cases per faculty member(MEXT)

210

196

204

205

193

205

213

1.00

1.53

1.63

1.65

1.62

1.80

1.88

62

57

55

9

14

22

18

Donations
Number of cases
Contract

Collaborative➢➢➢

Health and Labor
Sciences Research
Grant

Number of cases
Number of cases per faculty member

0.49

0.45

0.44

0.07

0.12

0.19

0.16

Total Acquisition
cases

Number of cases

543

553

575

555

558

587

621

Number of cases per faculty member

4.28

4.32

4.60

4.48

4.69

5.15

5.50

The Number of cases column shows the number of cases of income from external sources acquired by all faculty
members of IMSUT. (Including acceptances other than the principle investigator.)
The number of faculty members shows the number of full-time faculty members, not including project related
faculty members.
"Contract" includes contract research expenses, etc., which are competitive income from external sources fundedby the government such as AMED.

33

General Statement: Current Status of IMSUTAt the Joint Usage/Research Center, each research fund is mainly financed by Grants-in-Aid for
Scientific Research (KAKENHI) and by the budget from AMED, while Center activity expenses
such as travel expenses to and from IMSUT and conference costs are covered by Grants for Creating
Research and Education Bases for the Formation of Research Centers from MEXT. After IMSUT
received an "S" rating in the FY2018 interim evaluation by the Commission of research environment
and infrastructure within the Scientific Subdivision on the Council for Science and Technology, abudget reallocation of 13.2 million yen was made. On top of this, IMSUT was authorized as theInternational Joint Usage/Research Center and received a budget reallocation of an addition 60.137
million yen (Material 25). With these funds, IMSUT has consolidated its system towards furthering
the center’s internationalization such as by the employment of a foreign Professor and theenhancement of communal equipment.

34

General Statement: Current Status of IMSUT【Material 25】Budget Situation of the (International) Joint Usage/Research Center【Core area of Joint Usage/Research Center】

Unit : JPY"International Joint Research Project on Promoting of Basic and Applied Medical Sciences"

Category

FY2016
Budget amount

FY2018Addition based onintermediate
evaluation result

FY2018Initialbudget amount

FY2017
Budget amount

FY2018Addition based on
authorization asinternational center

FY2019Budget amount

Joint Research Center
Supporting expenses for joint research

4,137,000

4,137,000

2,527,000

11,480,000

Research expenses for collaborators

35,000,000

35,000,000

27,000,000--

Operating expenses for center

5,860,000

5,860,000

4,420,000

1,720,000

7,840,000

Total

44,997,000

44,997,000

33,947,000

13,200,000

60,137,000

52,297,000

105,559,000
1.6%

about 25％
FY2018 Total Budget: 107,274,000※IMSUT was authorized as the "International Joint Research Center on 13 November 2018.

【Functional Enhancement Center】"Establishment of a Collaborative Platform for Research and Human Resources for the Control of Infectious Diseases"

Category
International Research Center for Infectious
Diseases
Operating expenses for center
Total

FY2016
Budget amount

FY2018Initialbudget amount

FY2017
Budget amount

129,430,000

122,955,000

90,995,000

19,410,000

18,443,000

13,640,000

148,840,000

141,398,000

104,635,000

5%

26%

FY2018Addition based onintermediate
evaluation result

FY2018Addition based on
authorization asinternational center

FY2019Budget amount--

90,995,000--

104,635,000

13,640,000±0%"Global Promotion of Strategic Research and Development for Mucosal Vaccines"

Category
International Research and Development
Center for Mucosal Vaccines
Operating expenses for center
Total

FY2016
Budget amount

FY2017
Budget amount

FY2018Initialbudget amount38,440,000

37,474,000

27,740,000

5,760,000

5,621,000

4,150,000

44,200,000

43,095,000

31,890,000

2.5%

26%

FY2018Addition based onintermediate
evaluation result

FY2018Addition based on
authorization asinternational center

FY2019Budget amount--

27,740,000--

31,890,000

4,150,000±0%"Organization of International Genomic Medicine Research Initiative for Innovative Therapies and Prevention"

Category

FY2016
Budget amount

FY2017
Budget amount

FY2018Initialbudget amount

Health Intelligence Center

49,912,000

48,659,000

36,008,000

Operating expenses for center

7,480,000

7,298,000

5,400,000

Total

57,392,000

55,957,000

41,408,000

1.5%

2.5%

26%

FY2018Addition based onintermediate
evaluation result-

FY2018Addition based on
authorization asinternational center---

FY2019Budget amount
36,008,000
5,400,000
41,408,000±0%5) Research Activities through International Collaboration
IMSUT has engaged vigorously in joint research and exchange projects. International Academic
Exchange Agreements have been concluded with nine overseas research institutions as of FY2019,
while joint research units were founded both at Institut Pasteur and IMSUT in FY2018. (Material 26).
In parallel, based on a memorandum on activities of the Japan Program for Infectious Diseases
Research and Infrastructure (AMED) with the Chinese Academy of Sciences, IMSUT scientists havebeen residing and working in China along with Chinese scientists. Meanwhile, joint research withclose collaboration has been conducted at joint laboratories, namely the Noguchi Medical ResearchInstitute, Ghana, and Sierra Leone University.

35General Statement: Current Status of IMSUT【Material 26】International exchange agreements
Partner Universities/Institutions

CountryType of Agreement

Date of First Signing

Chinese Academy of Sciences

China

University Wide

2005.4.29

Institut Pasteur

FranceDepartmental

2006.4.18

Sun Yat-sen University

China

University Wide2011.11.15

Arabian Gulf University, College of Medicine &Medical Sciences

Bahrain

Departmental

2013.7.14

Soonchunhyang University

Korea

Departmental

2013.9.26

The University of Chicago Medicine

United States

Departmental

2014.6.4

Vietnam National University, Ho Chi Minh City,
School of Medicine

Vietnam

Departmental

2015.3.23

Khon Kaen University, School of Medicine

Thailand

Departmental

2016.12.20

Fujian Institute of Hematology, Fujian Medical
University

China

Departmental

2020.6.3

Scientific symposiums are held regularly at the University of Tokyo New York Office, which
IMSUT established together with the Institute of Industrial Science, the University of Tokyo in
FY2015. Taking advantage of preferential tax treatment under U.S. accounting rules given forcontributors to the Office regardless whether companies or individuals, IMSUT has constructed aframework for fundraising for its research projects to enhance University corporate relations in the
U.S.
With the use of cross-appointment systems, two IMSUT Project Professors were appointed at
Stanford University and the University of California, San Diego respectively, and one professor was
appointed at the University of Chicago. Their cross-appointments have advanced interactive joint
research activities between Japan and the US as well as the establishment of our worldwide research
network.
6) Contribution to Academic Community
IMSUT was authorized as a Joint Usage/Research Center by MEXT in FY2010, which was
followed by its approval as an International Joint Usage/Research Center in FY2018 (Material 27).
Consequently, as a leading institute serving the life and medical science field, IMSUT has made asignificant contribution to the academic community by offering researchers from Japan and abroad
the same access to IMSUT facilities, equipment, and academic samples as its faculty members(Material 13 and 14).

36

General Statement: Current Status of IMSUT【Material 27】Introduction page of the IMSUT Joint Usage/Research Center (from the MEXT
website)A mass spectrometer in the Medical Proteomics Laboratory is used to support post-translational
modification analysis such as protein identification and phosphorylation by the highly sensitive andaccurate shotgun method, and relative quantitative analysis between different samples. 95
researchers in total utilized this instrument between FY2016 to FY2019 (Material 13).
The supercomputer system managed by the Human Genome Center of IMSUT is widely utilized
by researchers in universities, incorporated administrative agencies and companies. The average
number of users per fiscal year has grown to 1,042 (4,168 in total) since FY2016. The number
increased 2.2-fold between FY2015 and FY2019, from 630 to 1,408, respectively. These figures showthat the system has contributed greatly to satisfying the growing demand both at home and abroad(Material 13).
Multiphoton microscopes and confocal microscopes housed in the Imaging Core Laboratory havebeen used by 273 researchers per fiscal year on average (1,093 in total) since FY2016. 312 of them,
28.5% of the total, used such microscopes through the Joint/Usage Research Center. Since FY2016,
the number of users of the FACS Core Laboratory has grown to more than 3,222 per fiscal year on
average (12,891 in total) reaching 3,342 in FY2018, with a 1.3-fold increase compared to 2,592 in
FY2015. The figure decreased in FY2019 due to the impact of COVID-19 (Material 13).

37

General Statement: Current Status of IMSUTAs shown in the status of usage/provision/collection of research resources, the number ofpathogenic bacteria possessed by the Pathogenic Microbes Repository Unit, International ResearchCenter for Infectious Diseases increased to 1,800 strains in FY2018 from 1,440 strains in FY2015,
with 17 in use (66 in total) per fiscal year on average (Material 14).
Since FY2016, an average of 17 DNA samples has been provided per fiscal year by BioBank
Japan. BioBank Japan is one of the largest medical databanks in the world which stores medical dataand samples such as DNA, serum, and medical records from 267,000 patients with 51 diseases(Material 14).
Genetically modified mice are to be generated and provided on request from researchers in Japanand abroad. Since FY2016, an average of 24 mice per fiscal year has been generated, and an averageof 14 per fiscal year (57 in total) has been used by research collaborators (Material 14).
At the Joint Usage/Research Center, IMSUT has enhanced collaboration among its research bases
by holding annual research report meetings where researchers from various fields come together, as
well as by holding symposiums jointly with bases of other universities from anacademic/interdisciplinary point of view. Notably, the number of meetings held for researchers
increased to 55 in FY2019 from 23 in FY2016 and the number of participants nearly doubled to 1,714
from 922 (Material 28). Additionally, as part of young scientist development, IMSUT holds a Joint
Usage/Research Center-Young Researcher Symposium annually to provide young researchers withthe opportunity to organize a meeting on their own to stimulate open-minded discussion, along withregularly scheduled technical seminars which enable them to acquire new research techniques. In
FY2019, although 16 International Joint Usage/Research Center Seminars were held by the
researchers who work on joint research in Japan and abroad, some of the scheduled seminars, reportmeetings, and other research meetings were cancelled due to the spread of COVID-19.
【Material 28】Research meetings held at the Joint Usage/Research Center
For Researchers

FY

Symposium/

Seminar/

Lecture Meeting

Workshop

For the general public
Total

NumberNumberofAttendees

NumberNumberofAttendees

Number

2016

5

450

18

472

2017

8

861

19

519

2018

9

938

24

2019

5

525

50

Symposium/

Seminar/

Lecture Meeting

Workshop

Others

Total

NumberofAttendees

NumberNumberofAttendees

NumberNumberofAttendees

NumberNumberofAttendees

NumberNumberofAttendees

23

922

2

490

23

2,601

27

305

52

3,396

27

1,380

0

0

25

1,531

25

471

50

2,002

808

33

1,746

1

124

13

1,231

37

692

51

2,047

1,189

55

1,714

1

140

7

2,811

30

405

38

3,356

38

General Statement: Current Status of IMSUT(4) Status of Research Results
IMSUT has achieved remarkable success in both basic research aimed at integrated understandingfor diseases and applied research progressing towards advanced medical development. The Divisionof Infectious Diseases, for example, has achieved breakthrough innovations, namely the developmentof novel treatment and preventive medicine for influenza virus infections and the elucidation of theherpesvirus replication mechanism inside the cell, mechanisms that inhibit host immune response,
and the molecular basis of susceptibility to herpes simplex encephalitis. Meanwhile, the Departmentof Rheumatology and Allergy has achieved pioneering results including the identification of cells
that suppress the development of autoimmune diseases, self-RNA recognition control related to SLE
onset, functional analysis of IL-25 in contact dermatitis, and the mechanism underlying theestablishment of mucosal immunity. In the field of cancer research, important results relating to theelucidation of pathologic molecular processes, effectiveness of treatment, and determination of
prognosis have been obtained. The Division of Regenerative Medicine has successfully shed newlight on the novel molecular basis by which self-renewal of hematopoietic stem cells (HSCs) is
controlled, and has developed innovative technology for stem cell transplantation. Notably, IMSUT
has offered invaluable advice on examining “Ethical, Legal and Social Issues” (ELSI) to support
medical science in the future, which created an opportunity for deliberations on such issues atgovernment ministries including the office of the Prime Minister and the Health, Labour and Welfare
Ministry, as well as for deliberations at the national legislature on a new bill on genomic medicine.
Following these results, 300 academic papers were published in journals with an impact factor often or above over the four years starting in 2016 and became disseminated through the Media suchas newspapers and TV programs including the Japan Broadcasting Corporation (NHK) (Material 29).
IMSUT research achievements were highly evaluated by the government and academic conferences.
Since FY2016, 25 awards such as the Japan Academy Prize have been received on average per fiscal
year, compared to 19 during the second period (Material 30 and 31).
【Material 29】Mass media coverage of research results
Press DateMedia

Title of Article

2016/4/10

Asahi Shimbun

An IMSUT research team starts clinical trials of peptide vaccine therapy in lungcancer treatment.

2016/5/5

NHK

An IMSUT research team starts clinical trials of vaccine to prevent recurrence oflung cancer.

2016/5/24

The Nikkei/
Asahi Shimbun/
The Mainichi
Shimbun/The Yomiuri Shimbun

An IMSUT research team has developed a new technique for accurately predicting
antigenic variants of seasonal influenza viruses.

39

General Statement: Current Status of IMSUT

2016/8/4-8/6

The Nikkei/
NHK News 7/
The Sankei Shimbun/
The Yomiuri Shimbun

The University of Tokyo’s artificial intelligence (AI) “Watson” can detect thecorrect leukemia type in difficult-case patients in just 10 minutes and advise doctors
on treatment methods.

2017/1/26

The Mainichi
Shimbun/
The Nikkei/
The Mainichi
Shimbun/The Sankei Shimbun/
The Yomiuri Shimbun

An IMSUT research team succeeded in treating diabetic mice by using iPS cells tocreate a mouse pancreas in the rat body and transplanting it.

2018/5/25

ABC TV

An IMSUT research team has elucidated a new mechanism of pancreatic cancer
development.

2018/6/26

The Mainichi Shimbun

An IMSUT research team has succeeded in in vivo imaging the tissue infectedwith influenza virus.

2019/2/13

The Yomiuri Shimbun

An IMSUT research team has elucidated the mechanism by which the intestinal
flora enhances the effect of influenza vaccine.

2019/3/10

The Yomiuri Shimbun

Sharing the biological samples and their information accumulated in Biobank
Japan leads to personalized medicine.

2019/3/13

Asahi Shimbun

Members of IMSUT have created mice for modeling pediatric brain tumors using
human iPS cells to elucidate its pathological condition and identified newtherapeutic targets.

2019/5/30-5/31

Asahi Shimbun

A University of Tokyo research team has discovered that hematopoietic stem cells
can be cultured in large quantities with glue than with expensive culture media.

The Mainichi Shimbun

A University of Tokyo research team has discovered that hematopoietic stem cells
can be cultured in large quantities with glue. This finding may contribute to thetreatment of leukemia.

NHK News

The University of Tokyo starts the clinical trials of Ebola vaccine first in Japan.

The Nikkei

The University of Tokyo starts Phase I clinical trials of its own developed Ebola
vaccine.

The Nikkei

IMSUT and Hitachi reduce the analysis time by about 80% compared to theconventional model in a verification aimed at speeding up genomic data analysis
using Shirokane5, a supercomputer for human genome analysis.

Nippon Television
Network Corporation
NEWS 24

The University of Tokyo has announced that Nafamostat, an existing Japaneseacute pancreatitis drug, can be expected to prevent the transmission of newcoronavirus infection (COVID-19).

MEZAMASHI TV

The University of Tokyo has announced that a therapeutic drug for acutepancreatitis can be expected to have a therapeutic effect on COVID-19.

The Nikkan Kogyo
ShimbunThe University of Tokyo has announced that their research team has identified adrug candidate for the treatment of COVID-19 and will begin to administer it topatients as early as next month.

NHK News

An IMSUT research team has discovered that cats are susceptible to the novel
coronavirus.

The Nikkei

An IMSUT research team has discovered that the novel coronavirus spreads easily
among cats.

The Nikkei

A University of Tokyo research team has developed an accurate and rapid
diagnostic method for the novel coronavirus infection using CRISPR-Cas3.

The Mainichi Shimbun

Using genome editing technology, a University of Tokyo research team hasdeveloped a method that can diagnose the novel coronavirus infection in about
one hour.

2019/12/5

2020/3/10

2020/3/18
3/19

2020/5/14

2020/6/3
-6/4

-

40

General Statement: Current Status of IMSUT【Material 30】Number of awards
Awarding Body

FY
2010

FY
2011

FY
2012

FY
2013

FY
2014

FY
2015

FY
2016

FY
2017

FY
2018

FY
2019

Government

2

5

3

1

0

1

3

4

2

2

Academic Societies

10

5

7

9

8

15

10

20

18

12

Foundations

4

2

1

8

5

12

6

6

2

3

Others

0

8

1

2

3

3

5

2

2

2

Total

16

20

12

20

16

31

24

32

24

19

【Material 31】Major awards
Award Date

Name of Award

Title

Name ofAwarded Faculty
Member2016/4/23

The 36th JES Research Award(The Japan Endocrine Society)

Elucidation of the mechanism and physiologicalsignificance of the control of skeletal muscle
protein metabolism by Glucocorticoid

Noriaki Shimizu

2016/6/27

Japan Academy Prize(The Japan Academy)

Molecular basis of pathogenicity and control of
influenza viruses

Yoshihiro Kawaoka

2016/10/8

FY2016 (The 35th) The Young
Investigator Awards of the JapaneseCancer Association(The Japanese Cancer Association)

International comparison of pharmaceuticalregulations for anti-cancer agents andcompanion diagnostics

Sumimasa Nagai

2016/11/30

The 3rd Innovator of the Year
(Japan Hospital Association/Japan
Association for Development ofCommunity Medicine/ MSD)

Development of viral therapy for cancer
originating in Japan

Tomoki Todo

2017/4/19

FY2017 The Young Scientists’ Prize(The Commendation for Science andTechnology by the Minister of
Education, Culture, Sports, Scienceand Technology)

Studies on host proteins involved in
intracellular transport of RNA viruses

Seiya Yamayoshi

2017/4/19

FY2017 The Young Scientists’ Prize(The Commendation for Science andTechnology by the Minister of
Education, Culture, Sports, Scienceand Technology)

Studies on the control mechanism of intestinal
homeostasis by intestinal bacteria and type 3
natural lymphocytes

Yoshiyuki Goto

2017/4/19

FY2017 The Young Scientists’ Prize(The Commendation for Science andTechnology by the Minister of
Education, Culture, Sports, Scienceand Technology)

Studies on pathogenic mechanism of herpes
simplex virus

Jun Arii

2017/9/30

FY2017 (The 36th) The Young
Investigator Awards of the JapaneseCancer Association(The Japanese Cancer Association)

Elucidation of control mechanism of cancer
microenvironment by non-protease activity ofmembrane type I-matrix metalloproteinase(MT1-MMP)

Takeharu Sakamoto

2017/10/25

The 2017 Sugiura Incentive Award of
the Japanese Society for Virology(The Japanese Society for Virology)

Functional analysis of host proteins that
contribute to the growth process of RNA viruses

Seiya Yamayoshi

41

General Statement: Current Status of IMSUT

2017/12/2

The 6th Takahashi Incentive Awardof the Japanese Society for
Vaccinology(The Japanese Society for
Vaccinology)

Studies on Nasal Influenza Vaccine Combinedwith Adjuvant

Takeshi Ichinohe

2018/10/26

The 54th the Cultural Award for the
Memorial of Saburo Kojima(Kurozumi Medical Foundation)

Elucidation of the mechanism of proliferationand pathological expression of herpes simplex
virus

Yasushi Kawaguchi

2018/10/29

The 2018 Sugiura Incentive Award of
the Japanese Society for Virology(The Japanese Society for Virology)

Elucidation of cell invasion and particle
formation processes of herpes simplex virus

Jun Arii

2018/12/27

The 2nd Japan Medical Research andDevelopment Awards -AMED
President’s Award(Japan Agency for Medical Researchand Development (AMED))

Development of anti-metastatic drug for cancer
targeting oxygen sensing mechanism with highsafetyTakeharu Sakamoto

2019/2/22

FY2018 (The 48th) Princess
Takamatsu Cancer Research Fund
Prizes(Princess Takamatsu Cancer
Research Fund)

Clinical Development of Oncolytic Virus
Therapy Using Genetically Engineered Herpes
Virus

Tomoki Todo

2019/7/25

The Kodama Prize, JapaneseElectrophoresis Society Award(Japanese Electrophoresis Society)

Electrophoresis for the latest clinical medicine
to hematopoietic tumors

Hiroshi Yasui

2019/8/2

The 56th Young Investigator Awardsof the Japanese Society for Mucosal
Immunology(The Japanese Society for Mucosal
Immunology)

Analysis of human enterovirus flora and its
database construction

Kosuke Fujimoto

2019/10/2

FY2019-2020 Veterinary Science
Young Investigator Awards(Japanese Society of Veterinary
Science)

In vivo imaging of influenza virus-infectedlungs

Hiroshi Ueki

2019/10/11

The 8th Japan Society of Hematology
Award (JSH Award)(The Japanese Society of
Hematology)

Studies on the molecular biological analysis ofhematopoietic tumors using a mouse model andthe possibility of therapeutic application

Toshio Kitamura

2019/12/12

The 22nd (2019) The JapaneseSociety for Immunology Award (JSIAward)(The Japanese Society for
Immunology)

Vaccine adjuvant: the old wisdom towards
novel immunotherapeutics

Ken Ishii

2020/1/10

The 3rd Japan Medical Research andDevelopment Awards -AMED
President’s Award(Japan Agency for Medical Researchand Development (AMED))

Development of low-cost mass culture
technology for hematopoietic stem cells

Satoshi Yamazaki

The total number of academic papers released by the Joint Usage/Research Center over the past
four years has grown to 721 (Material 17), while IMSUT has applied for three patents since FY2016,
based on the inventions in the joint research funded by the Joint Usage/Research Center project42

General Statement: Current Status of IMSUT(Material 21).
In FY2018, IMSUT received an "S" rating in the FY2018 interim evaluation by the Committeeof MEXT. The Committee commented: IMSUT has many excellent researchers and a good range
of facilities and equipment for its joint usage to conduct research activities vigorously. Also, its
members are successfully implementing three projects at the Functional Enhancement Center,namely “International Genomic Medical Research Organization”, “Alliance in Research and
Education for the Control of Infectious Diseases”, and “International Base for Research andDevelopment of Mucosal Vaccines Furthermore, in the same fiscal year, IMSUT was authorized
by MEXT, as the only International Joint Usage/Research Center in the fields of medical scienceand biology.

(5) Status of Education Activity
The number of PhD recipients increased from FY2016 to FY2018, yet the trend turned downward
in FY2019 due to a gradual decrease in the number of students. Regarding the employment situation,
most job applicants in FY2016 obtained work as post-doctoral fellows, while there has been an
increasing number of PhD recipients who became employed as university faculty staff or as company
staff in recent years (Material 32).
【Material 32】Number of doctoral degree recipients and their employment situation

FY

Number of Doctoral
Degree Recipients（those employed inoverseas institutions）

Facultymember at
University

Postdoc

PublicInstitutions

Company

Others

2016

21
(4)

1
(0)

12
(3)

2
(0)

4
(1)

2
(0)

2017

27
(3)

2
(0)

10
(2)

1
(0)

10
(1)

4
(0)

2018

31
(1)

4
(0)

8
(1)

3
(0)

11
(0)

5
(0)

2019

17
(2)

3
(0)

5
(2)

1
(0)

4
(0)

4
(0)

(6) Status of Social Cooperation
IMSUT set up several Social Corporation Research Programs and Corporate Sponsored Research
Programs to vigorously promote industry-academia-government collaboration. Since FY2016, three43General Statement: Current Status of IMSUT

new programs have been launched to promote the social implementation o f research results
targeting the development of biopharmaceutical and immunity/gene therapy , the study ofthe disease prophylaxis based on genome information, and the cultivation of young scientists inthese areas: namely the Project Division of Advanced Biopharmaceutical Science, theProject Division of Cancer Biomolecular Therapy, and the Project Division of Genomic
Medicine and Disease Prevention. Furthermore, it has been decided that three Social Corporation
Research Programs (the Project Division of RNA Medical Science, the Project Division ofInternational Advanced Medical Research, and the Project Division of Advanced
Biopharmaceutical Science) shall be renewed from FY2020 onward. Meanwhile, two Corporate
Sponsored Research Programs launched in FY2014 and in FY2015 (the Project Division of
Molecular and Developmental Biology and the Project Division of Fundamental Studyon Cutting Edge of Genome Medicine) have been renewed to promote the development ofRegenerative therapy and Genomic medicine, respectively (Material 33).
【Material 33】Social Cooperation Research Programs and Corporate Sponsored Research
Programs
Social Cooperation
Research Programs(Period)

Purposes of Research

Research Activities

RNA Medical
Science(2012.4 - 2015.3)(2015.4 - 2020.3)(2020.4 - 2023.3)

・Understanding of the possibilities andfunctions of RNA in the life sciences
・Exploration of the great potential of RNA
・Research into development of new RNA drugs
that respond to unmet medical needs by new
functional mechanisms

・Aptamer molecules that specifically bind tovarious target proteins has been created using
systematic evolution of ligands by exponential
enrichment (SELEX).
・A practical drug discovery platform has been
constructed.
・Research and development for clinical trials iscurrently underway in the program.

Systems
Immunology
Research(2014.9 - 2019.3)(2019.4 - 2019.9)

・Creation of a new academic field calledsystems immunology which is a fusion of
immunology and systems biology
・Development of young scientists in this field

Using supercomputer,・super-high speed analysis platform for intestinal
microbiota has been constructed.
・relations between symbiosis, homeostasis anddiseases have been studied.

Advanced
Regenerative
Medicine(2014.10 - 2017.9)

・ Advancement of fundamental study ofclinical research that can be expanded
internationally to realize the most advanced
regenerative medicine
・ Development of young scientists in this field・Through fundamental research on regenerative
medicine using mesenchymal cells, disease-specific
iPS cells for pathological analysis and drug
discovery have been established.

International
Advanced Medical
Research(2014.11 - 2017.10)(2017.11 - 2019.10)(2019.11 - 2022.10)

・ Enhancement of human resources necessary
for the development of advanced medicine andconsideration of the formation of bases, for the
purpose of returning the research achievements ofgenome, cancer, infectious diseases, etc. tosociety・Cutting edge medical research and the activationof the "place" necessary for its further development
are currently ongoing.
・Development of young scientists in this field has
been promoted.

44

General Statement: Current Status of IMSUTALA Advanced
Medical Research（2015.4 - 2020.3)

Through basic and clinical application researchof 5-aminolevulinic acid, the program has aimedfor:・ contribution to the development of basic
medicine and medical fields
・ social contributions such as the improvementof the standards of medical institutions andmedical educational institutions in Middle East
Gulf countries

Preliminary experiments have been started relating
to:・detection of circulating cancer cells using 5aminolevulinic acid・enhancement of cell lethality by combination
with oncolytic virus
・promotion of differentiation of induced
pluripotent stem (iPS) cells

Advanced
Biopharmaceutical
Science(2017.4 - 2020.3)（2020.4 - 2023.3)

・ Study into advanced antibody creation in thebiopharmaceutical research field・ Development of specialized young scientists
in this field

・To address the molecular structure problems ofbiopharmaceuticals such as glycan heterogeneity,
the program has aimed to conduct research on thecreation of protein pharmaceuticals such as
antibodies, using artificial intelligence and an
epoch-making biopharmaceutical creation
evaluation technique.
・Development of young scientists to lead the next
generation of this research field and thedissemination of international standardization
technology have been facilitated by the
implementation of advanced creative research.

Cancer
Biomolecular
Therapy（2018.4 - 2021.3)

・ Study into immunotherapy and gene therapy
using various biomolecules to develop innovative
treatments for cancer
・ Development of specialized young scientists
through the research process

・Research and development of "advanced cancer
immunotherapy" such as a technique to release theimmunosuppressive state, and "gene therapy"
including treatment with oncolytic virus withinvasion selectivity are currently ongoing.
・The program aims to develop young scientists tolead the next generation of this research area and to
give back epoch-making technology to society by
the implementation of advanced drug discovery
research.

Genomic Medicine
and Disease
Prevention（2019.7 - 2022.6)

・ Clarification of disease risk factors based on
genome information and health check-up data
・ Research towards social implementation ofeffective disease prevention methods
・ Development of young scientists in this field・Identification and verification of disease-related
alleles among the Japanese; construction of adisease risk prediction model and examination of
prevention measures; and further study of ethical,
legal, and social issues (ELSI) on the social
implementation of these methods are currently
ongoing in the program.

Purposes of Research

Research Activities

・Formation of a base for basic research into theclinical application of tissue stem cells and neuralcancer stem cells; and its international
development

・Creation of retinal degeneration models andelucidation of the molecular basis involved in theonset and progression of its pathogenesis
・Identification of genes that can be therapeutictargets in the development of brain tumors

Corporate SponsoredResearch Programs(Period）
Molecular andDevelopmental
Biology(2014.4 - 2019.3)(2019.4 - 2020.3)(2020.4 - 2021.3)

45

General Statement: Current Status of IMSUT

Fundamental Studyon
Cutting Edge ofGenome Medicine(2015.10 - 2018.9)(2018.10 - 2020.3)(2020.4 - 2021.3)

・ Implementation of fundamental research on
system development to realize advanced genomic
medicine・Establishment of cooperation among multiple
facilities
・Acquisition of informed consent in the clinic andestablishment of an information protection system
・Maintenance of data/sample management

As a regional partnership, IMSUT and the Minato Ward Medical Association have been jointly
holding monthly medical open lectures (23 times since FY2016, with 1,726 participants in total). On
top of this, IMSUT has been promoting an ongoing relationship with the residents based on the
IMSUT-Minato Ward Partnership Agreement since FY2013.
As part of IMSUT outreach activities, IMSUT provides junior high and high school students with
opportunities to visit its laboratories and research centers. Since FY2016, the number of schools andstudents joining such activity has significantly increased (Material 34).
【Material 34】Acceptance of visits from junior and senior high school groups
FY

2016

2017

2018

2019

Number of schools students
were accepted from

25

22

29

28

Number of students accepted

245

261

370

345

(7) Issues and Future Prospects
IMSUT has maintained a consistent standard in recent research activities, with regard to bothquantity and quality of academic papers. Regarding the fund-raising situation, the amount of income
from external sources has steadily increased. Our education programs also maintain an adequate
standard in terms of both the number of postgraduates and of degree recipients. In the future, IMSUT
aims to devote our efforts to further improve research and educational activities by enhancing ouroverall research and educational environment. Meanwhile, as of November 2018, IMSUT has beenauthorized by MEXT as the only International Joint Usage/Research Center in the fields of life
science and biology. Our mission at the Center is to accelerate these activities, furthering not only
IMSUT yet also the entire life science field in Japan, as well as to play the leading role in thedevelopment of this research network in Japan and abroad. Furthermore, IMSUT plans to expand its
organization and provide full support to various projects adopted by the Grants-in-Aid for Scientific
Research, such as the Scientific Research Project on Innovative Areas "Platforms for Advanced
Technologies and Research Resources", the BioBank Japan Project for Genomic and ClinicalResearch "Management of BioBankJapan (BBJ) for utilization of the human materials and medical

46

General Statement: Current Status of IMSUT

information", and the Translational Research Network Program "Strategic Promotion and Expansionof a Translational Research to Establish a Global Base for Knowledge Collaboration".

47

II. Detailed Exposition

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Department of Microbiology and Immunology
Chair Kensuke Miyake（１）Missions and Features
The growing concern in emerging and re-emerging infections increases a demand for understanding
and controlling such infectious diseases. Our department focuses on: the elucidation of molecularinteractions between pathogens and hosts; molecular recognition of microbial products by the immune
system; and molecular mechanisms controlling host defense systems. The department is composed of
5 divisions. Our department particularly studies the pathogens such as Inﬂuenza virus, Ebola virus,
Herpes Simplex Virus, and malaria. We are working together to understand molecular mechanisms
underlying host-pathogen interactions and develop novel vaccines or small chemicals to control
infectious diseases and related immune disorders. Our research activities go beyond our institute andhave been successfully running joint research projects in the area of infection and immunity with otherresearch groups in Japan and abroad. The department is also promoting collaborative projects with
IMSUT Research Hospital as well as with pharmaceutical companies for the development of drugs
and vaccines. Another important mission of our department is to promote development of young
independent investigators in the ﬁelds of microbiology and immunology.

This figure below shows 5 divisions in the Department of Microbiology and Immunology. Threedivisions mainly focus on pathogens such as Inﬂuenza virus, Ebola virus, Herpes Simplex Virus, andmalaria, whereas two divisions focus on host immune responses against pathogens. These divisions
work together to understand the molecular bases underlying host-pathogen interaction and to develop
novel vaccines or novel therapy for infectious diseases or related immune disorders.

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（２）Organization
Division of Virology
Division of Mucosal Immunology
Division of Infectious Genetics
Division of Molecular Virology
Division of Vaccine Science
Division of Malaria Immunology（３）Activity Reports
１）Research Activities
Each division, with its own goals, publishes papers, presents results in scientific meetings, andfiles patents. Details are described below.
２）Education Activities
Each division trains graduate students in its own lab and gives lectures in graduate schools.
３）Social Activities
Each division contributes to out-reach activities. For example, the Division of Virology have beenorganizing a seminar “Love Labo” and welcoming a visitor outside the academic community.
４）International Activities
Professor Yoshihiro Kawaoka takes advantage of cross appointment in the University of Tokyo
to have concurrent appointment in University of Wisconsin in USA. Project Professor Hiroshi
Kiyono also holds a post in the University of California at San Diego. Furthermore, a number ofcollaborations with research groups abroad, such as those in Pasteur Institute in France, are ongoing.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
Our department continues our research activities and training for young scientists to understandand control infectious diseases. To accomplish this mission, we need to recruit young talented
scientists. Profs. Sasakawa, Iba, and Kiyono retired, whereas Profs. Ishii and Coban have joined inour department. Further recruitment of young talented scientists is essential for our department.

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Division of Virology（１）Members
Professor

Yoshihiro Kawaoka

Visiting Professors

Takeshi Noda, Tokiko Watanabe

Associate Professor

Masaki Imai

Project Associate Professor

Seiya Yamayoshi

Assistant Professors

Kiyoko Iwatsuki-Horimoto, Shinya Yamada

Project Assistant Professors

Maki Kiso, Hiroshi Ueki

Research Associate

Yuko Sakai-Tagawa

Postdocs

1

Graduate students

9Technicians

1

Others4（２）Research objectives
Viruses can cause devastating diseases. The long-term goal of our research is to understand themolecular pathogenesis of viral diseases by using influenza and Ebola virus infections as models.
Interactions between viral and host gene products during viral replication cycles determine theconsequences of infection (i.e., the characteristics of the disease and whether it is limited orwidespread); hence, our research has centered on studying such interactions in these viral infections.
We are now also conducting research on SARS-CoV-2.
（３）Activity Reports
１）Research Activities
We are performing various molecular biology, immunology, and epidemiology studies. The
following summarizes some of our achievements. In influenza research, we characterized highly
pathogenic H7N9 avian influenza virus in China (Cell Host & Microbe, 2017), elucidated theinfluenza virus packaging mechanism (Nature Commun, 2018), established a method to predict
future human influenza strains (Nature Microbiol, 2019), identified new neuraminidase antigenic
epitopes recognized by human monoclonal antibodies (Nature Microbiol, 2019), found the frequent
emergence of baloxavir marboxil-resistant influenza viruses in humans (Nature Microbiol. 2020),
and developed a cell line that can efficiently isolate H3N2 seasonal influenza viruses without
mutation (Nature Microbiol, 2019). In Ebola virus research, we developed an inactivated Ebola
vaccine (Science, 2015), and identified biomarkers that predict the severity of Ebola virus disease(Cell Host & Microbe, 2017). Most recently, we reported the efficient transmission of SARS-CoV51

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2 in cats (New Engl J Med, 2020) and the efficient serum treatment of COVID-19 and lack of reinfection in a hamster model (PNAS, in press).
Specifically, we published the following papers. FY2016, 17 papers (including 1 in Nat
Microbiol; 1 in Nat Immunol; 1 in Proc Natl Acad Sci USA); FY2017, 19 papers (including 2 inCell Host & Microbe; 1 in Proc Natl Acad Sci USA; 1 in Nature Commun); FY2018, 33 papers(including 1 in Cell; 1 in Nature; 2 in Cell Host & Microbe; 2 in Proc Natl Acad Sci USA); FY2019,35 papers (including 1 in Cell; 3 in Nature Microbiol; 1 in Nature Protocol); and FY2020 as of June01, 7 papers (including 1 in N Engl J Med)We also filed the following patent applications:Filing date 23 Feb 2017; Suction retainer and method for observing internal tissues
Filing date 27 Mar 2017; Adjuvant and vaccine containing the adjuvant
Filing date 22 Aug 2017; Monoclonal antibody against hemagglutinin antigen of the influenza avirus, and its antigen-binding fragment
Filing date 08 Feb 2019; Humanized cell line (PCT filed)
２）Education Activities
Our laboratory takes on average 2 new doctoral students and 2 new master's students each year.
We train our students to obtain their degree without a drop or delay. Our goal is to train young
scientists to work internationally. Since 2016, we have taken the following graduate students: 2
doctors and 3 masters in Apr 2016, 3 doctors and 2 masters in Apr 2017, 2 doctors and 3 masters in
Apr 2018, and 3 masters in Apr 2019. From FY2017 to FY2019, we accepted and mentored 2
students from other PhD programs (internal medicine and surgical medicine).
Of the students who graduated from the master's course in FY2016 to 2019, one student went on
to the doctoral course each year. Of the students who graduated from the doctoral course in FY2016
to 2019, three students became Postdoctoral Researchers of the Univ. of Wisconsin-Madison, Mt
Sinai medical school, and Osaka Univ., a student became a doctor of the Infectious Disease
Emergency Specialist Training Program, the Ministry of Health, Labour and Welfare, and two
student became assistant professors at Tohoku Univ. and the Univ. of Tokyo.
In April 2019, one postdoctoral researcher became a researcher (PI) at the Institute of Biomedical
Sciences, Academia Sinica, Taiwan, and one postdoctoral researcher was promoted to assistantprofessor at the Univ. of Tokyo.
３）Social Activities
We hold open seminars "LOVE LABO" and "LOVE LABO Laboratory Tour" during every
summer vacation. We also host a laboratory tour of 40 high school students from Kobe High School
every year. In addition, from April 21 to August 31, 2016, we exhibited panels and images at the52

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influenza and Ebola booth of the special exhibition "World of Invisible Viruses" at the Museum of
Health and Medicine of the Univ. of Tokyo.
４）International Activities
Prof. Kawaoka also holds a professorship at the Univ. of Wisconsin-Madison, USA using theUniv. of Tokyo’s cross-appointment system. We have conducted many international collaborative
studies with the Univ. of Cambridge, Univ. of Pittsburgh, New York Univ., Univ. of Chicago, NIH,
CDC, Vietnam NIHE, Gabriel Rene Moreno Univ. (Bolivia), Sierra Leone Univ, Erasmus Univ.
Rotterdam (Nederland), and Univ. Estadual Paulista (Brazil).
We have also conducted international joint research on influenza viruses with Harbin Veterinary
Research Institute as a Sub-Center of Asian Infectious Disease Research Center of IMSUT.
In addition, we held the following international symposia:
26 Aug 2017: Neo-virology: co-evolution and symbiosis of viruses
28 Aug 2018: Neo-Virology: co-evolution and symbiosis of viruses
02 Nov 2018: The 7th China-Japan Bilateral Symposium on All Influenza Viruses
19-20 Feb 2019: Influenza and Other Infections５）Other matters to be noted
Lab members received the following awards:
Feb 2017 The 45th Annual Meeting of the Japanese Society for Immunology, Best presentation
award winner (Postdoc Ueki)
Mar 2017 IMSUT Outstanding student publication award FY 2016 (D3 Nakatsu)
Apr 2017 Young Scientist Awarded by MEXT (Project Assoc Prof Yamayoshi)
Sep 2017 The Japanese Society of Veterinary Science, the 8th Vet. Microbiology Best
presentation award winner (D3 Nakao, D2 Takada)Aug 2017 Sugiura Young Investigator Award, The Japan Society for Virology (Project Assoc Prof
Yamayoshi)
Apr 2018 Japanese Society for Immunology, Tadamitsu Kishimoto International travel award
winner (Postdoc Ueki)
Sep 2018 The 27th Annual Meeting of the Bioimaging Society of Japan BIOIMAGING, Bestimaging Carl Zeiss award winner (Postdoc Ueki)
Mar 2019 The 47th Annual Meeting of the Japanese Society for Immunology, Best presentation
award winner (Postdoc Ueki)
Mar 2019 IMSUT Most outstanding student publication award FY 2018 (D3 Yasuhara)Sep 2019 The Japanese Society of Veterinary Science, Veterinary Science Young InvestigatorAward winner (Project Assist Prof Ueki)
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Mar 2020 Outstanding student publication award FY 2019 (D4 Takada)（４）Challenges and Future prospects
Professor Kawaoka is scheduled to retire from his current position. Whether he will continue his
research at the IMSUT of the University of Tokyo remains unknown. Nonetheless, his lab members
continue to work hard to try to control influenza viruses, Ebola viruses, and SARS-CoV-2.

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Division of Infectious Genetics（１）Members
Professor

Kensuke Miyake

Associate Professor

Shin-ichiroh Saitoh

Assistant Professors

Ryutaro Fukui, Takuma Shibata

Project Assistant Professor

Ryota Sato

Graduate students

7

Technicians

3

Others1（２）Research objectives
Division of Infectious Genetics focuses on Toll-like receptor (TLR), pathogen sensors in the innate
immune system. We would like to understand molecular mechanisms controlling pathogen sensing
and TLR responses. We also would like to understand cellular and molecular mechanisms by which
TLRs drive inflammatory diseases and to develop a novel therapy targeting TLRs to control such TLRdependent diseases. Since April 2016 to March 2019, we tryed to publish papers on the relationshipbetween TLR trafficking and type I interferon production. We focused on single stranded RNA sensor
TLR7 and double stranded RNA sensor TLR3. We also tryed to publish a paper and file a patent on
the control of autoimmune and inflammatory diseases with a monoclonal antibody to TLR9. As foreducation, we tried to train graduate students in our laboratory and by give lectures.
（３）Activity Reports
１）Research Activities
We published 28 papers including a paper in Nat Immunol, 2 papers in Immunity, 3 papers in
Nat Commun, a paper in PNAS, and 3 reviews. We reported that TLR7 traffics from the perinuclear
region to the peripheral region beneath the plasma membrane to induce type I interferon (IFN) (S.
I. Saitoh et al., Nat Commun 8, 1592, 2017)。TLR7-trafficking depends on a GTPase Arl8b. TLR3dependent type I IFN production, on the other hand, depends on Rab7a-dependent lysosomal
trafficking to the cell periphery. (R. Sato et al., Nat Immunol 19, 1071-1082, 2018)。Furthermore,
we have established anti-mouse TLR9 monoclonal antibody (mAb), which is able to inhibit TLR9
responses. The anti-TLR9 mAb protects mice from TLR9-dependent lethal hepatitis caused by
TLR9 ligands (Y. Murakami et al., Sci Rep 7, 44042, 2017).
We also obtained a patent on anti-TLR7/8/9 mAb (Aug 1, 2018). Furthermore, 3 patents havebeen filed as below.
1. Analyses of soluble TLR7 in human samples.
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2. Anti-human TLR7 mAb
3. Anti-TLR9 mAb
２）Education Activities
Four students in master course and a student in PhD course finished their courses. Prof. Miyake
gave 6 lectures a year in Faculty of Sciences.
３）Social Activities
None.
４）International Activities
We are collaborating with Prof. Eicke Latz in Bonn University, Germany. A student in Bonn Univ.
came to our lab and she is going to work here for 2 and half years.
５）Other matters to be noted
We are collaborating with Prof. Eicke Latz in Bonn University, Germany. A student in Bonn Univ.
came to our lab and she is going to work here for 2 and half years.
（４）Challenges and Future prospects
We were able to publish a paper as aimed in the beginning of this term. We also filed and obtained
patents as planned. As for education, we trained graduate students in my laboratory and gave lectures.
In the next term, we would like to publish a paper on the relationship between TLR7 and histiocytosis.
In parallel, we would like to develop anti-human TLR mAb for the control of an autoimmune disease
in collaboration with a pharmaceutical company. The goal of our research is to understand molecularmechanisms behind pathogen sensing by TLRs, and roles of TLRs in human autoimmune diseases.
For education, we would like to have all the graduate students to finish their master or PhD courses.

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Division of Molecular Virology（１）Members
Professor

Yasushi Kawaguchi

Assistant Professors

Akihisa Kato, Naoto Koyanagi, Yuhei Maruzuru

Technicians

4

Graduate Students

6

Others3（２）Research objectives
We have set as one of our short-term goals to have several reports on the results of our research
activities each year concerning the basic research in virology published in the Journal of Virology(JVI), which is regarded as the well-established and authoritative journal in the field of virology. In
addition, we aim to develop a strategy for the treatment and prevention of herpes simplex virus
infections that can benefit society. Regarding our educational activities, we have set a target for 80%
of our PhD students to earn their degree.
（３）Activity Reports
１）Research Activities
Research to date focusing on the herpes simplex virus has made progress in clarifying themechanisms of viral growth and pathological expression in vivo. The goal of these research
activities is to publish multiple reports in the JVI every year, with our research staff being
recognized as the primary author (i.e. first author or corresponding author). As such, our goal from2016 to March 2020 was to publish more than eight results reports in the JVI, and in fact, during
this period, we published 27 academic papers and two review articles, with our research staff
recognized as primary author in 19 of these publications.
In addition, 12 of our papers were published in the JVI, and four were published in journals with
an impact factor (IF) of 10 or more (J. Clin. Invest: 1, Nat. Immunol.: 1, Nat. Commun.: 1, Cell
Host & Microbe: 1). The number of research reports published in the JVI reached our initial target,and notably, four reports were published in academic journals of IF10 or higher. Thus, from theperspective of research achievements, we believe our results have exceeded our target. Maintaining
this level of research productivity in the future will be a challenge, and we will strive to maintain(expand as needed) our body of research personnel and research equipment inventory.
２）Education Activities
Regarding our educational activities, we have set a target for 80% of our PhD students in the field57

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of viral disease control to earn their degree. In fact, 6 of 7 students (85.7%) who completed their
final year of their doctoral research from 2016 to 2019 successfully earned their degrees, allowing
our goal to be realized.
３）Social Activities
In this laboratory, our long-term goal is to develop a strategy for the treatment and prevention ofherpes simplex virus infections that can benefit society, and in March 2019, a novel herpes simplex
virus (HSV) vaccine developed from our research findings in this laboratory was licensed to acompany. In the future, we will aim to produce research results promising benefits to society byworking towards the concrete goal of “developing an HSV vaccine” together with our industry
partners.
４）International Activities
Professor Kawaguchi concurrently serves as the Project Director of the Research Center for Asian
Infectious Diseases, which promotes international collaboration between this Institute and several
Chinese research institutes, and the assistant professors in this laboratory are also members of thisresearch center. We have contributed greatly to international cooperative activities with Chinesescientists.
５）Other matters to be noted
Dr. Kawaguchi was the recipient of the 4th Terumo Foundation Award in 2016 and the 54th
Kojima Saburo Memorial Award in October 2018. Assistant Professor Arii was chosen for a
Commendation for Science and Technology Young Scientists’ Prize by the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) in April 2017 and received a Sugiura Incentive
Award from the Japanese Society for Virology in October 2018. Dr. Arii joined the faculty of theKobe University School of Medicine and was promoted to an Associate professor in August 2019.
Further, Special Research Appointee Dr. Oyanagi was promoted to Assistant Professor in August
2018, and Dr. Maruzuru was promoted to Special Assistant Professor in February 2019, and then to
Assistant Professor in February 2020.
（４）Challenges and Future prospects
As described above, we were able to announce the results of our research activities in this fieldfrom 2016 to March 2020, which have greatly exceeded our initial goals in both quantity and quality.
Maintaining the level of research productivity seen over the last four years will be a major challenge
for the future, and to meet this challenge, we will work to produce results promising benefits tosociety by promoting commercialization and clinical development of HSV vaccines licensed by58

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members of industry.

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Division of Vaccine Science（１）Members
Professor

Ken J. Ishii

Associate Professor

Kouji Kobiyama

Project Senior Assistant Professor

Hideo Negishi

Assistant Professor

Burcu Temizoz

Postdocs

1

Graduate students

3

Technicians

2

Others2（２）Research objectives
Primary goal of our laboratory is to understand the immunological mechanisms of the intra- andinter-cellular signaling pathways that mediate the immunogenicity of successful vaccines, as well as
biological responses to adjuvants.

Such knowledge will enable us to develop novel concepts,

modalities and next generation immuno-preventive and/or therapeutic agents against infectious
diseases, cancer and allergy as well as other non-communicable diseases.
（３）Activity Reports (2019-2020)
１）Research Activities
After moving from NIBIHON and Osaka U to IMS, U Tokyo, I successfully recruited Dr. Kouji
Kobiyama from K Lay lab, Lajolla Inst, CA, USA and Dr. Hideo Negishi from T. Taniguchi Lab, U
Tokyo, and Dr. Burcu Temizoz, Lab Vaccine Science, IFREC, Osaka U. It took time for us to set up
the lab, but now I feel lucky and motivated to initiate new research on vaccine science including
those on COVID-19 and boost our current on going research on cutting edge immunologicalresearch and development of novel vaccines and immune-therapeutics.
The recent progress during 2019-2020 are;17 research papers, 10 invited talks in the international meetings and 27 presentation in domestic
meetings. 2 patents are issued, 4 patents are filed.
The current on going projects are;
A. Extracellular nucleic acids and their immunological roles and therapeutic applications(supported by JST CREST (2018-2024, total 300M yen/5y)
B. Application of adjuvant for vaccine and immunotherapy; machine learning versus classicalimmunology (supported by AMED, 2019-2021, 30M yen/3y)
C. mRNA vaccine preclinical development and its mechanism of action (COVID-19, HPV, MERS,
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supported by MHLW, AMED CICLE, NIBIOHN, respectively. 50M yen 2019-2020)
D. R&D of vaccine adjuvant and its immunotherapeutic application to infectious diseases, cancer
and allergy. (supported by companies including Zeria Pharma, UMN pharma, Torii Pharma,
Daichi Sankyo, 30M yen 2020)２）Education Activities
During 2019-2020, we have one PhD student graduated (via Kumamoto U), One master student
graduated (via Osaka U). We have 3 students currently (One PhD, two MS students at CBMS, U
Tokyo). We are in charge of many lectures, including those in CBMS, School of Pharmaceutical
Science, School of Medicine, U Tokyo, and those in Osaka U, NUS (Singapore), Erasmus U(Netherland),
３）Social Activities
Since we joined IMSUT 2019, the latter half has been under COVID-19 pandemic. Nevertheless,we conducted many social activities during 2019-2020.
A. Editorial activities; Associate Editor: J. Immunology, Vaccine, Frontiers in Immunology, Int.
Immunology, Advisory board: EBIOmedicine, Oncotarget, npjVaccine,
B. Organizer activities; Elsevier Vaccine Congress 2019 (Journal Vaccine), ISV2019 (Internationalsociety of Vacciniology), JSV2019, JSI2019, Japanese Adjuvant Research Consortium meeting
2019
C. Advisor activities; Japanese Government (MHLW, MEXT, advisor for infectious diseaseresearch, COVID-19), AMED (Program officer for Rare Disease Dep). IVI (SAG member,International Vaccine Institute, Korea), GHIT (Scientific Committee member, Global fund inJapan), 2nd Human and Translational Immunology Conference 2019 (Co-organizer,
４）International Activities
International collaboration with NIH (US), FDA (US), Lajolla I (USA), Pen State U (USA),
Oxford U (UK), NUS (Singapore), Pasteur Inst (France). Erasmus Med Center (Netherland),Hacettepe U (Turkey), Bilkent U (Turkey), DNDi (Switzerland),５）Other matters to be noted
I am dually affiliated at National Institute of Biomedical Innovation, Health and Nutrition(NIBIOHNhttp://www.nibiohn.go.jp/adjuvant/index-e.html), and at Immunology Frontier ResearchCenter (IFReC), Osaka University (http://www.ifrec.osaka-u.ac.jp/en/laboratory/ken_j_ishii/)

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（４）Challenges and Future prospects
Vaccine target diseases are now not only restricted to a framework of infectious diseases but include
a broad range of diseases such as cancer, allergy, Alzheimer's disease, and many other lifestyle-relateddiseases. We will continue ‘innovative’ research and development vaccines against these diseases
together closely with our domestic and international collaborator accompanying active exchanges ofresearchers.

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Division of Malaria Immunology（１）Members
Professor

Cevayir Coban

Project Associate Professor

Takako Negishi-Koga

Project Assistant Professor

Michelle Sue Jann Lee

Graduate students

2

Others1（２）Research objectives
Malaria is an infectious disease caused by Plasmodium parasites that often leads to severe
complications such as cerebral malaria and death. Moreover, millions of people living in endemicareas suffer from asymptomatic- or post-malaria complications. In our lab, we focus on the elucidationof the mechanisms involved in the host and Plasmodium parasites interactions. Our final goal is todevelop vaccines and vaccine modalities against malaria and other infectious disease.
（３）Activity Reports
１）Research Activities (From June 1, 2019 to June 1, 2020)＜English original paper / Peer reviewed＞
1.

Lelliott PM, Momota M, Shibahara T, Lee MSJ, Smith NI, Ishii KJ, Coban C. Heparininduces neutrophil elastase dependent vital and lytic NET formation. Int Immunol., 2020, doi:
10.1093/intimm/dxz084. PMID: 31879779
2.

Momota M, Lelliott P, Kubo A, Kusakabe T, Kobiyama K, Kuroda E, Imai Y, Akira S,

Coban C, Ishii KJ. ZBP1 governs the inflammasome-independent IL-1α and neutrophil
inflammation that play a dual role in anti-influenza virus immunity. Int Immunol., 2019, Oct 20.
pii: dxz070. doi: 10.1093/intimm/dxz070. PMID: 31630209
3.

Ozasa K, Temizoz B, Kusakabe T, Kobari S, Momota M, Coban C, Ito S, Kobiyama K,

Kuroda E, Ishii KJ. Cyclic GMP-AMP Triggers Asthma in an IL-33-Dependent Manner That Is
Blocked by Amlexanox, a TBK1 Inhibitor. Front Immunol, 2019, Sep 26;10:2212. doi:
10.3389/fimmu.2019.02212. eCollection 2019. PMID: 31616416
4.

Lee MSJ, Natsume-Kitatani Y, Temizoz B, Fujita Y, Konishi A, Matsuda K, Igari Y, Tsukui

T, Kobiyama K, Kuroda E, Onishi M, Marichal T, Ise W, Inoue T, Kurosaki T, Mizuguchi K, Akira
S, Ishii KJ, Coban C. B cell-intrinsic MyD88 signaling controls IFNγ-mediated early IgG2c classswitching in response to a particulate adjuvant. Eur. J. Immunol., 2019, 49(9):1433-1440.

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5.

Lelliott PM, Momota M, Lee MSJ, Kuroda E, Iijima N, Ishii KJ, Coban C. Rapid

quantification of NETs in vitro and in whole blood samples by imaging flow cytometry.
Cytometry A, 2019, 95(5):565-578.
＜English books＞
1.

Lee MSJ, Coban C. Mucosal vaccines for malaria. In the book Mucosal Vaccines:

Innovation for Preventing Infectious Diseases, 2e. Chapter 49 (p. 831-840). (Edited by Hiroshi
Kiyono and David W. Pascual), 2019.

２）Education Activities
We have newly started enrolment into lectures for undergraduate and graduate level studies atUniversity of Tokyo. Most of them were delayed/changed due to Coronavirus pandemic.
Lectures given at Undergraduate Level:
1. Coban C. Host-Plasmodium parasites interactions Academic Frontier Lecture Series for students
in Junior Division, College of Arts and Sciences, The University of Tokyo. December 14, 2019.
３）Social Activities
None.
４）International Activities
Invited Lectures (international):

1.

Coban C. Immunopathology in bone during malaria infection. AAI

IMMUNOLOGY2020TM, May 8 – 12, 2020, Honolulu, HI, USA. CANCELLED DUE TO
COVID-19.

2.

Coban C. Imaging immune pathoology during malaria infection. World Immune

Regulation Meeting (WIRM)-XIV, March 4-7, 2020, Davos, SWITZERLAND. POSTPONEDDUE TO COVID-19.

3.

Coban C. Understanding host-Plasmodium interactions for developing sterile immunity

against malaria. The 5th SINGMALNET Singapore Malaria Network Meeting. February 20-22,
2020, SINGAPORE. POSTPONED DUE TO COVID-19.

4.

Coban C. Host-Plasmodium interactions and the sterile immunity against malaria: whereare we? Immunology at the Forefront. The 11th International Symposium of IFReC. January 24,
2020, Grand Cube Osaka, Osaka, JAPAN.

5.

Coban C. Mysterious interactions between Plasmodium parasites and their host. The

26th East Asia Joint Symposium, October 23-26, 2019, Seoul National University, Seoul, S.
KOREA.
Meeting organizer:
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I co-organized International Joint Usage/Research Center-Young Researchers Symposium
meeting with Prof. Ishii and Prof. Fujihashi in January 27th, 2020. We first time held this meetingin English and invited world famous immunologist Prof. Thirumala Kanneganti. Several Young
Scientist talked about their scientific studies in this 1-day workshop.
International Speaker Invitation to IMSUT:
Since June 1, 2029 until Coronavirus outbreak, I invited several international speakers either
together with support from the International Joint Research Center or alone. Seminars were held in
English. Name and affiliations of speakers:
2019-10-30: Moshe Arditi (Cedars-Sinai Medical Center, USA)2019-11-11: Pascale Cossart (Pasteur Institute, France)
2019-12-06: Shiroh Iwanaga (TMDU, Tokyo)
2019-12-17: Kazuki Tainaka (Niigata University, Brain Research Institute)
2020-02-05: Ihsan Gursel (Bilkent University, Ankara, Turkey)
2020-02-06: Katja Simon (The Kennedy Institute, University of Oxford, UK)
2020-02-06: Mayda Gursel (Middle East Tech. University, Ankara, Turkey)５）Other matters to be noted
None.
（４）Challenges and Future prospects
As a new team in IMSUT, we are determined to develop new and outstanding immunology andparasitology research in IMSUT and nurture and develop a creative science here.

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Department of Cancer Biology
Chair Yoshinori Murakami（１）Missions and Features
Cancer develops and progresses towards malignancy through multiple steps with structural andfunctional alterations of multiple genes involved in regulation of cell growth, differentiation, apoptosis,
and cell-cell and cell-matrix interaction. In the Department of Cancer Biology, we aim to clarify theentire picture of tumor development and progression on the basis of a molecular understanding ofphysiological and pathological features of these gene products. For this purpose, we take advantage
of applying various multi-disciplinary approaches in addition to established molecular biological andmurine genetics techniques, including proteomics, molecular imaging, structural biology, physicalchemistry and mathematical sciences. The ﬁndings from our research will provide innovative targets
for translational research of cancer diagnosis and treatment. Ongoing research topics in individual
divisions are described as follows.
1) Division of Molecular Pathology: 1) Molecular analysis of cancer progression by aberrant celladhesion and its application to diagnosis and treatment of cancer. 2) Genomic, epigenomic, andmolecular pathological analyses of lung, breast, bile-duct, and other solid tumors and adult T-cellleukemia/lymphoma.
2) Division of Genetics: 1) Studies on molecular signals that regulate a variety of cellular activities,
aiming to address how deregulated cellular signals cause neoplastic, neuromuscular or otherintractable disorders. 2) Pathophysiological analyses of animal models for the above-mentioned
diseases, aiming to develop new therapeutic approaches.
3) Division of Cancer Cell Biology: 1) Elucidation of in vivo anticancer mechanisms anddevelopment of innovative cancer therapies. 2) Studies on regulatory mechanisms of in vivo aging.
3) Molecular basis underlying DNA methylation abnormalities in early stages of carcinogenesis.
（２）Organization
Division of Molecular Pathology
Division of Genetics
Division of Cancer Cell Biology
Division of Molecular and Cellular Biology (-2020.3)（３）Activity Reports
66G2１）Research Activities
Research activities in the Department of Cancer Biology are essentially based on the curiositydriven science by each principal investigator rather than project-oriented research shared by all
divisions in the department. Each division sets individual aims and goals of its research activities
with well-designed schemes and key performance indicators, including the number of papers to be
published from 2016 April to 2020 March, as described in the sessions for each division. Everydivision has mostly achieved each goal or overcome problems if any.
２）Education Activities
Department of Cancer Biology recognized the importance of educating young scientists forcontinuous development of this research field in the future. For this purpose, we set the following
achievement goals from FY2016 to FY2019. 1) To hold a “G2 retreat meeting” once a year, where
all graduate students participate in a 2-day meeting and present and discuss their works andexchange the relevant information in English. 2) To hold a series of “G2 seminars” three times a
year, where guest scientists in the relevant fields are invited to give cutting-edge lectures toencourage young scientists.
According to this plan, we held the “G2 retreat” as a 2-day meeting every year from FY2016 toFY2019, where 2 graduate students from each Division or Laboratory provided an oral presentationof 10 min in English, whereas the other students provided a short talk of 1-2 min in English.
Furthermore, we invited two lecturers, Dr. Robert Whittier, Professor of Juntendo University, and
Dr. Philip Hawke, Assistant Professor of University of Shizuoka, to give special lectures on English
presentation skills for Japanese scientists. Dr Whittier and Dr. Hawke not only gave detailed
comments in individual English presentations but also recorded videos of individual presentations
and sent it to each student with special comments to brush up his/her English presentation. Thanks
to the “G2 retreat meeting” and the great contribution of these 2 lecturers, the English presentation
skill of the graduate students is improving greatly every year. We are going to continue this activity
in the future.
Another activity, a series of “G2 seminars,” is held independently of the institutional seminarseries, which are formal seminars of the Institute of Medical Science by invited lecturers. In “G2seminars,” Professors in the Department of Cancer Biology organize and choose lecturers who makegreat achievements directly in the fields of cutting-edge cancer science. All the graduate students
are obliged to attend the seminar and to participate in discussion. Although the number of active
participants is gradually increasing, the graduate students are still shy to participate in English
discussion in comparison with the presentation of their own works. Taken together, more practicewould be required for graduate students to brush up their English presentation skills and to acquire
an attitude towards active discussion, although we recognize that the initial goals of improvement67

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of English presentation by graduate students have mostly achieved in these 4 years.
３）Social Activities
Department of Cancer Biology does not set a common goal in terms of social cooperation but
each division seeks programs for social cooperation, as described in the session for each division.
４）International Activities
Department of Cancer Biology does not set a common goal in terms of international collaboration
but each division seeks active international collaboration and cooperation as described in the session
for each division, including 4 international joint research projects.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
Challenges and Future prospects in the activities of research, social cooperation, and international
collaboration are described in the sessions for each division. As to the educational activity, theDepartment of Cancer Biology has recognized the continuous mission of educating young scientists
for sustainable development of this research field for the future. For this purpose, we will continue tohold an annual meeting of “G2 retreat” and a series of “G2 seminars.” Furthermore, we will invite
participants from other departments in IMSUT to accelerate the multi-disciplinary science andresearch in this department.

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Division of Molecular Pathology（１）Members
Professor

Yoshinori Murakami

Project Professor

Takayuki Morisaki

Assistant Professor

Takeshi Ito

Project Assistant Professor Masaru Koido
Postdocs

3

Graduate students

11Technicians

3

Others4（２）Research objectives
Human cancer develops and progresses toward malignancy through accumulation of multiple
genetic and epigenetic alterations. Understanding of these alterations is essential to developing
molecular targets for prevention, diagnosis, and treatment of cancer. The Division of MolecularPathology aims to elucidate the roles of cell-cell interaction in invasion, metastasis, immune
checkpoint, and drug resistance of cancer and to develop new diagnostic and therapeutic approaches
to cancer, including a serum marker of small cell lung cancer (SCLC). Genomic and epigenomic
abnormalities involved in human tumors, as well as genetic susceptibility to various common diseases,
are also investigated in collaboration with others to obtain a complete view of human diseases,
including human cancer.
（３）Activity Reports
１）Research Activities
The Division of Molecular Pathology has been investigating the molecular mechanisms
underlying cancer invasion and metastasis from the view point of cell-cell interaction and its
disruption. In these four years, we developed a proto-type of a novel serum diagnostic marker ofSCLC. Moreover, we recently started the projects on immune checkpoints and on resistance ofcancer against molecular targeting drugs, in which cell-cell interaction plays important roles.
The goals of the research activity in this division from FY2016 to FY2020 are as follows. 1) To
identify novel molecular pathways that CADM1 serves as a tumor suppressor in epithelia and as an
oncogene in SCLC or adult T-cell lymphoma/leukemia, and to publish several original papers. 2)
To establish a novel serum diagnostic marker of SCLC with high sensitivity and specificity bytargeting a splicing variant of CADM1v8/9 specifically expressed in testis and SCLC, and to file apatent application. 3) To complete cloning of more than 150 human IgSF molecules involved in69

G2cell-cell interaction, to assess specific interactions among these IgSFs using physico-chemical
analyses, and to identify novel interactions between IgSFs with important functions in immune
checkpoint and cancer metastasis. 4) To participate in large collaborative studies on the genomewide association studies (GWAS) or sequencing analysis and to identify novel SNPs or mutations
associated with various human diseases, including cancer.
The achievements in individual challenges are as follows. 1) We demonstrated the involvementof CADM1 in Hippo pathways as a possible starter of signaling from the cell membrane. We also
demonstrated the suppressor function of CADM1 in Src-signaling in colon cancer by binding with
c-Src binding protein (CBP). Moreover, we showed suppressor function of CADM1 in EGFR- or
MET-signaling in gefitinib-resistant lung adenocarcinoma using mathematical models. Thesestudies were published in four original papers. 2) We demonstrated the CADM1v8/9 fragments inthe serum from SCLC patients caused by extracellular shedding, and generated an antibody against
soluble fragments of CADM1v8/9. Then, we developed a sandwich assay to detect CADM1v8/9 inthe serum from SCLC patients with high sensitivity and specificity. CADM1v8/9 is shown to be
useful for monitoring SCLC after chemotherapy, which is more useful or at least equivalent tocurrent available markers, ProGRP or NSE. We filed a domestic patent application in 2018 and a
PCT application in 2019 and started collaboration with a company in Japan in 2020. 3) We havecloned 289 IgSF molecules and identified several immune checkpoint molecules serving as ligands
to orphan receptors using amplified luminescent proximity homogeneous assay (Alpha) and surface
plasmon imaging (SPRi) technologies, which are going to have patent applications filed. We also
identified novel IgSF interactions involved in cancer metastasis and published a paper. 4) We
participated in multi-institutional collaboration of GWAS or target sequencing of various humandiseases, including cancer and served as co-authors of more than 30 original papers identifying key
SNPs and mutations. Thus, achievements in projects 2 and 3 are more than expected and those inproject 4 are satisfactory, whereas those in project 1 are steady but need more publication withhigher impact. In fact, we have identified several additional cross-talks of CADM1 with novel
cascades leading to promising therapeutic targets for advanced or drug-resistant cancer. We plan to
publish these findings in original papers. We are also recruiting staff scientists for this division.
２）Education Activities
Prof. Murakami served as an adjunctive professor in the Graduate School of Medicine (GSM)
and the Graduate School of Frontier Sciences (GSFS) and a part-time lecturer in the School of
Medicine (SM), the University of Tokyo. He served and is serving as a supervisor for 6 PhD students
from GSM and 5 PhD students and 12 Master Degree students from GSFS in addition to giving
lectures to GSM, GSFS and SM. He also served as an inspector of the thesis for 16 PhD students
and 11 Master Degree students from GSM and GSFS.
70

G2３）Social Activities
Division of Molecular Pathology concluded a joint research agreement with Koichi Tanaka Mass
Spectrometry Research Laboratory, Shimadzu Corporation, Japan and conducted collaborative
research on glycosylation analysis of cancer. Prof. Murakami served as a principal investigator of
Biobank Japan project supported by AMED, Japan between 2014-2019 and contributed to the
management and renewal of the project from 2018 to 2023 and the resultant increase in the numberof distributed human DNA and serum to academic and industrial societies. He also started acollaboration with NTT Corporation, Japan, to establish a social cooperation research program,“Project Division of Genomic Medicine and Disease Prevention” as described in the relevant
session.
４）International Activities
Based on the partnership agreement between GSFS and Lyon University, France, the Division of
Molecular Pathology hosts 6 Master Degree graduate students from Lyon University for around 6
months every year. In addition, on the basis of the MOU between the Institute of Medical Scienceand Khon Kane University (KKU), School of Medicine, Thailand, this division has beencollaborating with scientists in KKU on the study of cholangiocarcinoma, hosted a young scientist,and published a paper. This collaboration was renewed in 2019 as an International Joint Research
Project.
５）Other matters to be noted
None.
（４）Challenges and future prospects
The research on cell adhesion and cancer progression must be completed by March 2024 when Prof.
Murakami will retire. A novel serum marker of SCLC targeting CADM1v8/9 fragments is to beestablished and the export to the industry will be sought with a candidate company in Japan. An
antigen-drug conjugate using an anti-CADM antibody will be also developed in collaboration with acandidate pharmaceutical company in USA. In the basic science, cross-talk of CADM1 and related
IgSF molecules with growth factor signaling or transporter networks will be established to publish
original papers and review articles summarizing the multiple functions of CADM1. Furthermore,novel promising targets in immune checkpoints are to be identified by comprehensive binding assayof IgSF molecules and at least one or two seeds applicable to cancer immune therapy will be developed.
With combinatorial sequencing analyses of human genes encoding cell adhesion molecules, a conceptof disorders caused by aberrant cell-cell interaction will be established. For educational activity, Prof.
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Murakami will continue to devote himself to the education of graduate students and undergraduate
students and will supervise at least 5 PhD students in the Division of Molecular Pathology.

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Division of Cellular and Molecular Biology (-2020.3)（１）Members
Professor

Jun-ichiro Inoue

Associate Professor

Takeharu Sakamoto

Assistant Professors

Yuu Taguchi, Mizuki Yamamoto

Graduate students

9

Others5（２）Research objectives
The Aims of our laboratory are 1) to elucidate the molecular mechanisms of signal transduction
pathways that activate transcription factor NF-κB, which is crucial for regulation of immune system,
formation of various organs and cancer development, and 2) to develop therapeutic strategies to treat
various diseases by understanding physiological and pathological roles of NF-κB.
（３）Activity Reports
１）Research Activities
We have identified and been interested in Tumor necrosis factor receptor-associated factor 6(TRAF6), which acts as an E3 ubiquitin ligase to generate Lys63-linked polyubiquitin chains thatare crucial for transducing signals emanating from the TNFR superfamily or the TLR/IL-1R familyleading to activation of transcription factor NF-κB and AP-1. By generating TRAF6-deficient mice,
we found that TRAF6 is essential for osteoclastogenesis, immune self-tolerance, lymph nodeorganogenesis and formation of skin appendices. We also demonstrated that NF-κB maintains
cancer stem cell population in basal-type breast cancer. From April 2016 to March 2020, our goal
was to publish around 5 papers, in which the first, last and corresponding authors belong to ourlaboratory, about one of the following five subjects: 1. Elucidation of the molecular mechanisms of
NF-κB-mediated carcinogenesis; 2. Elucidation of the molecular mechanisms of NF-κB oscillation
between nucleus and cytoplasm and mathematical simulation of the oscillation; 3. Elucidation of
the role of NF-κB in the regulation of epithelial-mesenchymal transition of mammary epithelial
cells to understand how NF-κB is involved in breast cancer malignancy; 4. Elucidation of themolecular mechanisms of regulation of inflammation by macrophages; 5. Identification of inhibitor
drugs that block fusion between viral envelope and cellular membrane in collaboration with
Research Center for Asian Infectious Diseases. For subject 1, we demonstrated that human T cellleukemia virus type 1 oncoprotein Tax generate Lys63- and Met1-linked hybrid polyubiquitin
chains to form a macromolecular complex of IκB kinase, thereby maintaining constitutive activationof NF-κB (PLoS Pathogens 2017). For subject 2, in collaboration with Professor Takashi Suzuki in73

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Osaka University, we proposed a novel mathematical model, in which the NF-κB oscillation isrobustly maintained by introducing phosphorylation of NF-κB and IκB (J. Ther. Biol. 2019). For
subject 3, we demonstrated that TRAF6 maintains mammary stem cells and promotes pregnancyinduced mammary epithelial cell expansion (Commun. Biol. 2019). For subject 4, we identified
Mint3, a key molecule in regulating inflammation (Proc. Natl. Acad. Sci. USA 2017). For subject 5,
We have established experimental system to monitor fusion that mimics fusion between viralenvelope and the cellular membrane. Using the fusion monitor system, we performed high throughput screening of the FDA-approved library and identified Nafamostat as a potent inhibitor of MERS
coronavirus infection (Antimicrob. Agents Chemother. 2016, J. Biol. Chem. 2019). We recently
demonstrated that Nafamostat also blocked infection of SARS-CoV-2, a causative agent of COVID19 (Viruses 2020). We have published 35 papers during the period. Among them, 15 papers include
at least one of our members as the first or corresponding author. All the staffs received KAKENHI
from MEXT. Prof. Inoue is a member of innovative area. Prof. Inoue and Associated Prof. Sakamoto
received a grant from AMED for each. One paper that has impact factor of more than 10 was
published.
２）Education Activities
Prof. Inoue was involved in education activities in three graduate school; Graduate School of
Medicine, Department of Molecular Cell Biology; Graduate School of Frontier Sciences,
Department of Computational Biology and Medical Sciences; Graduate School of Pharmaceutical
Sciences, Department of Pharmaceutical Sciences. Prof. Inoue weekly discussed progress ofexperiment with his students asking them to think what to do next by yourself. During the period,
11 students have completed master course. Five students have completed doctor course and four ofthem received Ph. D degree. All students are actively working in their companies. In preparation for
coming globalization, a portion of the regular seminar was performed in English. In 2017, a French
student was joined. Thus, we think we achieved our goal in education activities.
３）Social Activities
To return scientific achievements to society, we applied a patent of viral infection inhibitor. We
also collaborate with some private company to develop a diagnostic method for malignant cancer.
Thus, we think we achieved our goal in social activities.
４）International Activities
During the period, Prof. Inoue went to Beijing three or four times in a year to visit China-Japan
joint laboratory to pursue international collaboration. We have published 11 papers regarding thiscollaboration. Thus, we think we achieved our goal in international activities.
74

G2５）Other matters to be noted
None.
（４）Challenges and Future prospects
This Division has completed and closed as of March 31, 2020.

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Division of Genetics（１）Members
Professor

Yuji Yamanashi

Assistant Professors

Ryo Ueta, Akane Inoue-Yamauchi, Takahiro Eguchi

Postdocs

1

Graduate students

6

Technicians

2

Others2（２）Research Objectives
Our research objective is to elucidate the molecular signals that play important roles in regulating
the generation, maintenance, and functions of organisms, tissues, and cells as a path toward clarifying
the molecular pathology of malignant tumors and other intractable diseases resulting fromdysregulation of molecular signals. We aim to develop diagnostic and therapeutic interventions basedon our findings, in order to promote societal benefit from these technologies, and to foster highly
creative young scientists able to pursue a wide range of issues in the fields of life and medical sciences.
（３）Activity Reports
１）Research Activities
The Division of Genetics has attempted to identify unknown signaling molecules and pathways,
focusing on those regulating cellular activities, to elucidate their functions and modes of action froma physiological or pathophysiological viewpoint. The goals of this division from April 2016 throughMarch 2020 were as follows. First, we aimed to elucidate signal transduction mechanisms related
to cancer, immunity and inflammation, bone metabolism, and formation and maintenance ofneuromuscular junctions (NMJs). We mainly focused on the DOK-family of proteins that we had
previously discovered. Second, we wished to promote the research and development of therapeutic
methods for neurological and muscular diseases based on the knowledge we obtained regarding
NMJs. Third, we aimed to publish the results as five peer-reviewed English research papers withstudents, researchers, and faculty members as the first, last, and corresponding authors. In fact, we
published papers on the following: the roles of Dok-1, Dok-2, and C/EBP

in intestinal

inflammation (BBRC 2016; Genes Cells 2019), the roles of Dok-1, Dok-2, and Dok-3 in bonemetabolism (BBRC 2018); the roles of Dok-7 in the formation, maintenance, and functional
regulation of NMJs (Genes Cells 2016; J Biochem 2017; BBRC 2020); and treatment of a mousemodel with amyotrophic lateral sclerosis (ALS) through enhancement of NMJ formation (EMBO
Mol Med 2017). Therefore, we believe that almost all goals have been met, although no paper was
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published regarding cancer within the set period. Aiming to publish this paper by 2021, we will
accelerate our research by increasing the number of researchers, including graduate students,
postdoctoral researchers, and technical staff, and through joint research with others inside andoutside the institute.
２）Education Activities
The Division of Genetics has provided: 1) education and research training for master's anddoctoral students based on the above research activities, to cultivate a wide range of knowledge inthe fields of life and medical sciences; 2) deep insights into specific research subjects in order totrain researchers to be able to set and solve unique research problems; and 3) young scientists able
to use their abilities to contribute to the development of society. The goal of the division from April
2016 through March 2020 was to develop all the students registered in this period into such humanresources. In fact, of the eleven students who joined the division as master's students, three havepublished peer-reviewed English-language papers and achieved PhDs, one of whom has been
appointed as an assistant professor at the institute, and two have received research-based jobs inpharmaceutical companies. Two more have achieved master's degrees, one who is now employed
at a pharmaceutical company, and the other who is employed at a clinical laboratory company. One
student left graduate school for personal reasons. The remaining five are still at the university; three
have transferred to other laboratories during their master's courses, due to a health reason or change
in interest. Based on these facts, we believe that all students who achieved master’s and/or doctoral
degrees successfully became the envisioned human resources. We are trying to provide more
attentive education and research guidance in consideration of students whose motivation forresearch faded.
３）Social Activities
In the Division of Genetics, social collaborations have been carried out for the study ofneuromuscular diseases. The goal of the division from April 2016 through March 2020 was toconduct drug discovery research through one or more collaborative activities. We engaged in drug
discovery research jointly with a pharmaceutical company and a public interest incorporated
foundation (two research activities in total) throughout the period. In this respect, we believe that
this goal has been achieved.
４）International Activities
In the Division of Genetics, international collaborations have been carried out for the study of
NMJs and NMJ-related disorders. The goal of the division from April 2016 through March 2020
was to conduct one or more international joint research activities. In fact, more than three77

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international activities were carried out throughout this period. In this respect, we believe that thisgoal has been met.
５）Other Matters to be noted
The patent for the DOK7 gene, invented by faculty members [Yamanashi, Yamauchi (Inoue)] andalumni of this division was acquired in Europe [2031062 (EP), published on October 24, 2018](Japan and US patents have previously been acquired).
（４）Challenges and Future Prospects
As mentioned in “(3) Activity Reports,” the Division of Genetics has propelled research andeducation activities, together with social and international collaborations. The current challenges are
to enhance the PR activities of our findings and to provide attentive education and research training
for students. Upon achieving this, higher levels of education and research outcomes, together with theenhancement of social and international collaborations, are expected.

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Division of Cancer Cell Biology（１）Members
Professor

Makoto Nakanishi

Associate Professor

Atsuya Nishiyama

Assistant Professor

Yoshikazu Johmura

Postdocs

2

Graduate students

14

Technicians

4

Others1（２）Research objectives
In response to genetic and epigenetic insults, normal human cells execute various cellular responses
such as transient cell cycle arrest, apoptosis, and cellular senescence as an anti-tumorigenesis barrier.
Our research interests are to elucidate the mechanisms underlying the induction and regulation ofcellular senescence. Our final goal is to develop innovative cancer therapies, prevention, and antiaging strategies through regulating and/or eliminating senescent cells in vivo (senotherapy). We are
currently focusing on identification and characterization of senescent cells in vivo. To do so, we havegenerated a mouse model in which p16-positive senescent cells are visualized by fluorescent labelling.
Mechanisms underlying maintenance of genomic and epigenomic integrities such as DNA methylation
maintenance are also under investigation.
（３）Activity Reports
１）Research Activities
The division of Cancer Cell Biology was inaugurated in 2016 as the 4th division in Department ofCancer Biology. Our research interests are 1) elucidation of mechanisms underlying age-associatedcarcinogenesis, 2) investigation of molecular basis underlying DNA methylation maintenance andgenomic instability due to impaired DNA methylation, and 3) study of regulatory mechanisms
underlying chromosomal segregation. For these purposes, we established various innovativetechnologies and materials as follows: 1) pure senescent cells in culture, 2) senolytic technology(elimination of senescent cells from an aged body) by targeting metabolic processes specific tosenescent cells, 3) establishment of a mouse model in which p16-positive senescent cells arevisualized by fluorescent labeling and analytical methods of their transcriptomes at a single cell level,and 4) establishment of a mouse model in which senescence can be induced by ectopic expressionof p53 fused with geminin degron, which is specifically functional during S to G2 phase. Using thesetechnologies and materials, we have uncovered the following mechanisms: 1) Innovative senolytic
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technology targeting metabolic vulnerability in senescence in which glutaminolysis was activatedby lysosome-mediated intracellular low pH. Inhibition of GLS1, a rate limiting enzyme ofglutaminolysis, effectively induced senolysis both in vitro and in vivo. Most intriguingly, treatmentof aged mice with GLS1 inhibitor ameliorated various forms of age- and senescence-associatedorgan dysfunction, such as age-associated glomeruloscrerosis, lung fibrosis, cardiac hypertrophy,
and adipose tissue atrophy as well as senescence-associated atherosclerosis. Our results suggest thatcells in a senescent state require glutaminolysis, and its inhibition offers a promising strategy for
inducing senolysis in vivo. 2) A mechanism coupled with DNA replication machinery for the
recruitment of DNMT1 to replicating chromatin in which UHRF1-mediated dual monoubiquitylation of PCNA-associated factor 15 (PAF15) plays an essential role. In Xenopus cell- free
extracts, PAF15 accumulates on chromatin with dual mono-ubiquitylation (PAF15Ub2) in a PCNA-,UHRF1- and DNA replication-dependent manner. PAF15Ub2 interacts with DNMT1 with astructural mode similar to that of H3Ub2. Suppression of DNMT1 interaction with H3Ub2 in theextract shows that PAF15 and histone H3 have non-redundant roles in the recruitment of DNMT1and subsequent DNA methylation. Consistent with this, in mammals, PAF15 is also subjected to
UHRF1-dependent dual mono-ubiquitylation and is capable of binding to DNMT1. Mouseembryonic stem cells expressing PAF15 carrying substitutions of lysine to arginine at ubiquitylationsites demonstrate a marked reduction in the DNA methylation level. Together, our study reveals that
PAF15 and histone H3 have non-redundant roles in the regulation of DNA methylation maintenance.
These results were published in 5 high impact journals (more than 10 impact factor) in the last
three years and thus we believe that our research mission has been achieved. Now, two more papers
with high impact journals are under revision. In total, 14 papers were published as peer reviewed
original articles during this period. We also patented two issues including a diagnosis of luminal Atype breast cancers and a senolytic technology. We received 8 grants from MEXT and 6 grants from
AMED as well as a couple of private grants during this period.
２）Education Activities
We take immense pleasure in training young researchers-to-be. Not only do we endeavor to foster
appropriate research skills and attitudes to do experiments in the laboratory, but also we aim todevelop and expand upon logical thinking.
Until now, we have had 9 PhD students and 15 master’s students, two of whom received their PhD
and ten of whom received their MS degree. It should be noteworthy that two of our master’s students
have been awarded as students of World-leading Innovative Graduate Study Program for Life
Science and Technology, within which master’s student received a Best Poster Award in Foundation
Memorial Symposium of our institute, a Funakoshi Ryutaro Award, and a Best Student Award in
Graduate School of Science, University of Tokyo.
80G2３）Social Activities
Breast cancer is the most frequently diagnosed cancer in women. Approximately 70% of breast
cancers are positive for estrogen receptor-alpha (ER), and tamoxifen (TAM) is the standard drug fortreatment of ER-positive breast cancer, especially for premenopausal women. Treatment with TAM
as an adjuvant decreases the annual breast cancer mortality by approximately 30%. However, up to
25% of patients with early stage breast cancer treated with TAM experience relapse of the disease
within 15 years. Hence, modification of the treatment is absolutely required for some populations.
In order to overcome the above problems, we are now developing a new diagnostic kit for luminal
A-type breast cancers under the collaboration with pharmaceutical companies.
４）International Activities
We are doing tight collaborative research on DNA methylation maintenance and genomic
instability with a research group at the Memorial Sloan Kettering Cancer Center in US, theUniversity of Munich in Germany, and the University of Paris in France.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
Expanding our research on age-associated carcinogenesis and DNA methylation maintenance byintegrating all members in our laboratory as well as materials, equipments, and technologies.

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Department of Basic Medical Sciences
Chair Mutsuhiro Takekawa（１）Missions and Features
The mission of this department is to develop new fields in basic biomedical science and to apply
the results of such research to the prevention and control of human diseases. In order to elucidate
the causes and mechanisms of diseases, and to develop more effective diagnostic and therapeuticstrategies, it is essential to understand life processes at the molecular level.

This department wasestablished as one of three core research departments in the institute, to explore and advance life
sciences without regards to specific diseases or research fields. Thus, this department is a collectionof diverse and unique research groups with no limit to the direction of their research. At the sametime, this department provides support to the research of other departments in the institute.
（２）Organization:
Division of Molecular Cell Signaling
Division of Neuronal Networks
Division of Cell Signaling and Molecular Medicine（３）Activity Reports
１）Research Activities
In this department, fundamental questions pertinent to basic life processes are addressed at thelevels of molecules, cells, tissues, and whole organisms.

The following is a summary of theresearch activities of each division.
Up to the end of the fiscal year 2016, the Division of Molecular Cell Signaling studied the cellularresponses to extracellular stress stimuli, including high-osmolarity stress, in budding yeast andmammalian cell models using cell biological, biochemical, and molecular genetic approaches.
The major research interest of the Division of Neuronal Networks is the molecular mechanismsof higher brain functions such as emotion, learning, and memory in mammals. The Division isespecially focusing on the roles of molecules that function in neuronal information processing, using
electrophysiological, biochemical, molecular biological and behavioral approaches.
The Division of Cell Signaling and Molecular Medicine studies regulatory mechanisms of
biological signal transduction systems such as MAPK cascades and stress-granules that are
responsible for cell-fate decisions. Since perturbation of these signaling systems is involved invarious life-threatening diseases including cancer and autoimmune diseases, the Division also aims
to develop new diagnostic and/or therapeutic tools for currently intractable disorders in which these82

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pathways are involved.
Thus, a broad range of basic medical research is conducted in this department.
２）Education Activities
The principal investigators in this department supervise many graduate students (in master’s anddoctoral courses) from three different graduate schools of the University of Tokyo: the Graduate
School of Science; the Graduate School of Frontier Science; and the Graduate School of Medicine,and they serve as chairs or members of thesis review committees every year. The faculty membersof this department also contribute to the education of undergraduate and graduate students not onlyat the University of Tokyo but also at other universities by lecturing in the biomedical sciences.
３）Social Activities
Some laboratories in this department promote joint research with pharmaceutical companies withthe aim of developing new diagnostic tools for human diseases.
４）International Activities
Some faculty members in this department carry out international collaborations with the US, theUK, and France, and they hosted an international symposium in Tokyo in 2019.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
This department currently consists of only two divisions, as the Division of Molecular Cell
Signaling has been vacant since the end of the fiscal year 2016. It is therefore obviously importantto recruit new laboratories that will be leaders in the field of basic medical science. Nevertheless,the remaining Divisions will continue to pursue original, basic life science research as well astranslational research aimed at overcoming currently intractable diseases.

Focusing on themechanisms of biological signal transduction associated with human diseases, we will advance avariety of research projects at molecular, cellular and organismal levels by employing new
methodologies such as molecular imaging, omics, and bio-mathematical analysis.

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Division of Molecular Cell Signaling (-2017.3)（１）Members
Associate Professor

Kazuo Tatebayashi

Graduate students

1

Technicians

1（２）Research objectives
The aim of this unit is to address how cells appropriately respond to various environmental stresses
such as high osmolarity. Our research focuses on the stress-sensing mechanisms as well as theregulatory mechanisms of stress-activated MAP kinase (MAPK) signaling pathways. Our final goal is
to understand the molecular bases of cellular stress responses, for developing the technology to confer
environmental stress resistance to animals and plants to survive in severe environmental conditions
caused by global warming, and also for developing methods of treating human diseases such as cancer
and autoimmune diseases caused by dysregulation of the stress response machinery.
（３）Activity Reports
１）Research Activities
This division studied the cellular responses to extracellular stress stimuli including highosmolarity stress using budding yeast and mammalian cells with cell biological, biochemical, andmolecular genetic approaches. We focused on the sensing mechanism of high osmolarity in theosmoregulatory Hog1 MAPK pathway of Saccharomyces cerevisiae, to identify the interaction sitesof the transmembrane osmo-sensors Sho1 and Opy2 by biochemical and genetic analyses. This
study was published in PLOS ONE later (Takayama et al. 2019).
２）Education Activities
The unit member supervised a graduate student, served as a member of the evaluation committees
for the assessment of PhD or MA theses and dissertations, and gave the lectures of molecular andcellular biology at the graduate school of Science, the University of Tokyo. In addition, the unit
member was engaged in health and safety education for the students of this institute as a managerof the health and safety office.
３）Social Activities
None.
４）International Activities
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None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
This division has completed and closed as of March 31, 2017.

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Division of Neuronal Network（１）Members
Professor

Toshiya Manabe

Assistant Professors

Shizuka Kobayashi, Takahiko Chimura

Technicians

2（２）Research Objectives
The objective of this Division is to elucidate the function of nervous systems and to publish at least
three papers per year in the related research field.
（３）Activity Reports
１）Research Activities
In Division of Neuronal Network, we have examined synaptic functions and learning andmemory to elucidate the mechanism of higher brain functions in the field of neuroscience. From
April of 2016 to March of 2019, the aim of this Division was to elucidate the function ofneurotransmitters and their receptors, signal transduction molecules and adhesion molecules that
regulate properties of the central nervous system and to publish about three papers per year within
the period. As concrete outcomes, we have published the papers on the topics as follows: (1) The
role of cytomatrix at the active zone structural protein (CAST) in neurotransmitter release(Kobayashi et al., Eur. J. Neurosci. 44:2272-2284, 2016); (2) The role of Rho GTPase activating
protein 33 (ARHGAP33) in the traffic of receptor tropomyosin-related kinase B (TrkB) (Nakazawa
et al., Nat. Commun. 7:10594, 2016); (3) The role of ARHGAP32 isoform 1 (PX-RICS) in thetransport of γ-aminobutyric acid type B (GABAB) receptors in autistic spectrum disorders(Nakamura et al., Nat. Commun. 7:10861, 2016); (4) The role of the phosphorylation ofsynaptosomal-associated protein of 25 kDa (SNAP-25) in the regulation of neurotransmitter release(Katayama et al., Sci. Rep. 7:7996, 2017); (5) The role of cyclin-dependent kinase-like 5 (CDKL5)
in the localization of the GluN2B subunit of N-methyl-D-aspartate (NMDA) receptors inneurodevelopmental disorders such as West syndrome (Okuda et al., Neurobiol. Dis. 106:158-170,
2017); (6) The role of cadherin 11 in the development of the middle ear (Kiyama et al., Lab. Invest.
98:1364-1374, 2018); (7) The effect of ketamine metabolites in depression that is not mediated by
the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Yanget al., Biol. Psychiat. 84:591-600, 2018); (8) The role of the Toll-like receptor 3 (TLR3)mechanistic target of rapamycin (mTOR) system in the infection of herpes viruses (Sato et al., Nat.
Immunol. 19:1071-1082, 2018); (9) The role of lemur tyrosine kinase 3 (LMTK3) in the transportof AMPA receptors in the abnormality of behaviors (Montrose et al., Neuroscience 414:154-167,86G12019). Through these studies, we believe that Division of Neuronal Network contributes
considerably to this research field, and the aim of this Division has sufficiently been fulfilled.
２）Education Activities
In the Faculty of Medicine, we have given lectures and evaluated theses at the graduate school.
We have also undertaken teaching of young scientists.
３）Social Activities
None.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and Future Prospects
We would like to carry on further analysis of other functional molecules and publish more papers.
Currently, we are examining important functional molecules and would like to contribute further tothis research field.

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Division of Cell Signaling and Molecular Medicine（１）Members
Professor

Mutsuhiro Takekawa

Assistant Professors

Yuji Kubota, Takanori Nakamura

Postdocs

1

Graduate students

11Technicians

2

Others1（２）Research objectives
The ongoing research projects in this Division are aimed at elucidating the regulatory mechanismsof biological signal transduction systems such as MAP kinase cascades and stress granules that are
responsible for cell-fate decisions. Perturbation of these critical signaling systems is involved in avariety of life-threatening diseases including cancer, autoimmune diseases, neurodegenerative
disorders, and type 2 diabetes. This Division also aims to develop new diagnostic and/or therapeutic
tools for currently intractable disorders in which these pathways are involved.
（３）Activity Reports
１）Research Activities
Our research is focused on intracellular signal transduction systems that dictate cell fate decisions
such as cell proliferation, differentiation, survival and death. In particular, over the evaluation
period we studied the regulatory mechanisms of mammalian MAP kinase signaling pathways (i.e.,
ERK, p38 and JNK pathways) as well as stress granule signaling, and investigated the molecularbasis of human diseases including cancer, neurodegenerative disorders, and inflammation. Our
major achievements include the discovery of:• A novel human oxidative-stress sensor that mediates the delayed and sustained activation of the
p38 and JNK pathways and its role in proinflammatory cytokine production during respiratory burst
in macrophages (Science Advances, 2020).
• Oxidative stress-mediated abnormal suppression of stress granule formation and its role inneurogenerative diseases (Nat Commun., 2016).
• A novel role of MCRIP1, an ERK-substrate protein, in epigenetic regulation of lung surfactant
protein expression during embryonic development (Commun. Biol., 2019).
• Genomic loss of dual-specificity phosphatase 4 (DUSP4) in pancreatic and colonic cancers and its
roles in tumor invasion and metastasis (Cancer Res., 2016; Cancer Sci., 2018).
• Novel post-translational modifications, such as phosphorylation and SUMOylation, of the MEK88G1

MAPKK and its physiological relevance (Proteomics, 2016; Methods Mol. Biol., 2017).
• A novel method (i.e., WGA-based lectin affinity gel electrophoresis) for the quantitative detectionof O-GlcNAc modified proteins in cells (PLoS ONE, 2017; Bio-protocol, 2018).
• A new MEK inhibitor produced by Streptomyces sp. and its application as an anti-cancer drug (JAntibiot. 2018)２）Education Activities
We have supervised approximately 25 graduate students (in master and doctor courses) from threedifferent graduate schools at the University of Tokyo: the Graduate School of Science; the Graduate
School of Frontier Science; and the Graduate School of Medicine. A number of these graduate
students were awarded prizes in sevral scientific meetings.

We have also contributed to theeducation of undergraduate and graduate students not only at the University of Tokyo but also atother universities by lecturing in the biomedical sciences.
３）Social Activities
We have promoted joint research with pharmaceutical companies with the aim of developing new
diagnostic tools for human diseases.
４）International Activities
We have carried out international collaborations with the US and with European countries
including the UK and France, and have hosted an international symposium entitled “FirstInternational symposium on Interdisciplinary Approaches to Integrative Understanding ofBiological Signaling Networks” in Tokyo in 2019.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
We will continue to pursue not only original basic biomedical research that clarifies molecularmechanisms of fundamental biological processes, but also translational research aimed at overcoming
human diseases. Since we have identified several signal transduction molecules that may be involvedin human diseases including cancer, we will explore their physiological and pathological roles at themolecular, cellular and organismal levels, and apply the findings to the development of effective
diagnostic and/or therapeutic tools.

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Human Genome Center
Director Satoru Miyano (-FY2019)
Acting Director Yuji Yamanashi (FY2020-)（１）Missions and Features
The mission of Human Genome Center is to promote human genome research and personalized
medicine. We manage the supercomputer system SHIROKANE, which support the medical and life
sciences' research activities in Japan and international collaborative research.
（２）Organization
Laboratory of Genome Database
Laboratory of DNA Information Analysis (-2020.3)
Laboratory of Molecular Medicine
Laboratory of Genome Technology
Laboratory of Sequence Analysis
Laboratory of Functional Analysis in Silico
Department of Public Policy
Division of Medical Data Informatics (2020-)
Division of Health Medical Intelligence (2020-)
Division of Metagenome Medicine (2020-)（３）Activity Reports
１）Research Activities
With the social implementation of genomic medicine, we have promoted personalized genomic
medicine based on genomic and medical information. To make a significant contribution to humansociety through the diagnosis, prevention and development of treatments for disease, we have beenin the following researches by utilizing the supercomputer for large-scale data analysis and theartificial intelligence technology to extract knowledge from big data; we are the pioneer in Japan.
In this context, we have taken the lead in ELSI issues. The Center as a whole publishes about 100
papers in a year, with several papers per year with IFs more than 30.
1. Promotion of next-generation genomic research for personalized genomic medicine andmedical informatics research: By utilizing ultra-speed sequencing technology, supercomputers, andartificial intelligence, we have made a number of remarkable achievements in cancer genome
research. Furthermore, we have developed information technologies based on supercomputers andartificial intelligence in order to promote researches for clinical sequencing and its implementation.
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We have conducted researches of medical informatics and based on the achievements we havetrained researchers and physicians who have skill to organize, analyze and translate genome andmedical information in personalized genomic medicine.
2. Public policy science for ethical, legal and social issues (ELSI): We have conducted researchon various issues that arise at the interface with society in promoting life science and medical
research. The understanding of the public and the construction of a social consensus on the
maximizing usage of personal genetic information are essential for the promotion of personalized
genomic medicine and advanced medical care. Therefore, through empirical and comparative policy
research, we have promoted researches on the prevention of misuse and abuse of personal genetic
information, disclosure of diseases and sharing patients and medical practitioners' decision-making
processes, access right to their own genome and medical information, and appropriately priced
health care, and made policy proposal based on the obtained results. A total of 10 commissioned
projects were carried out.
２）Education Activities
We have been conducting hands-on workshops for users of Human Genome Center's
supercomputer SHIROKANE about 10 times a year.
３）Social Activities
We have contributed to a total of 16 government committees related to ELSI and research ethics.
４）International Activities
We participated and contributed to the International Cancer Genome Consortium (ICGC).
５）Other matters to be noted
The number of users, which had been hovering around 500 in the past, exceeded 1,000 by
improving the operation of Human Genome Center's supercomputer SHIROKANE and improving
its services. We worked on power-saving operations of the supercomputer system, and as a result,contributed to the evaluation of power savings for the University of Tokyo.
（４）Challenges and Future prospects
By the integration of Health Intelligence Center into Human Genome Center, reorganization of thecenter that enables to create personalized medicine in the Society 5.0 era ahead of the world is theprimary issue. Based on this integration and renewal, we will address the following four areas.
1. The challenge of addressing important issues in cancer genomics, such as the unveilingmechanisms of generating cancer heterogeneity, and the development of fundamental infrastructure91

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for genomic data and data sharing.
2. Promoting artificial intelligence research for clinical translation of new dimensional genomic
information (integrated genomic information from human genome, commensal bacteria and virus
genomes).
3. Proceeding medical informatics research, which organizes, analyzes, and interprets new
dimensional genomic, medical, and health-related information and training researchers and physicians
who translate it for personalized medicine.
4. ELSI research addressing a variety of issues, which arise at the contact point between medical
research such as advanced medicine including new dimensional genomic medicine and society.

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Laboratory of DNA Information Analysis (-2020.3)
Laboratory of Genome Technology
Laboratory of Genome Database
Laboratory of Sequence Analysis
Division of Computational Science (Health Intelligence Center) (-2020.3)（１） Members
Professors

Satoru Miyano (-2020.3),
Tatsuhiro Shibata (Laboratory of Genome Technology) (2020.4-),
Kenta Nakai(Laboratory of Genome Database) (2020.4 -),Seiya Imoto (Laboratory of Sequence Analysis) (2020.4-)

Associate Professors

Rui Yamaguchi (Laboratory of DNA Information Analysis) (-2020.3),
Tetsuo Shibuya (Laboratory of Sequence Analysis)(-2020.3)

Assistant Professors

Yaozhong Zhang (Laboratory of DNA Information Analysis),
Kotoe Katayama (Laboratory of Sequence Analysis),
Chizu Tanikawa (Laboratory of Genome Technology),
Atsushi Niida (Division of Computational Science)

Project Assistant Professor Taku Onodera (Laboratory of Sequence Analysis)
Postdocs

5

Technicians

2

Others8（２）Research objectives
Technological innovations, including next-generation sequencers, have produced biomedical big
data with ultra-high dimensionality and heterogeneity. In particular, cancer genomics research has
become large-scale based on whole-genome sequencing of an individual. In this situation, the missionof four laboratories in HGC and one division in HIC directed by Miyano is to develop
computational/informatic strategy for medical informatics and proceed researches for the
implementation of personalized medicine by utilizing genomics, systems biology, supercomputing,and artificial intelligence.
（３）Activity Reports
１）Research Activities
In addition to the management expenses grants for Human Genome Center, we have obtainedcompetitive external funds to conduct research on the following subjects.
•

A commissioned project from MEXT, "Post K-Computer Priority Issue 2 - Integrated
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computational life science to support personalized and preventive medicine" (Core institute:
IMSUT, PI: Satoru Miyano)•

Grant-in-Aid for Scientific Research on Innovative Areas "Conquering Cancer through Neodimensional Systems Understanding" (N0. 4701) PI as a whole.

•

AMED Practical Research Project for Rare/Intractable Diseases. "Development of analysis
platform for understanding cause of intractable hematopoietic diseases and improving theirdiagnosis using omics analysis and artificial intelligence technologies" (PI: Satoru Miyano)•

Collaborative research on cancer genomics with other organizations•

Conducting clinical sequencing studies and medical informatics research (Collaboration with
Advanced Clinical Research Center, Health Intelligence Center, and IMSUT Hospital)•

Promotion of genomic medicine at Medical Genomics Research Initiative, The University ofTokyo.

•JST Center of Innovation Program "Self-Managing Healthy Society (The University ofTokyo)". We joined this project from 2015 and have promoted researches on clinical sequenceand metagenome analysis of intestinal microbiome. This project will be continued until
academic year of 2022.

•

Joint management of Health Intelligence Center (directed Division of Health Medical
Computer Science)•

Research to understand the cancer genome using AI (Utilizing Watson for Genomics andcollaborative research with Fujitsu Laboratory)•

Development of MYCODE by the collaborative research with DeNA Life Science, andpromotion of MYCODE Research, which is a research platform for internet cohort.
Researches funded by competitive external funds were evaluated and they are highly regarded.
From 2016 to 2018, we published about 50 papers per year and totally about 150 papers were

published in three years. In 2016, Satoru Miyano was awarded as a winner of the Uehara prize(Jointly awarded with Prof. Seishi Ogawa at Kyoto Univ., “Understanding molecular mechanism ofcancer by advanced genomics”).
２）Education Activities
As a cooperative laboratory of Department of Computer Science, Graduate School of Information
Science and Technology, we contributed to training of about 10 graduate students from 2016 to
2018, who are now working in academia and industry with keeping high activity.
３）Social Activities
In the project “Innovative AI Hospital System (Program Director: Prof. Yusuke Nakamura)” of94

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Cross-ministerial Strategic Innovation Promotion Program (SIP), Cabinet Office, Satoru Miyano isserved as a sub-Program Director and makes effort to promote the project. Also, Satoru Miyano isa member of “Cancer Genomic Medicine Consortium” of Ministry of Health, Labour and Welfare,and he manages office of a nonprofit organization “Health and Medical care Promotion(Chairperson of the board of directors; Prof. Hiroshi Shiku)” (board of director). Satoru Miyano has
been contributing to promote the collaborative research among industry, government and academia.
４）International Activities
As a member of International Cancer Genome Consortium (ICGC), we have been operating
Human Genome Center supercomputer system SHIROKANE as a computational resource. Thismethod of operation is a model for the six facilities that provide computational resources worldwide.
We collaborated with University of Chicago on joint research on cancer immunity and on a
symposium on big data analysis in the University of Tokyo's Strategic Partnership. The Center for
Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV) in Mexico andus have organized an annual hands-on seminar on bioinformatics and systems biology using
SHIROKANE. In addition, Boston University, Humboldt University, the University of Tokyo, andKyoto University have held the International Workshop on Bioinformatics and Systems Biology forstudents on a rotating basis since 2000. In 2016, we held this workshop at IMSUT. We have been
involved in discussions to create an international data sharing ecosystem (Anderson WP et al. Nature2017).
５）Other matters to be noted
None.
（４）Challenges and Future prospects
As Professor Miyano will be retiring at the end of March 2020, these four laboratories will follow
to the future vision of the Institute of Medical Science, the University of Tokyo. It may be a great loss
for the researchers and technical staffs who have been trained over a long period of time to leave
IMSUT, but it may be a necessary process for creating an innovative future.

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Laboratory of Molecular Medicine（１）Members
Professor

Tatsuhiro Shibata

Associate Professor

Atsushi Niida

Graduate students

1

Technicians

3（２）Research objectives
To discover novel therapeutic, diagnostic and prevention targets and molecular pathways, we will
perform comprehensive molecular-genomic analysis of intractable diseases including cancer that are
frequent and critical health issues in Japan and other Asian countries. Furthermore, we aim to discovernovel concepts and mechanisms in these diseases through the development of new bioinformatics tools
including machine-learning algorithms for analyzing multiple omics data and mathematical modeling.
（３）Activity Reports
１）Research Activities
Pan-Cancer Whole Genome analysis by the international consortium
As part of the International Cancer Genome Consortium (ICGC), we characterized mutationalsignatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome
sequences that encompass most types of cancer (5, 6). We identified 49 single-base-substitution, 11
doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion
signatures. We revealed associations of signatures to exogenous or endogenous exposures, as wellas to defective DNA-maintenance processes.
Metagenomic landscape in human colon carcinogenesis
We performed fecal metagenomic and metabolomic studies on samples from a large cohort of616 participants who underwent colonoscopy to assess taxonomic and functional characteristics ofgut microbiota and metabolites (8-10). Microbiome and metabolome shifts were apparent in casesof multiple polypoid adenomas and intra-mucosal carcinomas, in addition to more advanced lesions.
We found two distinct patterns of microbiome elevations. We also identified metagenomic andmetabolomic markers to discriminate cases of intra-mucosal carcinoma from the healthy controls.
Development and application of analytical informatics tools
We have developed a novel deep leaning algorithm to diagnose cancer types based on molecular
genetic alterations (7). We have developed an original simulating model for tumor evolution (1).
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G0Using our own pipelines for RNA sequencing data, we have assisted collaborative molecularresearches in our institute (2-4).
Epigenetic landscape of the liver cancer genome
We analyzed correlation between the occurrence of epigenetic features and genetic aberrations
by whole-genome bisulfite, whole-genome shotgun, long-read, and virus capture sequencing of 373
liver cancers.
References (selected publications in FY2019-present)
1.

Niida A, et al. A unified simulation model for understanding the diversity of cancer evolution.
PeerJ. 2020 Apr 8;8:e8842. doi: 10.7717/peerj.8842.

2.

Takeda R, et al. HHEX promotes myeloid transformation in cooperation with mutant ASXL1.
Blood. 2020 Jun 3:blood.2019004613. doi: 10.1182/blood.2019004613.

3.

Hirata M, et al. Integrated exome and RNA sequencing of dedifferentiated liposarcoma. Nat
Commun. 2019 Dec 12;10(1):5683. doi: 10.1038/s41467-019-13286-z.

4.

Hayashi Y, et al. Antitumor immunity augments the therapeutic effects of p53 activation on
acute myeloid leukemia. Nat Commun. 2019 Oct 25;10(1):4869. doi: 10.1038/s41467-01912555-1.

5.

Alexandrov LB, et al. The repertoire of mutational signatures in human cancer. Nature. 2020
Feb;578(7793):94-101. doi: 10.1038/s41586-020-1943-3.

6.

ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis ofwhole genomes. Nature. 2020 Feb;578(7793):82-93. doi: 10.1038/s41586-020-1969-6.

7.

Jiao W, et al. A deep learning system accurately classifies primary and metastatic cancers
using passenger mutation patterns. Nat Commun. 2020 Feb 5;11(1):728. doi:
10.1038/s41467-019-13825-8.

8.

Yachida S, et al. Metagenomic and metabolomic analyses reveal distinct stage-specificphenotypes of the gut microbiota in colorectal cancer. Nat Med. 2019 Jun;25(6):968-976. doi:
10.1038/s41591-019-0458-7.

9.

Thomas AM, et al. Metagenomic analysis of colorectal cancer datasets identifies cross-cohort
microbial diagnostic signatures and a link with choline degradation. Nat Med. 2019
Apr;25(4):667-678. doi: 10.1038/s41591-019-0405-7.

10. Wirbel J, et al. Meta-analysis of fecal metagenomes reveals global microbial signatures thatare specific for colorectal cancer. Nat Med. 2019 Apr;25(4):679-689. doi: 10.1038/s41591019-0406-6
２）Education Activities
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Teaching staff in World-leading INnovative Graduate Study Programs for Life Science andTechnology (WINGS LST)
Committee Member of the Life-Science Organization and Genome Medical Science Organizationin the University of Tokyo
３）Social Activities
None.
４）International Activities
Participation in the International Cancer genome Consortium (ICGC/ICGC-ARGO)
Participation in the Mutographs consortium by UK Sanger Institute and WHO IARC
５）Other matters to be noted
Organizing Committee Chair of the 49th International Symposium of the Princess Takamatsu
Cancer Research Fund
Committee member of the Promotion of Clinical Development for Rare Cancers under the
direction of the Pharmaceuticals and Medical Devices Agency (PMDA) Science Board（４）Challenges and Future prospects
We will further continue and expand molecular genomic analyses of the intractable diseases andattempt to discover novel therapeutic/diagnostic/prevention molecular targets. New activities include
mutational signature analysis for cancer prevention, mathematical modeling of tumor evolution for
diagnosis and new pathological views on tumor heterogeneity, single cell analysis and metagenomic
analysis for biomarker discovery and pathobiology of disease-associated immune system.

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Laboratory of Functional Analysis in Silico（１）Members
Professor

Kenta Nakai

Associate Professor

Sung-Joon Park

Project Assistant Professor

Luis Augusto Eijy Nagai

Graduate students

10Technicians

1

Others3（２）Research objectives
The research objective of this laboratory is to conduct computational (in silico) studies on thefunctional aspects of genome information. Thus, our scope includes the structural analysis of themolecular function of each gene product as well as the analysis of its regulatory information forunderstanding its cellular role, played through the inter-gene networks. Currently, we rather focus on
the analysis of gene regulatory information through the analyses of multiple types of NGS data, suchas ChIP-seq, Hi-C, WGBS, ATAC-seq and scRNA-seq.
（３）Activity Reports
１）Research Activities
In recent years, one of our major research interests was to understand how various kinds of
epigenetic features, including DNA methylation (CpG/CpH), histone marks, TADs and A/B
compartments, can specify cell type-specific gene expression. Similarly, we have also studied how
DNA sequences can specify such epigenetic information. Methodologically, we have sought thepossibility of finding new biologically-relevant discoveries from combined public data, which are
now quite plenty, though we have also been quite keen in promoting collaborative works with otherlabs. As for our quantitative targets from April 2016 to March 2020, we have set them as 1) topublish original research papers, either the first author or the corresponding author of which is a lab
member; and 2) to publish at least one paper in a journal with its impact factor equal to or more than
10. The numbers of papers that satisfy the condition 1) were: 2-4-5-3 for the four years while thosethat satisfy the condition 2) were 0-3-1-0 (of the three papers for fiscal year 2017, two were
published in the database issue of Nucleic Acids Research, which might be regarded as exceptional;
in 2019, one paper was published in Dev. Cell (IF9.6)). Therefore, though we could (almost) succeed
on average while failed in several years. One of the situations that we can improve is that the topics
of our works may have been too diverged considering the size of our lab. Although it is importantto respect spontaneous research activity of each member, we should more focus on our major topics
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and enhance our mutual synergy. Since one of our staffs has been renewed recently and since thebackground of the staff has thus been switched from protein science to artificial intelligence, we
expect that more focused research activities would become possible.
２）Education Activities
In our lab, we accept graduate students from two departments: the department of computerscience in the graduate school of information science and technology, U. Tokyo and the departmentof computational biology and medical sciences in the graduate school of frontier sciences, U. Tokyo.
In total, the numbers of students who have succeeded in getting their Master and PhD degree,
respectively, in each fiscal year from 2016 to 2019 were: 1-2-1-3 for Master degree and 1-2-3-0 for
PhD degree. In addition, we have accepted 1-3-4-5 international internship students (from France
and India) from 2016 to 2019 (in 2020, one had to go back to his home country earlier and two
could not come because of the COVID-19 problem). It is noteworthy that we accept students froma variety of countries, which include China, Korea, Spain, Cuba, Brazil, Iran, and Malaysia. Thus,
considering the size of our lab, it can be said that our lab has contributed actively to education. Itshould be also added that Prof. Nakai has been a main contributor of the annual certification
examination program for technicians in bioinformatics, held by the Japanese Society of
Bioinformatics, for more than a decade.
３）Social Activities
So far, collaboration with private companies has not been so active but we have accepted several
graduate students who have their job position elsewhere (such as a pharmaceutical company).
Moreover, from May 2020, we have accepted a visiting researcher from another pharmaceuticalcompany.
４）International Activities
We have conducted several international collaborations. As a rather successful example, we
published a paper in Cell in 2017, through a collaboration with a group of Harvard University (atthat time). Notably, Prof. Nakai has been repeatedly elected as an ExCo member of APBioNet (Asia
Pacific Bioinformatics Network, which is an organization for fostering the growth of bioinformatics
in the Asia-Pacific region) for many years and have contributed to their activities. He has also been
taking responsibility in serving as a PC member (or sometimes as a co-chair) of various international
conferences, such as InCoB, BIBM, IWBBIO, GIW and APBC. He is on the editorial board of DNA
Research, PeerJ, and Mathematical Biosciences.

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５）Other matters to be noted
Prof. Nakai has served as a reviewer of several grants funded by national agencies, such as MEXT,
JST and AMED, as well as an external evaluation committee member of several institutions, such
as NIBIOHN. He has been a selection member of the young scientist award by the Ministry of
Education (MEXT).
（４）Challenges and Future prospects
We are aware that the amount of acquired external funding has been decreasing. Also, the numberof invited talks from major conferences is decreasing, too. The situation may improve because we are
now applying to several big grants but it seems to be a good opportunity to consider our new challenges.
As noted above, one important issue is to direct our diverged research activities to more focused ones.
Another is to take part into some leading international conferences in our field, knowing whatareregarded as the cutting-edge topics and advertising our activities.

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Department of Public Policy（１）Members
Professor

Kaori Muto

Associate Professor

Yusuke Inoue

Project Assistant Professor

Akiko Nagai

Postdocs

2

Graduate students

6

Others6（２）Research objectives
The Department of Public Policy aims to conduct theoretical, experimental, and policy research.
We respect the viewpoints of patients and the public with regard to the ethical, legal, and social
implications (ELSI) of the application in society of research results relevant to the fields of medical
studies and emerging technology. In terms of research ethics involving human participants and clinicalethics regarding decision-making in medical practice, we contribute to the society.
（３）Activity Reports
１）Research Activities
To date, the Department of Public Policy has conducted theoretical, experimental, and policy research
involving ELSI, research ethics, and clinical ethics. From April 2016 to March 2019, the goals for the
Department were to reconstruct ELSI research and research ethics, which tend to be biased toward
research ethics support as academic research. We have promoted collaborative research within Japan andabroad. During this period, the Department achieved a virtuous circle of research and support throughthe plan–do–check–act cycle, and substantial outcomes may be considered to have been obtained in theform of 27 European-language papers, 10 Japanese-language papers, and four textbooks published.
２）Education Activities
A total of five compulsory and elective subjects in the Graduate School of Frontier Sciences, two
required lectures in the Graduate School of Interdisciplinary Information Studies and one elective
subject in the College of Arts and Sciences were offered.
From April 2016 to March 2019, the Department produced two master’s candidates and one
doctoral candidate in the Graduate School of Frontier Sciences as well as three master’s and two
doctoral candidates in the Graduate School of Interdisciplinary Information Studies. Furthermore,
five postdoctoral researchers in the Department were promoted to researchers and faculty members
independently capable of research ethics support.
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Within the Institute of Medical Science, the Department cooperates in the management of the
Office of Research Ethics and contributes to its implementation of education and training involving
research ethics.
３）Social Activities
From April 2016 to March 2019, professors and associate professors of the Department of Public
Policy contributed to a total of 30 governmental and other committees on ELSI and research ethics.
They also contributed to the activities of academic associations across disciplines, such as the Japan
Association for Bioethics (director), Japanese Society of Health and Medical Sociology (director),
Japan Society of Human Genetics (councilor), Japan Association of Medical Law (director), andJapanese Society for Hygiene (councilor).
Moreover, the Department has conducted a total of six collaborative projects and research studies
with patient groups and support groups for cancer and intractable diseases.
４）International Activities
With regard to ELSI research and research ethics involving stem cell research and genomic medicine,
the Department is conducting collaborative research with the University of Edinburgh and the Universityof Oxford in the United Kingdom and with Seoul National University in South Korea and Monash
University in Australia.
５）Other matters to be noted
The Japan Agency for Medical Research and Development has commissioned the Department to
conduct a total of 10 projects involving medical ethics. Through the results, the Department hascontributed to research ethics consulting in Japan on issues including cancer, intractable diseases,
brain science, dementia, regenerative medicine, and genomic medicine. Furthermore, within theInstitute, the Department has provided support for the management of BioBank Japan in its ethicalaspects in addition to contributing to the administration of the Office of Research Ethics.
（４）Challenges and Future prospects
Although ELSI research and research ethics in Japan have not drawn much attention from academia
overseas, many topics, such as stem cell research, have garnered considerable interest abroad, andinternational collaborative research is beginning. The Department plans to work toward the realizationof leading large-scale international collaborative research projects.

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Division of Medical Data Informatics（１）Members
Professor

Tetsuo Shibuya

Postdocs

1

Graduate students

3

Technicians

1（２）Research objectives
Our objective is to develop fundamental data informatics technologies for medical data, such as big
data technologies, artificial intelligence, privacy preserving technologies, and algorithm theory.
Medical data, especially genome data are increasing exponentially in medical science from basics toclinical research. Our aim is to innovate the entire medical science with novel data informatics
solutions.
（３）Activity Reports
１）Research Activities
Our division started in March 2020. We are developing fast, accurate, and scalable algorithms foranalyses on large genome databases. We have developed a succinct data structure called BOSS for
genome assembly, which is used worldwide in various metagenome projects, including researches
on SARS-COV-2. We are also working on artificial intelligence and privacy preserving technologies
for analyzing clinical text data.
２）Education Activities
We had 5 students in 2019 and 2 of them graduated with master degrees. Currently we have 3
students. All the students are from department of computer science, graduate school of information
science and technology. We also give lectures at college of arts and sciences, and at department of
information science, faculty of science.
３）Social Activities
We are serving as the committee chair for the Bioinformatics Technician Certification Examsponsored by Japanese Society for Bioinformatics.
４）International Activities
None.

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５）Other matters to be noted
None.
（４）Challenges and Future prospects
The amount of medical data, especially genome data is still increasing rapidly. Currently weconsider data up to around the size of 100,000 individual genomes, but we suppose it could reach thecountry-wide size, which should be 1,000 times larger or more, around in next 10 years. We need next
generation data informatics technologies scalable to the size until then. In this point of view, data
informatics should be one of the keys to the next generation medical science. We are aiming tocontribute to the medical research from basics to clinics by supplying novel data informatics
technologies.

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Division of Health Medical Intelligence（１）Members
Professor

Seiya Imoto

Project Associate Professor

Yao-zhong Zhang

Assistant Professor

Kotoe Katayama

Graduate students

2Technicians

5

Others2（２）Research objectives
This division was started from April 2020 with the mission realizing genomic medicine based on
the integrated data from genomes of human and commensal microbes. Development of computational
data analysis methods including artificial intelligence for genomic, health, and medical big data is oneof our main focuses. We promote integrative analysis of human whole genome, RNA and other omics
data, commensal microbes including bacteriome and virome, and health and medical-related big data.
Furthermore, health medical intelligence aims at using the analysis results of such big data to create
personalized action plan of individuals.
（３）Activity Reports
１）Research Activities•

Development of omics data analysis methods for whole genome, transcriptome, epigenome,
proteome and metabolome especially in cancer researches. We were heavily involved in
ICGC/TCGA PanCancer Analysis of Whole Genomes (PCAWG) project and developed
several computational methods for cancer immunogenomics, such as HLA genotyping from
WGS, detection of neoantigen, and TCR repertoire analysis.

•

Implementation of genomic medicine by collaborative research with IMSUT hospital andAdvanced Clinical Research Center. Hematological and gastric cancers are our target. Using
artificial intelligence and supercomputer, we achieved 2 days and 16 hours of turn-around-time
when we apply WGS.

•

Development of artificial intelligence for interpreting the analysis results of human genome
and microbiome based on huge amount of literature information. For cancer genome, we
collaborate with Fujitsu Laboratory and developed an artificial intelligence to support
physicians to search for literature, which are useful to determine treatment plan and to assist
physicians to extract essential information from literature. We succeeded in showing this AI
can reduce the time physicians spent for this task to around half.
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•

Development of artificial intelligence for the analysis of long-read sequencing data produced
from cutting-edge sequencing technologies, e.g., Oxford Nanopore. Usually, long-readsequence data have more noise than short-read. Our developed U-net based neural network can
perform accurate base-calling.

•

Analysis of intestinal viruses, which are mostly bacteriophages. Although intestinal bacteria
have been analyzed in worldwide, intestinal bacteriophages are not well studied and recognizedas “viral dark matter”. Our interest covers the development of analysis methods for sequence
data derived from bacteriophages and unveiling host bacteria-parasite (bacteriophage)associations to implement next generation phage therapy.

•

Development of a computational method based on deep learning for the integrative analysis ofpathological image data and genomic sequencing data. We use TCGA data of multiple typesof cancers for this purpose. This is a collaborative research with researchers of Monash
University, Australia.

•

Health check-up data analysis integrated with genomic and microbiome data. We have received
15 years of health checkup data (approximately 30,000 records, WGS, intestinal and oral flora,
health checkup information, lifestyle habits, etc.) from Hirosaki University, and we aredeveloping a risk prediction model for lifestyle-related diseases.

•

In an effort to return analysis results to individuals, we are working with DeNA Life Sciencesthat conducts direct-to-consumer genetic testing MYCODE to analyze SNP information fromapproximately 100,000 users. We created a research platform called MYCODE Research topromote new research method on internet cohort.

•

SARS-Cov-2 virus genome and host human genome analysis. Prof. Imoto is a proposer of theCoronavirus Task Force (https://www.covid19-taskforce.jp/en/home/) and is served as aprincipal investigator of TCR analysis section of COVID-19 patients. The Coronavirus Task
Force is an on-going project. For SARS-Cov-2 virus genome, we have collected the sequences
obtained from COVID-19 patients from GISAID database and now (July 2020) more than
68,000. We focus on the diversity of viral sequences changing over time and across places.

•

Risk assessment of mass-gathering events in With-Corona era is now an important issue. We
collaborate with researchers who are experts in exposure analysis of environmental field. We
are performing simulations to assess the risk of infection and the effectiveness of each ofactions for prevention.

２）Education Activities
Accepting graduate students from Department of Computer Science (2 in 2020); and we provide
research guidance related to bioinformatics. We also provide training to motivated graduate students
who want to study bioinformatics in experimental laboratories (several students each year). We
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provided several bioinformatics related lectures to graduate and undergraduate students in the
University of Tokyo. Undergraduate students at the University of Tokyo who are interested in data
science are asked to visit the laboratory on a regular basis for guidance. We also provide the JapaneseSociety of Internal Medicine's Educational Lecture Series in 2020.
３）Social Activities•

Chairman of the third annual meeting of Japanese Medical AI Society (29-30 January
2021 (In the second meeting, more than 1,000 participants we have. The third one is now
planed as on-line style))•

A mediator of IBM Fuji Meeting•

Vice chancellor of Hitachi Academic System Society４）International Activities•

ICGC/TCGA PanCancer Analysis of Whole Genomes (PCAWG)•

Collaborative research with Center for Research and Advanced Studies, Mexico (Prof.
Martha Espinosa-Cantellano) was accepted and supported by the IMSUT International
Joint Research Center’s project (2019 and 2020)•

Collaborative research with China Medical University, Taiwan Genome Project (Dr. RoTing Lin) was accepted and supported by the IMSUT International Joint ResearchCenter’s project (2020)•

Collaborative research with Monash University (Assc. Prof. Jiangning Song) for Imageand Genome Analysis was started.

•

Intestinal microbiome research with Boston Brigham and Women's Hospital, UC San
Diego, and Pasteur Institute.

•

Bioinformatics education program with Japan (Kyoto University and us), USA (Boston
University), Germany (Humboldt-Universität zu Berlin, etc.)

５）Other matters to be noted•

Presentation and Panel Discussion at Tokyo Forum 2019’s session “Healthy Aging
Society”•

Press Releases (from April 2020)➢

with Osaka City Univ about the Cell Host & Microbe paper of intestinal microbe
project in July 2020➢

with Corona Task Force about COVID-19 study May 2020

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（４）Challenges and Future prospects
By COVID-19, we recognize that we are facing with a global crisis. We address several issues
related with COVID-19 such as viral sequence analysis, patients’ immune response analysis based on
genomic data, vaccine development and risk assessment of mass-gathering events by simulations. The
completion of these studies as soon as possible is essential for the normalization of research activities
and life. The current genomic medicine especially for cancer genomic medicine in Japan is limited inpanel sequence analysis. On the other hand, we have been promoting the use of whole genome
sequencing data for obtaining more accurate diagnosis and treatment plan. Although we have obtained
several achievements based on the current studies, for expanding genomic medicine to other diseases
than cancer, we consider the use of the information of commensal microbes are important. We call a
genomic medicine based on the integrated data of human genomic and medical data and informationof commensal microbe new dimension genomic medicine, which we will promote in the next five
years. Also, by considering with Post-Corona era, bringing pathological microbiota from abroad is aserious issue of Japan, especially for multi-agent resistant bacteria (MAR), which are generated byindiscriminate use of anti-bacterial drugs. WHO estimated that the number of death by MAR will begreater than that by cancers in 2050. By extending the achievement of our Cell Host & Microbe paper(we showed that prophage enzyme, endolysin, determined by metagenome sequencing data can kill C.
difficile specifically), we will compile phage-derived enzymes that can kill pathological bacteria
specifically and create next generation phage therapy for MAR.

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Division of Metagenome Medicine（１）Members
Project Professor

Satoshi Uematsu

Project Assistant Professor

Kosuke Fujimoto

Technicians

1

Others2（２）Research objectives１）Construction of a database of intestinal bacteria and virus in healthy subjects２）Development of therapeutic methods for dysbiosis-related diseases by metagenomic analysis（３）Activity Reports
１）Research Activities
1. Construction of a database of intestinal bacteria and virus in healthy subjects
In collaboration with Professor Seiya Imoto at the Human Genome Center, we are constructing an
ultra-high-speed analysis pipeline for intestinal bacteriome and virome by using IMSUTSupercomputer Shirokane. Using this pipeline, we are analyzing the stools of Japanese healthypeople and creating the world's first database of intestinal bacteriome and virome in the same stool.
Many enteric viruses are bacteriophages that infect enterobacteria, and we are also advancing hostidentification of bacteriophages based on sequence data. We are building the basis for a newbacteriophage therapy that can control intestinal bacteria.
2. Development of therapeutic methods for dysbiosis-related diseases by metagenomic analysis
In recent years, dysbiosis is present not only in intestinal diseases such as inflammatory bowel
disease, but also in autoimmune diseases, diabetes, cardiovascular diseases, and autism, and it isclear that they are closely related to the pathological condition. have become. Our laboratory
conducts metagenomic analysis of intestinal bacteria and viruses in dysbiosis-related diseases, andis engaged in searching for microorganisms related to pathological conditions and developing new
therapeutic methods.
２）Education Activities
We accept 3 PhD students at the dual post.
３）Social Activities
We are collaborating with EA Pharma Co., Ltd and Meiji Co., Ltd.

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４）International Activities
IMSUT has signed an agreement with the Pasteur Institute to create a joint unit for both parties.
Prof. James Di Santo, the counterpart of the other party, made the joint research contract together
with us. We are now conducting a joint research project to analyze the nasal microflora of allergic
patients in France.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
A database of intestinal flora and virus flora will be published. In the future, it will be necessary tocontrol intestinal bacteria using phages for various diseases. In addition, we believe that phage therapy
will be an indispensable treatment method against multidrug-resistant bacteria, which has become a
global problem. We think that it is necessary to carry out social implementation of phage therapy inJapan and, if possible, to establish a center in the Institute of Medical Science to practice phage therapy.

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Center for Experimental Medicine and Systems Biology
Director Yasuhiro Yamada（１）Missions and Features
The Center for Experimental Medicine and Systems Biology was established in 2007, renewed fromThe Center for Experimental Medicine organized in 1998. The current center consists of ﬁvelaboratories, Division of Stem Cell Pathology, Division of Genome Engineering, Laboratory of Innate
Immunity, Laboratory of Reproductive Systems Biology, and Laboratory of Genetically Engineered
Mouse Research.
Although an accurate and complete genome sequence of various organisms have been madeavailable, the function of genes, the epigenetic mechanisms that control gene expressions, the role ofgenomic elements, including non-coding elements, are not fully understood, especially at anorganismal level. The purposes of the center are to establish in vivo experimental platforms for various
research ﬁelds and develop animal models for investigating human diseases. Our center has a mission
to provide scientists at IMSUT and other academic institutes with genetically-engineered rodent
models for studying various aspects of biology as well as human diseases. Our eﬀort should promote
the interdisciplinary research that connects a wide range of research ﬁelds, including stem cell biology,
immunology, and cancer biology, which eventually contributes to the development of novel therapies
for human diseases.
（２）Organization
Division of Stem Cell Pathology
Laboratory of Innate Immunity
Laboratory of Reproductive Systems Biology
Division of Genome Engineering
Laboratory of Genetically Engineered Mouse ResearchLaboratory of Developmental Genetics (-2018.3)
Laboratory of Systems Biology (-2019.3)（３）Activity Reports
１）Research Activities
We have generated and provided genetically-engineered mouse models for scientists at IMSUT
as well as other academic institutes. We also provided various mouse models as a member of theAdvanced Animal Model Support, which is supported by Grant-in-Aid for Scientific Research on
Innovative Areas Platforms for Advanced Technologies and Research Resources from MEXT.
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The following is a summary of genetically-engineered mouse models that we provided during
the past four years.
FY 2016: 54
FY 2017: 14
FY 2018: 20
FY 2019: 34
Our center is also developing novel technologies for establishing advanced animal models forbiomedical research. For example, we devised doxycycline-inducible Cas9 platforms that
efficiently enable conditional genome editing at multiple loci in adult mice.
２）Education Activities
Our center has hosted training of genome-editing in mouse embryos and gene targeting in mouse
ES cells for young researchers and graduate students at IMSUT as well as other academic institutes.
Laboratories/Divisions in Center for Experimental Medicine and Systems Biology have accepted
master course and PhD course students in Graduate School of Medicine, Graduate School of
Frontier Sciences, and Graduate School of Sciences.
３）Social Activities
None.
４）International Activities
Researchers in our center are actively conducting international collaborative projects, including
collaborations with investigators at Harvard University, Johns Hopkins University, UCLA, and Max
Planck Institute.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
Genetically-engineered mice have oﬀered the opportunities of not only analyzing the complex genefunction in vivo, but also providing various human disease models, with which new therapeutic
approaches can be explored. In April 2020, Division of Stem Cell Pathology, Laboratory of
Reproductive Systems Biology, and Division of Genome Engineering established a core team tofurther facilitate generation of genetically-engineered mice and rats. The team takes advantage of theembryo engineering technologies as well as genome editing technologies to devise the in vivo
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experimental systems that link the basic science and medicine. The team will provide scientists at
IMSUT and other academic institutes with advanced animal models. To further promote the activity,
we will also develop technologies for rapid, efficient, and complex genome editing in rodents.

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Laboratory of Developmental Genetics (-2018.3)（１）Members
Professor

Nobuaki Yoshida

Associate Professor

Hirotake Ichise

Assistant Professor

Taeko Ichise

Postdocs

1

Graduate students

1

Technicians

2

Others2（２）Research objectives
Medium- to a long-term goal: To create gene manipulated mice by developmental engineering
technology, to clarify the mechanism of homeostasis maintenance in the living body, paying particularattention to lymphatic vessel development, immune function, and spermatogenesis.
Short-term Goal: To publish about 10 original papers during the period from 2016 to the end of thelab-closing in 2018.
（３）Activity Reports
１）Research Activities
The objectives of our lab are to elucidate the homeostasis maintenance mechanism of the living
body, especially on lymphatic vessel development, immune function, and spermatogenesis by using
gene manipulated mice. We also run many joint researches through the development and provisionof gene manipulated mice.
From April 2016 to March 2018, when our lab has closed, the goal of our lab is to elucidate themolecular basis of B cell antibody production by analyzing of alternative splicing and histone
epigenetics, development mechanism of lymphatic vessels, and to find out essential genes and theirmolecular roles that maintain sustainable spermatogenesis. We aimed to achieve at least 10
publications within the period. Also, we aimed to set up a genome-editing technique by
CRISPR/Cas9 using fertilized embryo, e.g., inducing indel mutation, short nucleotide
recombination using ssODN, or insertion of large cassette sequences using dsODN.
The number of papers we have published was seven in 2016, but no original paper was publishedin 2017. Therefore, it cannot be said that the achievement of the outcome was sufficient comparedwith the initial goal. The reason for this is that the number of postdocs and graduate students
decreased in 2017 because of lab closing in the next year, 2018. On the other hand, in 2019, after
the lab closed, two ongoing projects were published as original papers, so we believe that we have
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almost reached the goal finally. On the other hand, regarding genome editing with CRISPR/Cas9,
13 strains of indel loss-of-function mutation mice, and 3 strains SNPs-edited mice using ssODN
were developed during the period. On the other hand, the insertion of large cassette using dsODN
could not be developed so far. Thus, it cannot say that the initial goal could be achieved. This might
because genome editing of fertilized eggs by CRISPR/Cas9, especially for large sequence knockin, was in a start-up phase and it needs to be optimized.
２）Education Activities
For graduate student education, we encourage students to acquire techniques to develop genemanipulation mice that our lab is good at and to be a person who can discover and solve problemsby themselves through research. The goal of the master’s program is to develop at least one genemanipulated mouse line and have one oral presentation in any academic meetings until they finish
their degrees.
From 2016 to 2019, one Ph.D. student has received a doctor’s degree, and a master course student
is currently in the second year. The students who finished the doctoral program presented her
research results by an oral presentation in 2018, thus she could achieve the goal. On the other hand,a master's student, so far, has not presented in an academic conference. One of the reasons for thisis that the time to submit the abstract of the academic conference coincided with the peak period of
job hunting, and he could not have enough time to prepare his data.
３）Social Activities
None.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
This Laboratory has completed and closed as of March 31, 2018.

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Division of Stem Cell Pathology（１）Members
Professor

Yasuhiro Yamada

Assistant Professor

Sho Ohta

Postdocs

2

Graduate students

9Technicians

3

Others1（２）Research objectives
Epigenetic regulation involving multiple chemical modifications plays critical roles during
mammalian development and ensures stable gene expression, which is required for maintenance of
cellular identity. In addition, alterations in epigenetic modifications have been observed in many
diseases such as cancers. Our research focuses on studying the epigenetic regulation in various
biological aspects in multicellular organisms. Particularly, taking advantage of mouse genetics and iPS
cell technology in combination with genome-wide analysis of epigenetic modifications, we areinvestigating the role of epigenetic regulation on the cellular differentiation, the maintenance of
cellular identity, and the pathogenesis including age-related diseases such as cancer at the organismallevel.
（３）Activity Reports
１）Research Activities
Since its inception on December 2017, Division of Stem Cell Pathology has investigated the roleof epigenetic regulation in various biological aspects in multicellular organisms, including
mammalian development and diseases. The following are major research achievements:a) Distinct responses to cellular senescence determine cell type-specificity of cancer development
Cell type-specificity of cancer development has long been recognized. We established induced
pluripotent stem cells (iPSCs) from murine clear cell sarcoma (CCS) cells harboring cancerassociated genetic abnormalities and generated sarcoma-iPSC mice. Sarcoma-iPSC mice developed
secondary sarcomas only in soft tissue but exhibited oncogene-induced senescence in the othertissues. We showed that cell type-specific enhancers play a critical role in cell type-specificinduction of senescence. We propose that distinct responses to premature senescence are the basis
for the cell type-specificity of cancer development. Nature Commun. 10(1):3999, 2019.

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b) Modeling pediatric brain cancer using human iPS cells
Atypical teratoid/rhabdoid tumor (AT/RT), which harbors SMARCB1 mutation and exhibits acharacteristic histology of rhabdoid cells, has a poor prognosis. We established human SMARCB1deficient pluripotent stem cells (hPSCs). SMARCB1-deficient hPSCs efficiently gave rise to
AT/RT-like brain tumors in the mouse brain. We found that activation of an embryonic stem cell
(ESC)-like signature confers a rhabdoid histology and causes a poor prognosis. SMARCB1deficient hPSCs offer the human models for AT/RT, which uncover the role of the activated ESClike signature in the poor prognosis and unique histology of AT/RT. Cell Reports. 26, 2608–2621,
2019.
c) Unveiling epigenetic abnormalities in pluripotent stem cells
Imprinting control regions (ICRs) are protected from de novo methylation in somatic cells. We
conducted a comprehensive analysis of ICR methylation during somatic cell reprogramming. We
found that several ICRs are often de novo methylated in reprogrammed pluripotent stem cells(PSCs). Mechanistically, ablation of Dnmt3a prevented PSCs from de novo ICR methylation.
Notably, the ICR-preferred DNA hypermethylation was observed in pediatric cancers, while adultcancers exhibit genome-wide DNA hypermethylation. These results may have important
implications in the pathogenesis of pediatric cancers and the application of PSCs. Stem Cell Reports.
12(5):1113-1128, 2019.
d) In vivo reprogramming drives pancreatic cancer
The faithful shutdown of the somatic program occurs in the early stage of reprogramming. We
showed that the transient expression of reprogramming factors in pancreatic acinar cells results inthe transient repression of acinar cell enhancers, which are similarly observed in pancreatitis.
Notably, the transient expression of reprogramming factors in Kras mutant mice was sufficient to
induce rapid formation of pancreatic ductal adenocarcinoma. In contrast, the forced expression ofacinar cell-related transcription factors inhibited development of precancerous lesions in Krasmutated acinar cells. These results underscore a crucial role of dedifferentiation-associatedepigenetic regulations in the initiation of pancreatic cancers. Nature Commun. 9(1):2081, 2018.
２）Education Activities
During the period from December 2017 to March 2019, we accepted graduate students from
Kyoto University where Prof. Yamada belonged to before December 2017. During the period, one
PhD student received a degree. This doctoral study (Cell Reports. 26, 2608–2621, 2019) was highly
evaluated and the student won the award at the Japan Brain Oncology Society. In addition, twomaster's degree students completed the course and entered the doctoral course in 2019, continuing
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their research in this field.
３）Social Activities
Prof. Yamada is a member of Science Council of Japan, a councilor of Japanese Cancer
Association, The Japanese Society of Pathology, and The Japanese Society for Epigenetics.
４）International Activities
A joint project with Prof. Miguel Esteban at Chinese Academy of Sciences (CAS) is currently
ongoing as a JSPS-CAS joint program (Project title: Molecular roadmap of in vivo reprogrammingat the single-cell level). Our group is also collaborating with investigators at Harvard University,
UCLA, and Max Plank Institute. Prof. Yamada is a member of publication committee ofInternational Society for Stem Cell Research (ISSCR) and a Board Member of Cancer Research, anofficial journal of the American Association for Cancer Research (AACR). Prof. Yamada coorganized Stem Cell Crossroads, a Cold Spring Harbor Asia (CSHA) meeting in 2018.
５）Other matters to be noted
In April 2020, Division of Stem Cell Pathology, together with Laboratory of Reproductive
Systems Biology and Division of Genome Engineering, established a core team to facilitate
generation of genetically-engineered rodents.
（４）Challenges and Future prospects
We will investigate the role of epigenetic regulation on the cellular differentiation, the maintenanceof cellular identity, and the pathogenesis including age-related diseases such as cancer at theorganismal level. We will try to develop a novel therapeutic approach targeting epigenetic regulation
to treat patients.
As a member of Center for Experimental Medicine and Systems Biology, we will contribute toscientists at IMSUT and other academic institutes through providing advanced animal models. To
achieve this, we will develop technologies for efficient and complex genome editing in rodents.

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Laboratory of Innate Immunity（１）Members
Professor

Kensuke Miyake

Associate Professor

Shin-ichiroh Saitoh

Assistant Professors

Ryutaro Fukui, Takuma Shibata

Project Assistant Professor Ryota Sato
Graduate students

7

Technical assistants

3

Others1（２）Research objectives
Laboratory of Innate Immunity focuses on Toll-like receptor (TLR), pathogen sensors in the
innate immune system. We would like to understand molecular mechanisms controlling pathogen
sensing and TLR responses. We also would like to understand cellular and molecular mechanisms
by which TLRs drive inflammatory diseases and to develop a novel therapy targeting TLRs tocontrol such TLR-dependent diseases. Since April 2016 to March 2019, we tried to publish papers
on the relationship between TLR trafficking and type I interferon production. We will focus on
single stranded RNA sensor TLR7 and double stranded RNA sensor TLR3. We also tried to publish
a paper and file a patent on the control of autoimmune and inflammatory diseases with a monoclonal
antibody to TLR9. As for education, we tried to train graduate students in our laboratory and bygive lectures.
（３）Activity Reports
１）Research Activities
We published 28 papers including a paper in Nat Immunol, 2 papers in Immunity, 3 papers in
Nat Commun, a paper in PNAS, and 3 reviews. We reported that TLR7 traffics from the perinuclear
region to the peripheral region beneath the plasma membrane to induce type I interferon (IFN) (S.
I. Saitoh et al., Nat Commun 8, 1592, 2017) TLR7-trafficking depends on a GTPase Arl8b. TLR3dependent type I IFN production, on the other hand, depends on Rab7a-dependent lysosomal
trafficking to the cell periphery. (R. Sato et al., Nat Immunol 19, 1071-1082, 2018) Furthermore,
we have established anti-mouse TLR9 monoclonal antibody (mAb), which is able to inhibit TLR9
responses. The anti-TLR9 mAb protects mice from TLR9-dependent lethal hepatitis caused by
TLR9 ligands (Y. Murakami et al., Sci Rep 7, 44042, 2017).
We also obtained a patent on anti-TLR7/8/9 mAb (Aug 1, 2018). Furthermore, 3 patents havebeen filed as below.
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1. Analyses of soluble TLR7 in human samples.
2. Anti-human TLR7 mAb
3. Anti-TLR9 mAb
２）Education Activities
Four students in master course and a student in PhD course finished their courses. Prof. Miyake
gave 6 lectures a year in Faculty of Sciences.
３）Social Activities
None.
４）International Activities
We are collaborating with Prof. Eicke Latz in Bonn University, Germany. A student in Bonn
Univ. came to our lab and she is going to work here for 2 and half years.
５）Other matters to be noted
Prof. Miyake is on the board of trustees of the Japanese Society of Immunology since Oct 2018.
（４）Challenges and Future prospects
We were able to publish a paper as aimed in the beginning of this term. We also filed and obtained
patents as planned. As for education, we trained graduate students in my laboratory and gave lectures.
In the next term, we would like to publish a paper on the relationship between TLR7 and histiocytosis.
In parallel, we would like to develop anti-human TLR mAb for the control of an autoimmune disease
in collaboration with a pharmaceutical company. The goal of our research is to understand molecularmechanisms behind pathogen sensing by TLRs, and roles of TLRs in human autoimmune diseases.
For education, we would like to have all the graduate students to finish their master or PhD courses.

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Laboratory of Reproductive Systems Biology（１）Members
Professor

Masahito Ikawa

Associate Professor

Manabu Ozawa

Postdocs

1（２）Research objectives
Germ cells, i.e., sperms and eggs, are unique types of cells that are differentiated only for the
purpose to transfer genetic information to the next generation. The research aims of our laboratory are
to clarify the molecular system of how germ cells are developed, maintained, or fertilized to make a
new generation. Also, based on the basic information obtained from animal models, we also aimed touncover the causes of human infertility and develop therapeutic methods.
（３）Activity Reports
１）Research Activities
So far, our laboratory has conducted research to elucidate mechanisms that orchestrates germ cell
development, spermatogenesis, and fertilization in mammals. Also, since our laboratory is a core
member of the "Gene Manipulated Mouse Section", which is the core laboratory of the IMSUT, wehave carried out many collaborative researches with other fields through making gene-manipulated
mice.
From April 2016 to March 2019, the goal of our lab is to elucidate the molecular basis that
regulates continuous spermatogenesis or fertilization by using genome-editing mice models and toachieve at least 5 publications or 15 publications per each year or throughout the period, respectively.
In addition, we are trying to develop gene manipulated mice 20 or more annually on average in“Gene Manipulated Mouse Section”, and to develop 60 or more mice line during the period.
The actual number of original papers published was 4 in FY2016, 3 in FY2017, and 9 in FY2018,
and the total number of original papers are considered to have been sufficiently achieved the initialgoal. On the other hand, in FY2016 and FY2017, we could not reach the target of more than 5
publications within the year. The reason is that 2016 was the year in which the laboratory was started
up, and many research projects had just begun. It is expected that the results of those research
projects will come out in the near future, so we will continue to research with the goal of more than
5 original papers per year. The activities of the “Gene Manipulated Mouse Section” were 54 in
FY2016, 14 in FY2017, and 20 in FY2018. Therefore, we believe that we could achieve the initial
goal in total. On the other hand, the number of preparations in FY2017 did not reach the annual
target number. This might because genome editing of fertilized eggs by CRISPR/Cas9 was in a start122

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up phase and it took time to optimize it. Since the technology is currently tuned-up for developing
gene-editing mice stably, we will continue to support collaboration with similar goals at the
beginning.
２）Education Activities
For graduate student education, we encourage students to acquire techniques to develop genemanipulation mice that our lab is good at and to be a person who can discover and solve problemsby themselves through research. The goal is to have at least one oral presentation in an academic
meeting until they finish their degrees.
During this period, one Ph.D. student has received a doctor’s degree, and a master's student iscurrently in the second year. The students who finished the doctoral program presented her research
results by oral presentation in 2018, thus she could achieve her goals. On the other hand, a master's
student has, so far, has not presented at academic conferences. One of the reasons for this is that thetime to submit the abstract of the academic conference coincided with the peak period of job hunting,and he could not have enough time to prepare.
For future improvement, we will encourage students to have a strong awareness of conference
presentations from the beginning of the research.
３）Social Activities
None.
４）International Activities
We are actively promoting collaborative research with overseas laboratories, mainly bydeveloping and providing gene manipulated mice lines. From 2016 to 2019, we provided genemanipulated mice to four American laboratories as joint research. We will continue to actively
promote international collaboration.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
As a short-term goal, we aim to consistently publish more than 5 original papers annually on average.
Also, as a medium- to a long-term goal, we aim to uncover the entire development and fertilizationof mammalian germ cells using gene manipulated mice model. Furthermore, in the future, we will
promote joint research with the clinical field for human medical applications.

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Laboratory of Systems Biology (-2019.3)（１）Members
Associate Professor

Susumu Nakae

Postdocs

1

Graduate students

1

Technicians

1

Others2（２）Research objectives
Our research focus is the understanding of the pathogenesis of rejection and immune disorders suchas allergy and autoimmunity using gene-modified mice.
（３）Activity Reports
１）Research Activities
The goal from April, 2016 to March, 2019 is that we investigate the role of certain cytokines inthe development of allergic disorders such as asthma and dermatitis, and autoimmune disorders
such as arthritis and aortitis. The goal of the outcome is to publish one paper each year as acorresponding author by the researcher of our laboratory. In fact, we reported 9 publications as acorresponding author, and 27 publications (19: Japan and 8: other countries) as collaborators during
the period. Thus, in terms of the number of published papers, we achieved more than the goal.
Regarding the quality of publications, one of the 9 reports was published in the journal with <10
impact factor. In terms of this, we will improve the research environment so that we can report morehigh-quality researches.
２）Education Activities
Three students of master’s course (at Graduate School of Frontier Sciences, The University ofTokyo) and 3 students of PhD course (at other universities except The University of Tokyo)
conducted researches in our laboratory from April, 2016 to March, 2019. Two of master’s course
had completed their master’s degree, and then, got a job at a pharmaceutical company and national
institute, respectively. One of master’s course got a job without completing master’s degree.
PhD students have to publish their thesis reports in international journals during the period ofthesis to obtain a PhD degree. Two of PhD course published it during the period of thesis, and hadcompleted their PhD degree. Although one of PhD course could not publish it during the period ofthesis, he finally had completed PhD degree after publication of the thesis report.
To publish the PhD thesis report during the period of thesis (3-4 years), we are sometimes forced
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to reduce the quality of research to prioritize the acceptance of articles in international journals. To
avoid such situation, we will establish a system that enables an efficient instruction.
３）Social Activities
None.
４）International Activities
9 publications with collaborators in US, Euro and Korea from April, 2016 to March, 2019.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
This Laboratory has completed and closed as of March 31, 2019.

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Division of Genome Engineering（１）Members
Professor

Tomoji Mashimo

Senior Assistant Professor

Kazuto Yoshimi

Technicians

1（２）Research objectives
Genome engineering technologies, such as Zinc finger nucleases (ZFNs), TAL effector nucleases(TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas)
nucleases (CRISPR/Cas), have been widely used in life science and medical science. Now, we aredeveloping novel genome editing tools, such as CRISPR-cas3, which can overcome the limitations ofcurrent technology. Utilizing the different genome-editing tools, we are also developing the efficientgenome editing strategies, which can modify different genes in various living organisms with highefficiency.
（３）Activity Reports
１）Research Activities
The genome editing system could be powerful tools for development of effective cancer treatment.
We have reported that genome editing using Class 1 CRISPR-Cas3 system is possible in humancells as a novel independent genome editing technology from Class 2 CRISPR-Cas9 system. We
also established a new combinational method of NHEJ and HDR mediated by the CRISPR-Cas9
system, named Combi-CRISPR, which facilitates the efficient and precise of KIs the plasmid DNA
cassettes in mice and rats.
２）Education Activities
None.
３）Social Activities
None.
４）International Activities
None.
５）Other matters to be noted
None.
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（４）Challenges and Future prospects
We will continue to develop novel diagnosis strategy and more clinical application by using
CRISPR-Cas3 technology. Now we are working on chimeric antigen receptor T (CAR-T) cell therapy
by utilizing CRISPR-Cas3. This effective cancer immunotherapy applies genetically modified T cells
and precisely target and kill cancer cells.

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Advanced Clinical Research Center
Director Toshio Kitamura（１）Missions and Features
We aim to develop diagnostic procedures and therapies of diseases through investigating the
etiologies of diseases. To this end, we investigate the molecular bases of pathologies of a variety of
diseases in the Advanced Clinical Research Center, and collaborate with medical stuffs of the Research
Hospital in making good use of the research achievements.
（２）Organization
Division of Molecular Therapy
Division of Cellular Therapy
Division of Infectious Diseases
Division of Clinical Genome Research
Division of Innovative Cancer Therapy
Division of Advanced Medicine Promotion
Division of Advanced Genome Medicine
Division of Genetic Therapeutics (-FY2017)
Division of Bioethics（３）Activity Reports
１）Research Activities
Purpose: To clarify the etiologies and develop new therapies based on the basic research.
Achievements: Basic research on gene therapy lead to clinical research, and the clinical trial has
been started. A trial to use AI in diagnostics has been succeeded in the initial phase, and attracted
much attention from the public. The paper on the mouse model of clonal hematopoiesis has attracted
much attention from the scientific field, was introduced by a special review article in New England
Journal of Medicine. We have provided the model mouse to many laboratories for collaboration.
２）Education Activities
Purpose: To nurture physician scientists, and to contribute to development of novel therapies andbasic research.
Achievement: We have an average of 30 graduate students (master and doctoral courses), give
doctoral grades to 5~10 graduate students, some of whom go abroad for their postdoctoral works.
At present, there are about 10 researchers stay in the foreign countries for their research.
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３）Social Activities
Purpose: To collaborate with pharmaceutical countries to develop new drugs, and to giveseminars to public and middle/high school students.
Achievement: We collaborate with more than 10 domestic and foreign pharmaceutical companies
and biotech venture companies to develop novel drugs. As for outreach activities, we give about 10
seminars to the public. In addition, we accept 10~15 groups of high schools or middle high schools
annually (in total 50~100 students) and introduce them with the history of our institute as well as
recent achievements of our institute. These activities are organized by the director of researchhospital and the director of Advanced Clinical Research Center, and many researchers and medical
doctors are voluntarily involved in these activities.
４）International Activities
Purpose: Each laboratory collaborates with laboratories in the foreign countries, and publish
papers.
Achievement: We annually publish papers in collaboration with foreign groups in prestigious
journals including Nature, J Experimental Medicine, Blood and Leukemia.
５）Other matters to be noted
A trial to use AI in analyzing DNA mutations of AML succeeded in obtaining useful information
concerning the diagnostics and therapies, which attracted much attention and was reported in TV
news and newspapers. The paper on the mouse model of clonal hematopoiesis has attracted worldwide attention the scientific field, and was introduced by a special review article in New England
Journal of Medicine. Phase I and II trials for the therapy of brain tumors (glioma and glioblastoma)
by lytic herpesvirus vectors has been completed and are now ongoing, respectively, attracting muchattention of the field.
（４）Challenges and Future prospects
Our Research Hospital and Advanced Clinical Research Center has been leading the fields of bonemarrow transplantation, G-CSF therapy, cord blood transplantation, and therapy of HIV infection. In
addition, lytic virus therapy against brain tumors are now on-going. Many research activities would
lead to new therapies in the future.
Division of Infectious Disease is now setting up the laboratory with the new professor. In 2 years,
two professors (Divisions of Molecular Therapy) will leave the institute which are mainly involved inclinical hematology and basic research concerning hematology. Therefore, it is critical to choose two
professors to support clinical and basic parts of hematology of this institute.
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Division of Molecular Therapy（１）Members
Professor

Arinobu Tojo

Associate Professor

Satoshi Takahashi

Assistant Professors

Muneyoshi Futami, Masamichi Isobe

Graduate students

9Technicians

5

Others2（２）Research objectives
Our research has been focused on the development of novel therapeutic options against intractable
malignant disorders including leukemia, lymphoma and various cancers. For this purpose, we aremaking every effort to master the mechanisms of normal and neoplastic stem cells on the basis ofmolecular and cellular biology as well as medical informatics. We also try to develop novel therapies
in the field of regenerative medicine using bone marrow-derived mesenchymal stromal cells.
（３）Activity Reports
１）Research Activities
Our research activities cover the following topics:
1.

Artificial Intelligence (AI)-guided clinical sequencing for leukemia and related diseases

2.

Analysis of hematological abnormalities using genetically engineered mice and search fortherapeutic targets by integration of iPS cell technology and genome analysis

3.

Development of universal cellular drugs using genome editing technology

4.

Development of novel therapeutic modality for relapsed/refractory myeloma
We have promoted research on these topics through collaboration with researchers and companies

inside and outside IMSUT, and the research outcomes have been published in Nature, JAMA Oncol,
Blood, Blood Adv, PNAS, Cancer Res, Oncogene, Sci Rep, Mol Ther Oncolytics, and other journals.
We published 5 peer-reviewed original articles in 2016, 9 in 2017, and 13 in 2018.
２）Education Activities
Our division cooperates with Graduate School of Medicine, UTokyo in education of doctoral
students. We have 6 doctoral students in 2016, 10 in 2017 and 11 in 2018. Most of them are M.D,and our goal is to help them become respectable physician scientists. In addition, we encourage
non-MD students to apply for postdoctoral positions in academia or research positions in industry.

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As a result, 3 students in 2016, 1 in 2017, and 2 in 2018 have completed the doctoral course, all ofwhom obtained Ph.D. During this period, one Japanese and one overseas student were adopted for
Graduate Program for Leaders in Life Innovation (GPLLI), and two others were adopted as JSPS
research fellows (DC2), one of whom thereafter went abroad as a postdoctoral fellow. The
remaining two are working as postdoctoral fellows in domestic laboratories.
３）Social Activities
We conducted collaborative researches with several pharmaceutical companies in each fiscal year
in the fields of cell therapy and cancer drug discovery, resulting in acquisition of intellectual
property in two issues. We also collaborated with several project divisions, which belong toCorporate Sponsored Research Program or Social Cooperation Research Programs, to help themachieve their research projects toward social implementation.
We contributed to establish the Clinical Flow Cytometry Laboratory (IMSUT-CFC), which is
now operated by LSI Medience Co. as outsourcing business and helped IMSUT-CFC undertake
clinical and research testing services from outside the institute (research facilities, hospitals, andcompanies).
We participated in UTokyo program “Self-Managing Healthy Society”, which is one of Centerof Innovation Science and Technology based Radial Innovation and Entrepreneurship Program(COI-STREAM) by MEXT and contributed development of precision medicine based on wholegenome sequencing.
４）International Activities
We conducted an international collaboration with a research group at the University of Georgia,
USA, and published our findings in Nature.
５）Other matters to be noted
In order to realize genomic medicine, we are promoting clinical research termed as AI medicine
in which artificial intelligence (AI) is applied to interpret enormous data from NGS analysis ofcancer genome and to find therapeutic options deduced from driver mutations. Our trial for AI
medicine was introduced by various media including newspapers and TV program with a significant
impact.
（４）Challenges and Future prospects
In the field of clinical hematology, especially for hematological malignancies, a number ofinnovative drugs have been developed in recent years. A number of these drugs including CAR-T cells
were already approved for insurance coverage via clinical trials. Although the prognosis of some
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patients with hematological diseases is improving, there are still many disorders that have no standard
treatments and unfavorable prognosis. To solve this problem, it is essential to identify therapeutictargets using multi-omics data and to establish animal models recapitulating pathophysiology of these
diseases.

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Division of Cellular Therapy（１）Members
Professor

Toshio Kitamura

Assistant Professors

Tomofusa Fukuyama, Yosuke Tanaka

Postdocs

5

Graduate students

9Technicians

2

Others2（２）Research objectives
To clarify the etiologies of hematological malignancies through establishment and investigation ofmouse models, and to seek for the novel therapeutic strategies.
To investigate hematopoietic stem cells and leukemic stem cells to develop a strategy to completely
cure hematological malignancies without bone marrow transplantation. The research includes
screening for novel drugs, to seek for effective combination therapies, to identify the molecularmechanisms of drugs, and anti-tumor immunity.
（３）Activity Reports
１）Research Activities
Purpose: To devise the novel strategies for therapy of hematological malignancies including AML,MPN (including) CML, MDS, and CMML based on the results of basic research.
Achievements: We demonstrated that an MDM2 inhibitor is effective for the MLL-AF9-induced
AML model and that HIF1a inhibitor or anti-PDL1/PD1 antibodies enhance the therapeutic effectof the MDM2 inhibitor (Hayashi et al. Nat Commun, 2019). Concerning MDS, we demonstrated
that forced expression of an EZH2 mutant lacking its catalytic activity or of ABC-G2, derepressedby EZH2 mutations, induced MDS-like diseases in the mouse BMT model (Kawabata et al.
Leukemia, 2018). We also published a paper that presents the first evidence that the mutant ASXL1(ASXL1-MT) is indeed expressed in MDS/AML cells (Inoue et al. Exp Hematol, 2016). We also
reported that the ASXL1-MT-KI mouse is healthy but preleukemic, mimicking clonal
hematopoiesis (Nagase et al. J Exp Med, 2018). We also published a paper showing that binding of
ASXl1-MT and BAP1 stabilizes and activates BAP1, leading to derepression of downstream genes
including HoxA9 and Myb, which then transform the cells (Asada et al. Nat Commun, 2019).
２）Education Activities
Purpose: To recommend graduate students or postdoctoral fellow to go abroad for their research
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after getting doctoral grades or publishing papers. To help graduate students to get jobs as
researchers in pharmaceutical companies.
Achievements: During 2016 through 2020, 9 graduate students obtained doctoral grades, andamong them five got position as postdoctoral fellow, 2 in Canada from this year and 3 in USA fromnext April. One master student obtained a job as a researcher in a pharmaceutical company.
３）Social Activities
The lab annually offer 6~8 open seminars including one concerning epigenetics open to generalpublic.
４）International Activities
The lab has close connections with several foreign laboratories, several in USA and three in
Europe to do collaboration, exchange ideas and people. With Abdel-Wahab lab at Memorial Sloan
Kettering Cancer Center, we have many collaborations and published two papers (Inoue et al.
Leukemia, 2015; Nagase et al. J Exp Med, 2018) and another collaborative paper (Fujino et al.) is
now under revision. We also have close collaboration with Dr. Machiejewski at Cleaveland Clinic,
and has published a paper (Takeda et al. Blood, in press). In addition, we published a collaborative
paper with Dr. Gottgens lab in UK (Fukushima et al. Cell Rep, 2019).
The lab has also close relationship with Dr. Melnick lab at Weil-Cornell Medicine, Dr. Helin lab
and Dr. Levine both at Memorial Sloan Kettering Cancer Center, Dr. Skoda lab at University ofBasel, Dr. Schroeder lab at EZH Zurich, Dr. Scadden lab at Harvard and Dr. Goodell lab at Bailer
Medical College. We sent postdocs to Dr. Scadden lab, Dr. Abdel-Wahab lab, Dr. Melnick lab, Dr.
Helin lab (in Copenhagen at that time), and are going to send postdocs to Dr. Goodell lab, AbdelWahab lab, and Scadden Lab. We also sent a graduate student to Schroeder lab for a couple ofmonths for formal collaboration.
５）Other matters to be noted
We filed a patent application for the ASXL1-MT-KI mouse.
The lab hosted US-Japan Hematology Meeting in Hawaii in March, 2017, 9th JSH International
Symposium at Kyoto in July, 2018, and 24th meeting for hematopoietic malignancies at Kobe inJanuary, 2019. The rock band “Negative Selection”, composed of Hematology and Immunology
professors including Professor Toshio Kitamura as a drummer, gave gigs at the gathering parties forthe latter two. In particular, in 9th JSH International Symposium, we played several hit songs ofEagles, Pink Floyd, and Deep Purple together with Dr. Radek Skoda from Switzerland and Dr.
Margaret Goodell from USA.

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（４）Challenges and Future prospects
We plan to utilize results of mouse models to develop new strategies and drugs to cure patients withhematological malignancies in concert with pharmaceutical companies. In most cases, mouse models
rather accurately mimic the human disease. However, it is not clear how far we can extrapolate mousemodels to human diseases. Therefore, it is critical to simultaneously use human samples in theexperiments. Therefore, we are now seeking many hospitals who can supply samples from patientswith hematological malignancies.

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Division of Infectious Diseases（１）Members
Professor

Hiroshi Yotsuyanagi

Associate Professor

Takeya Tsutsumi

Assistant Professors

Michiko Koga, Makoto Saito

Postdocs

1

Graduate students

7

Technicians

5

Others1（２）Research objectives
In addition to HIV research and international infectious disease research, which have been mainly
focused on in our division, hepatitis virus research will also be conducted.
（３）Activity Reports
１）Research Activities- HIV research
Until the current professor's appointment (July 2016), HIV research in our division mainly
focused on analysis using clinical samples before introduction of antiretroviral therapy (viral gene
analysis/immunological analysis of peripheral blood mononuclear cells). Until July 2017, theexperiment could be operated only on a small scale., therefore we focused on building a researchbase for, (1) a database of these existing data (joint research with Dr. Tetsuro Matano, National
Institute of Infectious Diseases) (2) pathogenesis of co-infection of HIV and hepatitis virus, (3) the
relationship between the onset of complications after the introduction of antiretroviral therapy andhost immunity. Concerning (2) and (3), we aimed to publish one original paper each.
Regarding (1), about 90% of the data in our division that can be uploaded to the server installedat the National Institute of Infectious Diseases has been completed. Regarding (2), we could publish
only original paper in Japanese. As of March 2019, we will urgently turn into a paper for a projectthat is in progress (two English papers were published in FY2019). Regarding (3), we were able topublish one original paper. However, this is based on the analysis of existing databases, and the goal
is to disseminate the data based on the basic research in our division that is currently underway in
FY2019.
- International infectious diseases research
Regarding international infectious diseases, as of July 2016, the activities of the Department of
Infectious Diseases and Applied Immunology in IMSUT Hospital (participation in research groups,
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provision of rare drugs) were left. For this reason, the goal was to first start collaboration withresearchers (malaria, Chagas disease) inside and outside the institute, which are related to ourdivision, and build a system to start research. Research on malaria started in 2017. We will
disseminate research results in the future.
- Hepatitis virus researchWith the goal of continuing the research on viral hepatitis in HIV-infected persons and publishing
the original paper, we reported one English paper as described above. In addition, we set up an
experimental system to continue HCV research using conventional HCV transgenic mice, put it on
an orbit, and if possible, publish one English paper. The results based on work after 2016 have notbeen produced yet, and it is one goal for FY2019.
２）Education Activities
There were 4 graduate students at the time of the professor's arrival in 2016, but since it wasdifficult to conduct an experiment immediately in our division as mentioned above, 3 students wereasked to be instructed at the external research institute. Another student who was on leave returnedto their first year in 2017 and is conducting research activities in our division. Her goal is tocomplete a dissertation. By March 2019, the presentation of the first half of the dissertation was
performed at the academic conference, and writing of the thesis is underway, and progress isproceeding smoothly. Prof. Yotsuyanagi is also in charge of the Graduate School of Frontier
Sciences, and gives lectures, but currently no graduate students belong to our division.
３）Social Activities
None.
４）International Activities
None.
５）Other matters to be noted
As an activity of the Department of Infectious Diseases and Applied Immunology in IMSUT
Hospital, we conducted educational activities for citizens and opened an outpatient clinic foroverseas travels.
（４）Challenges and Future prospects
For two and a half years until March 2019, a great amount of time was spent building a system for
conducting research in our division. The system is almost established, and it is possible to carry out
research and disseminate the results in the future. There are some projects as mentioned above, and it
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is necessary to publish the papers from each project regularly.

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Division of Clinical Genome Research（１）Members
Professor

Yoichi Furukawa

Associate Professor

Tsuneo Ikenoue

Project Senior Assistant Professor

Kiyoshi Yamaguchi

Assistant Professor

Kiyoko Takane

Graduate students

3

Technicians

2（２）Research objectives
Our research objectives include elucidation of mechanisms underlying gastrointestinal tumors anddevelopment of new modalities for their diagnosis, treatment, and prevention. In addition, we havebeen carrying out a research project for the implementation of precision medicine in our hospitalthrough genomic analysis of cancer and individual genome.
（３）Activity Reports
１）Research Activities
In our laboratory, we have been investigating molecular mechanisms underlying gastrointestinal
tumors such as colorectal, biliary tract, and pancreatic cancer.
One of our research projects is the elucidation of molecular mechanisms involved in colorectal
carcinogenesis caused by activated Wnt signaling. Using expression profiles of colorectal cancer
cells treated with β-catenin siRNA and ChIP-seq data with anti-TCF7L2 antibody, we identified
several genes directly upregulated by β-catenin/TCF7L2 complex including FERM domain
containing 5 (FRMD5). Additionally, we disclosed that elevated FRMD5 expression in colorectal
cancer is associated with poor prognosis. We further identified interferon induced protein withtetratricopeptide repeats 2 (IFIT2) as a gene downregulated by Wnt signaling, and found that
reduced IFIT2 expression increased cell proliferation and suppressed apoptosis. Further
investigation unveiled that IFIT2 is transcriptionally regulated by interferon regulatory factor 1(IRF1), and that IRF1 is destabilized by the Wnt signaling through reduced UAF1 expression andsuppressed USP1 deubiquitinase activity. These data shed light on new mechanism of Wnt signaling
pathway. Besides these basic studies, we have been working on the development of Wnt inhibitors.
We previously performed a high throughput screening for Wnt inhibitors using a library containing
20,000 compounds, and identified several hit compounds. For the optimization of the hit compounds,
we are now collaborating with medicinal chemists in Basis for Supporting Innovative Drug
Discovery and Life Science Research (BINDS), the University of Tokyo.
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In addition, we have been generating cancer mouse models and analyzing tumors developed in
the mice. In a project, we established liver-specific knockin mice carrying a cancer-associatedhotspot mutation of FBXW7, which developed intrahepatic bile duct tumors. We are now analyzing
the role of FBXW7 mutation in cholangiocarcinogenesis.
In 2015, we started a precision medicine project for patients with solid cancer/hematologicalmalignancies in collaboration with doctors in IMSUT hospital and bioinformaticians in Human
Genome Center. In this project, we performed whole genome/exome sequencing and took advantage
of an artificial intelligence, IBM Watson for Genomics, for the interpretation of mutations andselection of anticancer drugs. In addition, we performed genetic screening for endometrial cancer
using liquid-based cytology samples in collaboration with Sapporo Medical University. We also
participated in international collaboration with the Pharmacogenomics Research Network (PGRN)
in USA, and searched for genetic variants associated with efficacy and/or adverse effect of drugs.
The collaborative studies consequently identified SNPs associated with adverse effects ofbevacizumab in adjuvant chemotherapy for breast cancer, and those associated with serum VEGFA levels.
２）Education Activities
Professor Furukawa has been taken charge of master and doctor-course education of Graduate
School of Medicine and Graduate School of Frontier Sciences in the University of Tokyo. In
addition, he has been in charge of an adjunct professor in Oita University and Iwate Medical
University. He gave several lectures and seminars in these universities. Associate professor Ikenoue
is a faculty member of Graduate School of Medicine. They have trained a number of master anddoctor-course students through the participation in their research projects.
３）Social Activities
Professor Furukawa has been playing a vital role as an associate editor of Cancer Science andHuman Genome Variation, journals supported by Japanese Cancer Society and Japanese Society of
Human Genetics, respectively. He is working as a board member of these societies. He is involvedin a project for promotion of genome-based medicine for cancer in Japan, and has given lectures for
medical doctors, nurses, and laboratory technicians. He was invited as an adviser in a meeting for
100 thousand whole genome-project in Japan in 2019. Professor Furukawa and associate professor
Ikenoue are collaborating in the development of guidelines for hereditary tumors such as Cowden
disease and Peutz-Jeghers syndrome in Japan.
４）International Activities
Professor Furukawa has been collaborating with the Pharmacogenomics Research Network
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(PGRN) in USA for more than six years.
５）Other matters to be noted
We opened a summer seminar for young students in elementary and junior high schools in 2019.
Students participated in the seminar with their parent(s), enjoyed lectures of genome, DNA analysis,
and genetic variations, and performed experiments using DNA from their parent. We do hope thatearly education of genomic variations will help their understanding of difference in individuals.
（４）Challenges and Future prospects
We will keep on working for the elucidation of molecular mechanism underlying gastrointestinal
tumors, and analyzing function of genes associated with the development and progression ofgastrointestinal tumors. Additionally, we will try to clarify new molecules, pathways, mechanisms
regulated by activated Wnt signaling in cancer, and make challenges for the identification of novel
target molecules for the treatment of tumors. In the development of Wnt inhibitors, we will investigate
small molecules structurally related to the hit compounds, and perform analysis of structure–activity
relationship for their optimization.
In the research of mouse models, we plan to establish novel genetically engineered mice models. In
addition, we will test efficacy and adverse effect of new compounds using our intrahepaticcholangiocarcinoma model in collaboration with pharmaceutical companies. Challenges will bestarted for the development of a treatment model targeting oncogene(s) by adenovirus expressing
guide RNA with dCas9.
We will continue the project of precision medicine for patients with solid cancer/hematologicalmalignancies, and assess the effectiveness of WES/WGS with AI for the selection of treatment.

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Division of Innovative Cancer Therapy（１）Members
Professor

Tomoki Todo

Project Associate Professor

Minoru Tanaka

Assistant Professor

Seisaku Kanayama

Assistant Professors

Yoshinori Sakata, Hirotaka Ito

Postdocs

1

Graduate students

2Technicians

4

Others3（２）Research objectives
With the steady increase in the mortality rate of cancer, it is difficult to cure intractable cancers andcancers that have recurred after standard treatment, and there has been an urgent need for developing
an innovative modality that can lead to the cure of disease. We developed genetically engineered
oncolytic viruses that only replicate and destroy cancer cells. In particular, G47Δ, a geneticallyengineered oncolytic herpes simplex virus type 1 with triple mutations, has high safety features and arobust antitumor effect, and is being applied in the clinical trials. Through the development of various
next-generation viruses that exert different anti-tumor functions and utilization of cancer stem cells
isolated from malignant brain tumors, we aim to develop an innovative cancer treatment that is
applicable to a wide variety of cancers and will overcome recurrence and metastasis in the near future.
（３）Activity Reports
１）Research Activities
Oncolytic virus therapy has been suggested to be effective for all solid tumors in pre-clinicalstudies, and is expected to be a new cancer treatment modality that is universally applicable. We
have been dedicated to developing a series of next-generation oncolytic viruses preclinically anddelivering them on the clinical pipeline. In 2016, G47∆ was designated as a ‘Sakigake’ breakthroughtherapy drug by the Ministry of Health, Labour and Welfare of Japan, and further as an orphan drug
for malignant glioma in 2017, allowing its priority review and fast-track drug approval. With anunprecedented high therapeutic efficacy in the interim analysis of the phase II clinical trial for
glioblastoma, the new drug application of G47Δ as the first-in-the-world, Japan-made oncolytic
virus product for malignant glioma is expected in 2020. A new clinical trial for malignant
melanoma using T-hIL12, a recombinant herpes simplex virus type 1 gene expressing humaninterleukin 12, also started in 2020.
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２）Education Activities
A wide range of graduate students from each department of internal medicine and surgery haveapplied, and a variety of preclinical researches have been conducted while considering the practicalneeds in each disease. Most of the graduate students have received their degrees, which yields corehuman resources who will be responsible for viral therapy in the future.
３）Social Activities
The principle investigator is anointed as the president of the Japan Society for Gene and Cell
Therapy, where he strives to spread gene therapy and viral therapy in Japan, and acts as a bridge
between regulators, researchers and companies. We have also been making a social contribution bycooperating in making a public comment on “Ethical guidelines for research that uses genetic
information modification technology for human fertilized embryos” related to the research that uses
technology that modifies genetic information such as genome editing technology.
４）International Activities
We have frequently exchanged ideas through international conferences.
５）Other matters to be noted
Specimens (tumor tissue, blood, saliva, urine, etc) from the clinical trials of G47∆ forglioblastoma, olfactory neuroblastoma, malignant pleural mesothelioma, were analyzed to evaluate
the safety and efficacy.
（４）Challenges and Future prospects
There has been a remarkable progress in the practical application of in vivo gene therapy andoncolytic virus therapy. In recent years, several products have been put on the market for rare diseases(hereditary diseases) and cancers, and new entry of many pharmaceutical companies have made thedevelopment race more intense. In particular, the scale of market for oncolytic virus therapies is
expected to be 1 billion dollars per drug. We are trying to seek the profits of research to the Japanesesociety by realizing the application of G47∆ in all cancer patients as early as possible.

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Division of Advanced Medicine Promotion（１）Members
Professor

Fumitaka Nagamura

Associate Professor

Masanori Nojima

Graduate students

2Technicians

1（２）Research objectives
Translational Research (TR) is the clinical application of the results of basic research. One of the
major missions of IMSUT is to promote TR. Division of Advanced Medicine Promotion cooperates
with Center for Translational Research to provide consistent support for conducting TR, from basic
research to conduct of clinical trials, and this includes the supports of patent applications and conductsof preclinical studies. Professor Nagamura mainly researches regulations and support methods as
regulatory science. And Associate professor Nojima mainly does biostatistical analysis and support
methods using biostatistics. As the numerical goals of research, at least five conference presentations
and at least three papers a year have been settled. Our long-term goals are that several kinds ofsupported “seeds” will be approved by regulatory authorities.
（３）Activity Reports
１）Research Activities
The biggest feature of the seeds we support is that most of them are classified as new modalities,
such as genetically modified Herpes Simplex Virus-1 and that Measles Virus as oncolytic therapy,
Rice-based vaccine for traveler’s diarrhea, artificial adjuvant vector cells for hematologic
malignancies, umbilical cord derived mesenchymal stroma cells for inflammatory/immune diseases.
Under such situation, the main topic of our researches is regulatory science for new modalities andbiostatistical methods for early clinical trials. We prepare for “Regulatory Science consultation on
R&D strategy” of Pharmaceuticals and Medical Devices Agency in all seeds, and utilized theexperience and information obtained from consultations for research. We made seven presentations
at domestic conferences in 2016, 12 presentations at domestic conferences and seven at international
conferences in 2017, 11 at domestic conferences and three at international conferences in 2018, andsix presentations at domestic conferences and two at international conferences in 2019. Regarding
the paper, we published 24 papers in 2016, 23 papers in 2017, 14 papers in 2018, and 22 papers in
2019. Another research interest is the education on TR, and we created the education syllabus on
TR and conducted a survey on TR education in graduate school. So far, we believe the goal of theresearch has been fully achieved. Other research interests include the development of diagnostic
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methods using machine learning methods. As a graduate school faculty, an epidemiological study
using the receipt data provided by the Ministry of Health, Labour and Welfare has been conducted.
２）Education Activities
Educations for non-MD researchers and workers are critical for the development of humanresources engaged in TR. We have been in charge of graduated school lectures of “Basic of
Translational Research”, “TR as clinical trial” and “Laws and regulations for TR” of department ofcomputational biology and medical sciences, graduate school of frontier sciences and “Nursing fortranslational research” of division of health sciences and nursing, graduate school of medicine. We
also take part in the project to create educational materials for workers engaged in vector
manufacturing for gene therapy and that to conduct annual workshop on bioethics of regenerative
medicine. For researchers and workers at IMSUT and IMSUT hospital, we provide e-learning on
TR and conduct several seminars.
３）Social Activities
Because there are few biostatistical education in Japan, we give biostatistics courses at othermedical institutes. We have released an explanation of terms on TR and teaching materials,
including materials for researchers and physicians related to TR on our webpage.
４）International Activities
We have been involved in the Nipa Vaccine development project, which had adopted by CEPI
(Coalition for Epidemic Preparedness Innovation) in 2018. Our role is to handle the matters related
to clinical trials. This project has been conducted by a consortium composed of the University ofTokyo, Stanford University, European Vaccine Initiative, and International Centre for Diarrhoeal
Disease Research, Bangladesh.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
The range we have been treating is very wide, from the patent application to clinical trial. On theother hand, the member of our division is very limited. Our challenge is to increase the number of staff
and treat various problems. One solution is to get external research funding for employment, and theother is to aggressively target new modalities to increase the attractiveness of our research. Our future
prospect is to secure adequate human resources by above activities, and to set up a research system
which responding to novel areas of TR.
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Division of Advanced Genome Medicine（１）Members
Associate Professor

Yoshihiro Hirata

Graduate students

2（２）Research objectives
Pathogenesis analysis and new therapy development for inflammatory diseases and malignancies
of digestive systems; for example, development of two novel diseases models, two new therapies, andpublication of six original papers during this term.
（３）Activity Reports
１）Research Activities
After arrival in September 2017, we performed several research projects mostly based on
genetically engineered mouse models. As major achievements, 1) We have shown the pathogenicrole of dendritic cell E-cadherin, and proposed a novel neutralizing antibody therapy using
originally developed mouse colitis model, 2) We have elucidated the mechanism and cell origin ofgastric metaplasia, which is known to be the precursor of gastric cancer. In total, nine original papers
were published. Therefore as an evaluation of achievements, 1) development of two novel diseases
models for pathogenesis analysis was achieved (gastritis model and colitis model), 2) developmentof two novel therapies using mouse models fell short (one novel therapy against colitis using Ecadherin neutralizing antibody), 3) number of publication was achieved (nine original papers).
As for an unachieved goal (novel therapy proposal against gastric metaplasia), we have set up
new research projects for the next term; generation of a new gastric metaplasia model with theinducible gene modification, which enables temporal-spatial, comprehensive analysis of gastricmetaplasia process. We believe this model will lead to the clear understanding of the mechanisms
and elucidate a novel therapy for reversal or prevention of metaplasia.
２）Education Activities
Our division took charge of Fundamental Exercise I for the graduate students of School of Fontier
Sciences, in which about 50 students annually got experienced in practical Medicine through therounding at IMSUT Hospital. We also offered similar practical Medicine course to ten students ofthe department of Psychology, Faculty of Human Science, Bunkyo University. Each exercise course
was evaluated by the students, and mostly got satisfactory responses. We also adjusted theshortcomings in the course, such as inconvenient time scheduling, unnecessary repetition of lecture
contents, with the lecturer or hospital staff. This kind of refinement by feedback will be continued
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to improve the quality of Fundamental Exercise I.
Graduate students who attended our division is going through the research project in which each
student pursue his/her own goal to explore the pathogenesis and the treatment of gastroduodenal
inflammatory and malignant diseases. They got practical lessons on biology, molecular biology, andgastroenterology through practices and lectures.
３）Social Activities
Our division offered a field trip for the high school students.
４）International Activities
Two publications, Hayakawa et al (gastroenterology), Kinoshita et al (Am J Physol Gastroint
Liver Physiol), were performed in collaboration with the researchers in the USA. Our original cellline (SIAC1 cell) was donated to the German researcher for the collaboration.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
This division included only one faculty member, and the lack of manpower have led to theinsufficient achievements in both research and educational activity. Currently, collaboration with otherlaboratories of the IMSUT, University of Tokyo Hospital, or others, have helped to keep research
activities. Thorough acquisition of new research grant and addition of faculty member and graduate
students, we try to improve research and educational activities of the division.

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Division of Genetic Therapeutics (-2018.3)（１）Members
Professor

Keiya Ozawa

Project Professor

Shin-ichi Muramatsu

Senior Assistant Professor Sumimasa Nagai（２）Research objectives
The main project of our division was to promote clinical development of novel gene therapy forcancer and chronic intractable diseases. We engaged in clinical development of immuno-gene therapy
with chimeric antigen receptor (CAR)-modified T cells for relapsed and refractory hematologicalmalignancies and gene therapy for neurological disorders using adeno-associated virus (AAV) vectors.
（３）Activity Reports
１）Research Activities
1. Immuno-gene therapy with CD19-directed CAR-modified T cells (CD19-CAR-T cells) for
adult patients with relapsed and refractory B-cell non-Hodgkin lymphoma
It has been reported that CD19-CAR-T cell therapy is highly effective for relapsed andrefractory B cell malignancies. In order to develop this novel promising gene therapy in Japan,
we conducted clinical study of CD19-CAR-T cell therapy for adult patients with relapsed andrefractory B-cell non-Hodgkin lymphoma in collaboration with Jichi Medical University and
Takara Bio Inc. (NCT02134262). This first clinical study of CAR-T cell therapy in Japan has
started in 2015.
2. Gene therapy for amyotrophic lateral sclerosis and spinocerebellar ataxia type 6
In sporadic amyotrophic lateral sclerosis (ALS) patients, down regulation of the RNA-editing
enzyme, adenosine deaminase acting on RNA 2 (ADAR2), is death-causing molecularabnormality that occurs in motor neurons. Gene delivery of the ADAR2 using tyrosine-mutant
AAV9/3 (AAV.GTX) vector in conditional ADAR2 knockout mice effectively prevented
progressive motor dysfunction without any adverse effects. We have started to produce GMP
grade AAV.GTX vectors that express ADAR2 for a clinical trial. In collaboration with Chicago
university, we have developed miR-based gene therapy for spinocerebellar ataxia type 6 (SCA6).
SCA6 is caused by abnormal expansions of the polyglutamine tract within a second CACNA1A
gene product, α1ACT. Selective translational block of SCA6-associated α1ACT by delivering
miR-3191-5p protected from the Purkinje cell degeneration and ataxia in a mouse model

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(Miyazaki Y. et al, Sci Transl Med, 2016).
By lending our expertise on gene therapy for Parkinson disease, we have supported an openlabel phase1/2 study of gene therapy for children with aromatic L-amino acid decarboxylase(AADC) deficiency in National Taiwan University. AADC is an essential enzyme for dopaminesynthesis. The primary phenotypes of AADC deficiency include severe developmental delay andmovement disorders. AAV vector-mediated gene delivery into the putamen resulted in marked
improvement of motor functions (Chen YH, et al. Lancet Child Adolesc Health, 2017).
3. International comparison of regulations on regenerative medical products and anticancer
drugs
Several expedited regulatory review projects for drugs and regenerative medical products havebeen developed in the US, the EU, and Japan. Understanding the global regulatory frameworks
is important for the conduct of translational research and clinical development of new therapeutic
products efficiently. Regulatory frameworks for the marketing authorization of oncologic drugs,
generic anticancer drugs, and gene and cellular therapy products in Japan, the EU, and the US
were examined. (Nagai S, et al. Int J Hematol 2016, Nagai S, et al. Invest New Drugs 2016, Yang
YT, Nagai S, Chen BC, et al. Lancet Oncol 2016, Nagai S, et al. Curr Gene Ther 2017, Nagai S,
et al. Invest New Drugs 2018)２）Education Activities
None.
３）Social Activities
Our division organized the 1st ~ 5th IMSUT-CGCT (Center for Gene & Cell Therapy) symposium
as the secretariat.
４）International Activities
S.M. contribute to European society for gene and cell therapy (ESGCT) as a reviewer of abstracts
and an invited speaker of annual congress in 2016.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
This Division has completed and closed as of March 31, 2018.

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Division of Bioethics（１）Members
Associate Professor

Ayako Kamisato

Postdocs

2

Others1（２）Research objectives
The objectives of our division are to study how medical science or medical care should develop
in society and what are needed for them to develop including regulations, and then to give practicalfeedbacks through policy proposals or tools development to society.
The following are the specific research themes.
(1) Human embryo research/human embryo genome editing(2) Creation of human and animal chimeras(3) Improvement of quality of ethical review(4) Protection of human subjects（３）Activity Reports
１）Research Activities
Regarding the above theme (1)⚫ As a member of the Expert Panel on Bioethics of Council for Science, Technology andInnovation set by Cabinet Office, Dr. Kamisato engaged in following policy makings;➢ Supplementary report on the revision of the Basic Principles on Handling of Human Embryos:
regarding the use of genome modification techniques including genome editing in assisted
reproductive medicine research. March 2018
➢ Second Report on the revision of the Basic Principles on the Handling of Human Embryos:
regarding the use of genome modification techniques including genome editing in assisted
reproductive medicine research. June 2019
⚫ As a member of the Council on Research Using Genome Editing Technology for Human
Fertilized Embryos set by the Ministry of Education, Culture, Sports, Science and Technology(MEXT), Dr. Kamisato engaged in making following guidelines;➢

Guidelines for Research Using Gene-altering Technologies on Human Fertilized Embryos⚫ As a member of the Council on Research Using Genome Editing Technology for Human
Fertilized Embryos set by the Health, Labour and Welfare Ministry (MHLW) , Dr. Kamisato
engaged in making following guidelines;➢

Guidelines for Research Using Gene-altering Technologies on Human Fertilized Embryos
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⚫ As a member of the Council on Clinical Use of Using Genome Editing Technology for Human
Fertilized Embryos set by the Ministry of Health, Labour and Welfare Ministry (MHLW) , Dr.
Kamisato engaged in making proposal.
Regarding the above theme (2)⚫ As a member of the Council on Specified Embryos set by the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Dr. Kamisato engaged in revising following
guidelines;➢ Guidelines on the Handling of Specified Embryos
Regarding the above theme (3)“Ethical Guidelines for Medical and Health Research Involving Human Subjects” and“Regulation for Enforcement of Clinical Trials Act” require researchers and research ethics
committee (REC) members to receive ethical education and training programs at least once a year.
We established the original program for researchers and REC members with support from the Japan
Agency for Medical Research and Development (AMED) since FY 2019. We have alreadyproduced and released 14 video programs.
Regarding the above theme (4)“Center of Healthy Aging Innovation project” promoted by Hirosaki University is one of the
projects of JST Center of Innovation (COI) Program. One goal of this project is to build aplatform of big data on health. We support the researchers involved in this program from the
aspect of research ethics, such as giving research ethics consultation, making tools for public
enlightenment.
２）Education Activities
Concurrent lecturer of Graduate School of Frontier Sciences, The University of Tokyo
Part-time lecturer of several universities
Holding many workshops for REC members
Conducting many educational lectures３）Social Activities
None.
４）International Activities
None.
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５）Other matters to be noted
None.
（４）Challenges and Future prospects
From the results of the questionnaire survey conducted by us in 2018, the need for publicawareness activities regarding medical research to the general public has emerged. In order to build
good relationships of trust between the general public and medical researchers and to promote
medical research, we will continue our research and give back the result to society.

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Center for Stem Cell Biology and Regenerative Medicine
Director Hideki Taniguchi（１）Missions and Features
Stem cell research has been a major part of regenerative medicine in the 21st century. This includes
transplantation therapy with artificial or whole organs as well as research into cancer and other disease
areas. The Center for Stem Cell and Regenerative Medicine was launched as a core research centerfor stem cell-based medicine. It aims to facilitate the transition of outcomes from stem cell biology
research into pre-clinical and clinical studies. Furthermore, there is also hope for developing
innovative approaches to treat to cancer and various other diseases.
（２）Organization
Division of Regenerative Medicine
Division of Stem Cell and Molecular Medicine
Division of Stem Cell Transplantation
Division of Stem Cell Signaling
Division of Stem Cell Processing
Division of Stem Cell Pathology
Division of Stem Cell Biology
FACS Core Laboratory
Stem Cell Bank
Division of Stem Cell Therapy (-FY2016)
Division of Stem Cell Dynamics (-FY2018)
Division of Stem Cell Cellomics (-FY2019)（３）Activity Reports
１）Research Activities
In each division, activities such as publication of papers, presentations at conferences andapplication/acquisition of patents are actively promoted in line with the respective goals of eachproject. For detailed information please see the description of each division with the results shown
below.
2016 April to 2017 March (Director: Dr. Hiromitsu Nakauchi)
2017 April to 2019 March (Director: Dr. Yoshinori Murakami)
Relating to hematology, it was discovered that the essential amino acid Valine is critical for the
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maintenance of hematopoietic stem cells (Taya et al. Science). In collaboration with the Weissman
Lab at Stanford University, we revealed that hematopoietic stem cells are localized to the side of
the vascular niche. (Chen et al., Nature). Furthermore, from research conducted in the division ofstem cell therapy regarding organ regeneration, it was discovered that primed ES / iPSCs andprogenitor cells committed to the endoderm lineage has the capacity to form chimeras by onlytransient expression of an apoptosis inhibitor (Masaki et al. Cell Stem Cell). A breakthrough results
was made by demonstrating that a mouse pancreas can be generated inside a rat and that the islets
derived from the pancreas can be transplanted into a diabetic mouse to normalize blood glucose
levels for long periods without immunosuppression. (Yamaguchi and Sato et al. Nature). A review
article on organ regeneration in xenogeneic animals was published in Nature (Wu et al. Nature).

2019 April~ (Director: Dr. Hideki Taniguchi)
In April 2019, Professor Hideki Taniguchi was appointed as the Director of the Center for
Regenerative Medicine. Alongside Professor Yasuhiro Yamada of the Graduate School of Stem
Cell Pathology, the resulting collaborative efforts further strengthened the ongoing stem cellresearch at the center. More recently in relation to hematology, a highly cost effective method of
expanding hematopoietic stem cells without aging was reported. The method relied upon the use of
polyvinyl alcohol (PVA), the main component of liquid glue, rather than expensive materials suchas serum or albumin that are routinely used in cell culture. (Wilkinson et al. Nature). In collaboration
with Columbia University, there was success in generating a functional lung from pluripotent stem
cells using a next-generation blastocyst complementation method and a novel pluripotent stem cell
culture system (Mori et al. Nature Med). Taken together, this research center has consistently
produced high-level research results.
２）Education Activities
In each division, the training of graduate students is actively ongoing. The center has also been
open to visits from junior and senior high school students to offer some exposure to a scientificresearch environment. In the past year, 57 graduate students (13 international) were trained and 15
visits were accepted.
３）Social Activities
Joint research with companies is ongoing in each division. In the past year, 21 collaborations(joint research with companies/contract research) were established and executed.
４）International Activities
A number of international cooperative research activities in different fields are taking place. For
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more information, please see specific descriptions from each division. In the past year, a total of 17
international collaborations were conducted at the center, including the following.
 The International Academic Exchange Agreements with Fujian Institute of Hematology aresearch project entitled "Co-development of novel cancer immunotherapy for hematologicalcancers such as multiple myeloma”.
 The International joint research project of the International Joint Usage/ Research center of theInstitute of Medical Science entitled “Virus-specific T-cell therapy for cord blood transplantpatients”.
 Research on ASXL1 with Dr. Omar Abdel-Wahab under an international joint research
agreement with Memorial Sloan-Kettering Cancer Center.
 Research on pluripotent stem cells with Dr. Austin Smith under an international joint research
agreement with University of Cambridge.
 The international joint research project of the International Joint Usage/ Research Center of
the Institute of Medical Science entitled "Development of innovative culture method forhematopoietic stem cell expansion" with Lund University and "Single-cell epigenomics for thecharacterization of HSC aging” with Marseille Cancer Research Center.
 The International joint research project of the International Joint Usage/ Research center of theInstitute of Medical Science with Sun Yat-sen University entitled “New treatment strategy inacute on chronic liver failure using iPSCs-derived liver organoids.
 The Bilateral Programs with Chinese Academy of Sciences (CAS), a joint research project
entitled “Elucidation of the molecular basis of in vivo reprogramming by single cell analysis”.
５）Other matters to be noted
Dr. Beate Heissig was one of only a few foreign female senior faculty members. She trained alarge number of international students and published excellent papers.
Annually the FACS Core Lab is used by more than 2000 internal and external researchers.
（４）Challenges and Future prospects
With regards to basic research on stem cells, a number of truly novel and innovative results has been
published. In the future, it is hoped that further progress can be made on research aiming at the
proliferation of human hematopoietic stem cells. With the support of the Institute of Medical Research
Hospital, the goal is to facilitate the realization of safer transplantation medicine.

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Division of Stem Cell and Molecular Medicine（１）Members
Professor

Atsushi Iwama

Assistant Professors

Motohiko Oshima, Yaeko Nakajima, Masayuki Yamashita

Postdocs

2

Graduate students

11Technicians

2

Others1（２）Research objectives
1. We aim to develop methods to manipulate hematopoietic stem cells through an understanding of
their self-renewal mechanism.
2. We aim to establish a new treatment method by conducting research on the aging of hematopoietic
stem cells and hematopoietic malignancy from an epigenetics point of view.
（３）Activity Reports
１）Research Activities
We, Division of Stem Cell and Molecular Medicine, have conducted research in order toelucidate:a) the molecular basis for the self-renewal mechanism of hematopoietic stem cells,b) epigenetics for the characteristic changes of hematopoietic stem cells associated with aging,c) epigenetic abnormality in the pathogenesis of hematopoietic malignancy.
From March 2018, the time I transferred here and set up a laboratory, until March 2019, theobjective for our division has been to research the working mechanism of epigenetic molecules that
control the self-renewal of hematopoietic stem cells and the pathogenic mechanism ofhematopoietic malignancy caused by dysregulation of self-renewal and differentiation ofhematopoietic stem cells. As for results, we planned to publish 1 to 2 English scientific papers
during the stated period.
In fact, we were able to unravel the function of Phf6 as a new epigenetic control gene for thehematopoietic stem cells (Blood 2019, IF 16.4）and elucidated how a dysfunction of Bcor affects
the onset of myelodysplastic syndrome, which is an aging-related myeloid malignancy (Blood 2018
IF 16.4). We wound up publishing 8 scientific papers (6 papers above IF 10).
From that viewpoint, we believe we have made fruitful achievements in those areas of research.
However, we have yet to publish papers on epigenetic analysis for characteristic change ofhematopoietic stem cells associated with aging, and there is some delay in this research.
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For this matter, we plan to increase the number of researchers who will mainly work on the said
theme and strengthen the research promotion system as well as optimize the quality of our researchby conducting a single cell epigenetic analysis and so forth.
２）Education Activities
We instructed 1 Master student from Department of Computational Biology and Medical
Sciences, 2 PhD students from Faculty of Medicine and 5 PhD students outsourced from Faculty of
Medicine, Chiba University. We taught a class for each of Faculty of Liberal Arts and Departmentof Computational Biology and Medical Sciences.
３）Social Activities
None.
４）International Activities
We conducted a joint research with Dr. Duprez at Marceille Cancer Center in France andunraveled the function of transcription factor PLZF in regulating enhancer activity associated withthe aging of hematopoietic stem cells.
５）Other matters to be noted
As head of the Grant-in-Aid for Scientific Research on Innovative Areas ‘Establishing a newparadigm of the pathogenesis of diseases through the understanding of stem cell aging’, I
endeavored to consolidate and promote this area of research.
（４）Challenges and Future prospects
There is a delay in the epigenetics analysis on the characteristic changes of hematopoietic stem cells
associated with aging. For this matter, we will strengthen the research promotion system by increasing
the number of researchers. At the same time, we will improve the quality of research by conducting
single cell epigenetic analysis and so forth. We also plan to start a project to discover how
inflammation is associated with self-renewal, differentiation and transformation of hematopoietic stem
cells and promote the research.
As a result of the above projects, we expect to publish 3 highly impactful scientific papers and 3
additional papers on unraveling the pathogenesis and treatment method of hematopoietic malignancies
associated with the inflammation and aging of hematopoietic stem cells by 2021. Among those papers
mentioned above, we aim to publish 1 to 2 papers above IF 20. Moreover, we intend to acquire 2
research funds from AMED for projects on the self-renewal control of hematopoietic stem cells aswell as the aging of hematopoietic stem cells.
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Division of Regenerative Medicine（１）Members
Professor

Hideki Taniguchi

Project Associate Professor

Tomoyuki Yamaguchi

Assistant Professor

Yunzhong Nie

Project Assistant Professor

Yasuharu Ueno

Postdocs

1

Graduate students

7

Technicians

4

Others2（２）Research objectives
In our lab, we are developing a method for creating and transplanting human tissues or organs
generated from human induced pluripotent stem cells (human iPSCs). Our goal is to establish thismethod as a new therapeutic modality as an alternative to whole organ transplantation. Between 2008
and 2009, a quality evaluation method for liver organoids generated from human iPSCs (human iPSC
liver bud) was developed. This included the establishment of a method for detecting undifferentiated
iPSCs, which is necessary for the clinical application of human iPSC liver bud, and to examine thetherapeutic efficacy after transplantation for treating urea cycle disorders and liver cirrhosis. In
addition, in order to evaluate the feasibility of utilizing the same differentiated cells to elucidate thepathology of infectious diseases, we aimed to establish an infection model using these liver buds toevaluate hepatitis B virus (HBV) infection.
（３）Activity Reports
１）Research Activities
1. Development of a quality evaluation method for human iPSC liver buds
To achieve therapeutic effect in treating liver diseases, it is necessary to transplant a large
number of human iPSC liver buds. In order to ensure safety by excluding the presence of residual
undifferentiated iPSCs that may cause tumor formation, it is necessary to establish a techniquefor detecting and evaluating undifferentiated cells within the liver buds. LIN28A was previously
reported to be a marker of undifferentiated iPSCs, but we confirmed that expression is retained
through the early stages of hepatocyte differentiation. Therefore, it is necessary to identify novel
markers suitable for the detection of undifferentiated iPSCs (purity test). Overall three different
markers for characterizing undifferentiated cells were identified. It is now possible to detect thepresence of undifferentiated cells at a frequency of 0.005% (reported at the 18th Annual Meeting
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of the Japanese Society for Regenerative Medicine, Japan Foundation for Applied Enzymology).
Single cell RNA sequence data analysis of human iPSC liver buds was performed. Subsequently
a novel marker that enables prediction of human iPSC liver bud function during the human iPSC
liver bud production process was identified. These evaluation methods are currently being
considered for implementation as part of the manufacturing process in the future.
2. Examination of the therapeutic efficacy of human iPSC liver bud for treating urea cycle
disorders and cirrhosis
Verification of the therapeutic efficacy of human iPSC liver bud transplantation involves twostages. First, a method for evaluating metabolic abnormality in mouse models of urea cycle
disorders was established. Thereafter, the therapeutic efficacy of human iPSC liver buds wasinvestigated using Ornithine Transcarbamylase (OTC) deficient mice. It could be confirmed thatammonia metabolism of OTC deficient mouse improved after subrenal transplantation of human
iPSC liver buds, and the therapeutic effect after transplantation was confirmed. An investigation
into the mechanisms revealed that that engrafted tissue showed OTC activity, which was
confirmed by a metabolic flux analysis method that was developed in this laboratory.
Furtheremore, preparation for the clinical application of human iPSC-derived liver bud is wellunder way in cooperation with Yokohama City University. Study results are being compiled anddocuments such as Standard Operating Procedures (SOP) have been prepared. This is alongsidewriting a regenerative medicine provision plan as well as other related documents. These will be
submitted as supporting documents for an application to be examined by the regenerative
medicine committee of the National Center for Child Health and Development.
3. Establishment an infection model for HBV
Human iPSC liver buds can recapitulate the tissue structure and metabolic functions of humanliver thus applications can extend to its establishment as a pathological model. An investigation
into the practical utility of these liver buds for assessing HBV infection revealed that HBV canpersistently infect human iPSC liver buds long-term and reproduce characteristic changes inhepatocytes associated with HBV infection (Nie YZ, Taniguchi H et al, EBioMedicine. 35:114123, 2018). From these results, it was confirmed that human iPSC liver buds are useful for
elucidating the infection mechanisms of HBV.
２）Education Activities
7 students (3 master course, 4 doctor course) were trained in educational research activities. Fiveof them are international students.

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３）Social Activities
Collaboration with various companies is crucial for promoting clinical application of human iPSC
liver bud. Recently, in collaboration with Ajinomoto Co., Inc., we established a protocol for
producing human iPSC liver buds that complies with GCTP (Good Gene, Cellular, and Tissue-based
Products Manufacturing Practice) standards. This allows production of manufactured cells to agrade that is required for clinical trials. In addition, discussions are advanced in strengthening ourcollaboration with Healios Co., Ltd., which is a biotechnology company with a strong track recordof conducting multiple clinical trials.
４）International Activities
Joint research is being conducted with Zhongshan University, Guangdong Province, China. Thisinstitution processes a large number of clinical liver transplantation (about 320 cases / year) andowns a large-scale facility for cynomolgus monkeys. Meetings have been held discussing such
topics as how a close cooperation system can be established. From the next fiscal year, Zhongshan
University clinicians and researchers will be accepted into the Center for Stem Cell Therapy to
begin acceleration of the joint research partnership.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
Although preparations for clinical trials are well under way, further progress will be highly
dependent upon securing new grants. International join research is vital to facilitate the exchange ofideas and scientific expertise. Collaboration with Zhongshan University allows our method ofgenerating and transplanting iPSC-derived organoids to be evaluated in larger mammals such as
cynomolgus monkeys. Provision of education will be equally important to train the next generation ofyoung researchers who can carry out the research associated with this laboratory. This includes
recruiting international graduate students. As part of the recruiting efforts, plans have been made tocreate an internationally appealing website and to actively promote the introduction of laboratories onopen campuses.

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Division of Stem Cell Transplantation（１）Members
Professor

Arinobu Tojo

Associate Professor

Satoshi Takahashi（２）Research objectives
We are conducting clinical stem cell transplantation, especially using cord blood as a promisingalternative donor for clinical use and investigating optimal strategies to obtain the best results in thisarea. We are also generating pre-clinical study to utilize virus-specific CTL for immune competentpatients such as post-transplantation. Our goal is as allogeneic transplantation to be safer therapeutic
option and to extend for older patients.
（３）Activity Reports
１）Research Activities
Our division plays a clinical part of Center for Stem Cell Biology and Regenerative Medicine,and is in charge of treatment of hematological disorders, especially relapsed/refractoryhematological malignancies. We have been conducting allogeneic stem cell transplantation(alloSCT) using a variety of stem cell source including cord blood (CB), bone marrow (BM) andmobilized peripheral blood (PB), and mainly focus on the preferential use of cord blood, since weare one of the pioneers of cord blood transplantation in adults. The clinical outcome of adult CBTin our institution is comparable to the best one in both Japan and western countries (5-year eventfree survival is around 60% for acute leukemias). Our publications on adult CBT have had manycitations so far. The annual number of alloSCT between 2016 and 2018 is shown in the following
table.
FY

The number of alloSCT

Total

BM (unrelated)

PB

CB

2016

3 (0)

0

18

21

2017

2 (0)

1

17

20

2018

2 (1)

1

18

21

In addition, we are conducting a physician-initiated clinical trial of cord-derived mesenchymal
stromal cell (C-MSC) therapy for therapy-resistant severe acute graft versus host disease (aGVHD)
and a commercially-sponsored phase I/II clinical trial of CD19-targeted CAR-T cell therapy forrelapsed/refractory B cell acute lymphoblastic leukemia (B-ALL).

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Based on our clinical database of alloSCT, we have extensively studied factors affecting on theclinical outcomes and complications in CBT and published many original articles in peer-reviewed
international journals; 7 papers in FY2016, 10 in FY2017, and 12 in FY2018.
２）Education Activities
Education and instruction to residents and clinical research fellows is achieved as On-the-JobTraining (OJT). We supervised 4 senior residents in 2016, 3 in 2017, and 2 in 2018 according to theclinical hematology program. All these residents were qualified to be board certified hematologistsof Japanese Society Hematology (JSH).
３）Social Activities
We have been in charge of coordination in the Japan Marrow Donor Program (JMDP) andinvolved in confirming the eligibility and final consent of unrelated volunteer donors for BM
collection. IMSUT Hospital is a BM collection facility authorized by JMDP, and then we conducted
BM harvest from 4 unrelated volunteer donors in FY2016, 2 in FY2017 and 3 in FY2018.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
Although alloSCT is progressing steadily, there still remain to be solved many problems including
availability and safety of donors, engraftment failure of donor cells, regimen-related toxicities, relapse,
GVHD, opportunistic infections and late complications. Among those, the most important issue isprevention of relapse after alloSCT. To challenge this issue, several modalities are being applied into
clinic. These include liquid biopsy of minimal residual disease, novel antibody drugs and CAR-T cells
and so on. In recent years, HLA-haploidentical related donors are becoming popular as alternative
donors, and GVHD treatment with MSC, fecal microbiota transplantation (FMT) as well as novel
agents are being developed. In these situations, we will take a problem-oriented approach to improve
clinical outcome and safety of alloSCT.

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Division of Stem Cell Processing/Stem Cell Bank
（１）Members （as of March 31, 2020）
Professor

Hideki Taniguchi

Postdocs

2

Technicians

2（２）Research objectives
Division of Stem Cell Processing / Stem Cell Bank has been working on its activities, aiming at thefollowings. 1) To improve efficacy and safety in innovative treatment modalities that include stem
cell gene therapy and allogeneic hematopoietic transplantation based on basic / pre-clinical studies;2) To develop new treatment strategies including drug discovery for intractable disorders in a broadcollaboration through disease studies utilizing induced pluripotent stem (iPS) cell-based technologies.
（３）Activity Reports
１）Research Activities
Through 2016 April ~ 2019 March, we had four publications describing the researches that wereconducted for the improvement of hematopoietic stem cell-based medicine (J Exp Med.
2016;213:1865, Stem Cells. 2017;35:989, ACS Synth Biol. 2018;7:1709, Stem Cell Rev.
2018;14:101-9). In addition, we had three papers published regarding disease-modeling studies
utilizing iPS cells, (Hum Gene Ther Methods. 2016;27:197, Stem Cell Reports. 2017;8:1155, Stem
Cell Reports. 2018;11:380). Besides the above publications, the results obtained through iPS cellbased research have been reported at either domestic (21) or international (5) academic meetings.
As Stem Cell Bank, we established 23 lines of disease-related iPS cells with their quality as researchmaterials assured by a series of defined analytical assessment. To contribute to wide applicationsof disease-specific iPS cells to research fields, we deposited 16 lines of those iPS cells to RIKEN
Bio-Resource Center.
２）Education Activities
Five Ph.D. students worked on each research theme that used human iPS cells, whereas one
young M.D. investigator conducted hematopoietic stem cell research. Each of them succeeded inearning a doctoral degree at the end.
３）Social Activities
One of the tasks assigned to Stem Cell Bank is to promote dissemination and enlightenment of
iPS cell-related technologies.

To support the on-site management of iPS cell-research at each
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laboratory, we had a substantial number of young investigators visiting or staying for days to months
at our place to learn the technologies.

Such training was given to investigators from many

locations, such as other campuses (Hongo and Komaba) of the University of Tokyo, Tokyo Medical
and Dental University, Tsukuba University, Hamamatsu University School of Medicine, and Showa
University. Also, we have established our unique instruction manual, in which researchers canfind the information necessary to handle human iPS cells appropriately for their research purposes.
These user manuals have already been distributed to a certain number of investigators.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
Although the generation of iPS cells has become a common practice in many laboratories, themethod we developed has proved highly valuable to the field with its extremely high iPS cell
establishment efficiencies (Stem Cell Res Ther. 2019; 10:185). Until recently, our special technicalskills related to iPS cell research have mainly been utilized for investigations targeting hematopoietic/ immune disorders. It is now highly desirable to extend the iPS cell-related study focuses on otherresearch fields, including those treating cancers, endodermal organs, or the others. Also, fruitfulcollaboration with other IMSUT-specialties, e.g., genomic medicine, infectious disease research, andproteomics, is expected to make this unique iPS cell study platform more invaluable for a wide variety
of applications in medical science.

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Division of Stem Cell Signaling（１）Members (common with those with Division of Cellular Therapy)
Professor

Toshio Kitamura

Postdocs

5

Graduate students

9Technicians

2

Others2（２）Research objectives
Purpose: To establish and characterize a knock-in mouse expressing a G0 marker mVenus-p27Kwhich we previously developed (Oki et al. Sci Rep, 2014).
Achievement: We established and characterized a knock-in mouse harboring mVenus-p27K- withthe lox-P cassette. We orally reported this in several academic meetings and published a paper(Fukushima et al. Cell Rep, 2019).
（３）Activity Reports
１）Research Activities
Purpose: Characterization of knock-in mouse of G0 marker and its application in research forleukemic stem cells (LSCs).
Achievements: We established a knock-in mouse harboring mVenus-p27K- with the lox-P
cassette, and crossed this mouse with Vav-Cre mouse to generate mice where mVenus-p27K- isexpressed in hematopoietic cells. Analyses of this mouse revealed that about 90% of long-term
hematopoietic stem cells (LT-HSCs) are in G0 phase as reported. After commitment to more matureprogenitors, cells in the G0 phase decrease in frequencies. Interestingly, most MEP (megakaryoerythroid progenitors) are cycling, leaving only 10% MEP in the G0 phase. In the peripheral blood,
all cells are terminally differentiated and G0 marker-positive. In addition, we also found thatcalcium concentrations are high in G0 marker-positive HSCs, and that calcium ionophore could
keep HSCs in G0 phase (Fukushima et al. Cell Rep, 2019).
We utilized the G0 marker mouse in investigation of CML-LSCs, and found that G0 markerpositive and CD27-positive fraction contains most LSCs in BCR-ABL-positive LSK cells(manuscript in preparation).
２）Education Activities (common with those with Division of Cellular Therapy)
Purpose: To recommend graduate students or postdoctoral fellow to go abroad for their research
after getting doctoral grades or publishing papers. To help graduate students to get jobs as
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researchers in pharmaceutical companies.
Achievements: During 2016 through 2020, 9 graduate students obtained doctoral grades, andamong them five got position as postdoctoral fellow, 2 in Canada from this year and 3 in USA fromnext April. One master student obtained a job as a researcher in a pharmaceutical company.
３）Social Activities (common with those with Division of Cellular Therapy)
The lab annually offer 6~8 open seminars including one concerning epigenetics open to generalpublic.
４）International Activities (common with those with Division of Cellular Therapy)
The lab has close connections with several foreign laboratories, several in USA and three in
Europe to do collaboration, exchange ideas and people. With Abdel-Wahab lab at Memorial Sloan
Kettering Cancer Center, we have many collaborations and published two papers (Inoue et al.
Leukemia, 2015; Nagase et al. J Exp Med, 2018) and another collaborative paper (Fujino et al.) is
now under revision. We also have close collaboration with Dr. Machiejewski at Cleaveland Clinic,
and has published a paper (Takeda et al. Blood, in press). In addition, we published a collaborative
paper with Dr. Gottgens lab in UK (Fukushima et al. Cell Rep, 2019).
The lab has also close relationship with Dr. Melnick lab at Weil-Cornell Medicine, Dr. Helin lab
and Dr. Levine both at Memorial Sloan Kettering Cancer Center, Dr. Skoda lab at University ofBasel, Dr. Schroeder lab at EZH Zurich, Dr. Scadden lab at Harvard and Dr. Goodell lab at Bailer
Medical College. We sent postdocs to Dr. Scadden lab, Dr. Abdel-Wahab lab, Dr. Melnick lab, Dr.
Helin lab (in Copenhagen at that time), and are going to send postdocs to Dr. Goodell lab, AbdelWahab lab, and Scadden Lab. We also sent a graduate student to Schroeder lab for a couple ofmonths for formal collaboration.
５）Other matters to be noted (common with those with Division of Cellular Therapy)
We filed a patent application for the ASXL1-MT-KI mouse.
The lab hosted US-Japan Hematology Meeting in Hawaii in March, 2017, 9th JSH International
Symposium at Kyoto in July, 2018, and 24th meeting for hematopoietic malignancies at Kobe inJanuary, 2019. The rock band “Negative Selection”, composed of Hematology and Immunology
professors including Professor Toshio Kitamura as a drummer, gave gigs at the gathering parties forthe latter two. In particular, in 9th JSH International Symposium, we played several hit songs ofEagles, Pink Floyd, and Deep Purple together with Dr. Radek Skoda from Switzerland and Dr.
Margaret Goodell from USA.
（４）Challenges and Future prospects (common with those with Division of Cellular Therapy)
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We plan to utilize results of mouse models to develop new strategies and drugs to cure patients withhematological malignancies in concert with pharmaceutical companies. In most cases, mouse models
rather accurately mimic the human disease. However, it is not clear how far we can extrapolate mousemodels to human diseases. Therefore, it is critical to simultaneously use human samples in theexperiments. Therefore, we are now seeking many hospitals who can supply samples from patientswith hematological malignancies.

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Division of Stem Cell Dynamics (-2019.3)（１）Members
Professor

Beate Heissig

Postdocs

1

Others1（２）Research objectives
The aim of the laboratory is to get a comprehensive understanding of the regulatory mechanisms of
how proteases and angiogenic factors control cell behavior in normal and pathological conditions,
namely 1) inflammation, 2) cancer growth, 3) and stem cell fate. Proteases perform highly selective
and limited cleavage of specific substrates including growth factors and their receptors, cell adhesion
molecules, cytokines, apoptotic ligand, and angiogenic factors. Understanding the target molecules ofproteases provides critical insights into basic biological cellular functions including proliferation,differentiation, and migration. Ultimately, it is our mission to identify novel therapeutic targets fordiseases like cancer or inflammatory diseases and to find novel ways to expand hematopoietic andmesenchymal stem cells. During the period 2016-2019, we focused on understanding the function of
two serine proteases, namely plasmin and tissue-type plasminogen activator in the field of
inflammatory diseases and stem cell biology.
（３）Activity Reports
１）Research Activities
The aim of the laboratory is to get a comprehensive understanding of the regulatory mechanismsof how proteases and angiogenic factors control cell behavior in normal and pathological conditions,
namely 1) inflammation, 2) cancer growth, 3) and stem cell fate. Proteases perform highly selective
and limited cleavage of specific substrates including growth factors and their receptors, celladhesion molecules, cytokines, apoptotic ligand, and angiogenic factors. Understanding the target
molecules of proteases provides critical insights into basic biological cellular functions including
proliferation, differentiation, and migration. Ultimately, it is our mission to identify novel
therapeutic targets for diseases like cancer or inflammatory diseases and to find novel ways toexpand hematopoietic and mesenchymal stem cells. During the period 2016-2019, we focused onunderstanding the function of two serine proteases, namely plasmin and tissue-type plasminogenactivator in the field of inflammatory diseases and stem cell biology. The research group consistedof the PI, a post-doc and graduate students.
Our research led to a total of 6 original manuscripts, including 2 with IF over 16, and 1 review
article (Adv Drug Deliver Review IF 16). My group showed that plasmin and tissue-type
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plasminogen activator contribute to inflammation (Blood IF 16.4, FASEB J IF 6), enhancemesenchymal stem cell expansion (Blood IF 16.4), and control tumor growth (FASEB J IF 6, BBRC
IF 3), and post-surgical adhesion (FASEB J IF 6). We identified plasmin and tPA as novel drugablepro-inflammatory molecules.
We also researched how the endothelial-derived growth factor Egfl7 controls stem cell fate. We
identified a novel regulatory mechanism on how the angiogenic factor Egfl7 controls stem cell
expansion that led to the initiation of a patent application through the University of Tokyo(international patent pending) and published that Egfl7 enhances T cell development (BBRC IF 3).
Research results obtained concerning the role of the angiogenic factor Egfl7 have not been
published yet, and research progress is delayed. The interest of companies on the patent required
experiments, which due to a lack of staff could not been done. More researchers (and not only apost-doc and myself) involved in the Egfl7-associated research projects and staff would haveaccelerated the research promotion. I am trying to improve the funding situation of the laboratory.
２）Education Activities
Over the period, 9 graduate students were instructed: 3 master students (Department of Medical
Genome, CBMS) and 3 Ph.D. students from the Medical Genome/CBMS, and 1 Ph.D. student and1 master student from the Graduate School of Medicine of the Tokyo University. 6 out of the 9students were international students. In addition, I mentored a Ph.D. student from Juntendo
University.
I was in charge of one class on the subject of stem cell biology for the Department of Medical
Genome (CBMS).
３）Social Activities
I have given two lectures on the role of female scientists and foreign scientists at the Delegationof the European Union to Japan.
Research results on the cancer study were made public to the society with more than 8 different
articles in newspapers in more than 4 countries, 2 different continents (Europe, Asia).
I have given a lecture at the Norwegian Embassy to enhance Norwegian-Japanese research effortson the expansion of mesenchymal stem cell studies both in preclinical and clinical studies.
４）International Activities
In collaboration with Dr. Schmidt at the University of Mainz (Germany), we clarified the functionof Egfl7 in hematopoietic stem cell biology.
In collaboration with the American-based company NapaJen, the laboratory concluded apreclinical study testing novel anti-GvHD drugs in murine acute Graft-versus-Host Disease models.
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In collaboration with Dr. Raeder at the University of Bergen, we study the role of protease inpancreatic cell development.
I have organized various meetings with researchers from the University of Bergen (Norway) at
the Institute of Medical Science, The University of Tokyo. Ultimately, these efforts led to the signingof a Memorandum of Understanding (MoU) of the University Bergen with the Institute of Medical
Science, the University of Tokyo.
In collaboration with researchers from the AnNaJah University in Palestine, we examine the roleof protease in stem cell biology.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
This Division has completed and closed as of March 31, 2019.

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Division of Stem Cell Cellomics (-2019.5)（１）Members
Project Associate Professor

Hiroshi Watarai

Others3（２）Research objectives
Centering around the field of immunology and stem cell biology, this division focused on
elucidation of functions and modes of differentiation and development of iNKT cell as the research
themes. In order to tackle new challenges, we participated in the ImPACT program “Creating new
Scientific values through planed serendipity”. We also worked on the development of engineeringand optical elemental technologies, aiming to introduce it as early as possible.
（３）Activity reports
１）Research activities
We newly achieved and reported creation of iNKT cell-deficient mice by establishing techniques
for single-cell analysis and introducing the CRISPR method, as well as elucidation of the associationof iNKT cells with obesity-induced inflammation and identification of neutrophil markers and iNKT
cell markers.
２）Education Activities
To advance research activities, we accepted students mainly from the collaborative laboratories
and gave them instruction. Eight students in the master’s course (including undergraduate students
in 6th-year) graduated and took jobs with pharmaceutical and food companies.
３）Social Activities
Every year the member of our laboratory participated in the outreach activity “Men-eki Fushigi
Mirai”, hosted by Japanese Society for Immunology as the chairperson, committee members, andsupporters (students) of the project and had opportunities to pass on the interesting aspects andimportance of immunity to the public.
４）International Activities
None.
５）Other matters to be noted
None.
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（４）Challenges and future prospects
This division concluded its term in May, 2019. As the term was limited, we could not recruit newstudents since we could not take responsibility for completing research instruction. And thus, someof the plans that should have been completed were delayed.

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Division of Experimental Pathology（１）Members
Professor

Yasuhiro Yamada

Assistant Professor

Sho Ohta

Postdocs

2

Graduate students

9Technicians

3

Others1（２）Research objectives
Stem cells play an important role in homeostasis of organ function in multicellular organisms. They
are responsible for tissue regeneration and their functional impairment causes various diseases inmammals. However, considering the complexity of multicellular organisms, it remains unclear how
tissue microenvironment affects stem cell functions. We aim to elucidate the molecular basis for stem
cell behavior in response to altered tissue microenvironments. The effort should eventually unveil thefundamental basis of how stem cells affect organismal functions in vivo and uncover the underlying
mechanisms of tissue regeneration, various diseases and organismal aging. These findings may
contribute to developing a feasible strategy to control the detrimental effects of stem cell dysfunction
in diseases and aging.
（３）Activity Reports
１）Research Activities
Since its inception on April 2019, Division of Experimental Pathology has investigated the stem
cell function in various biological aspects in multicellular organisms, including mammaliandevelopment and diseases. The following are major research achievements:a) Pluripotent stem cell features drive pediatric cancer development
Atypical teratoid/rhabdoid tumor (AT/RT), which harbors SMARCB1 mutation and exhibits acharacteristic histology of rhabdoid cells, has a poor prognosis. We established human SMARCB1deficient pluripotent stem cells (hPSCs). SMARCB1-deficient hPSCs, but not neuronal progenitor
cells, efficiently gave rise to AT/RT-like brain tumors in the mouse brain. We found that activationof an embryonic stem cell (ESC)-like signature confers a rhabdoid histology and causes a poor
prognosis. SMARCB1-deficient hPSCs offer the human models for AT/RT, which uncover atherapeutic target of AT/RT. Cell Reports. 26, 2608–2621, 2019.

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b) Unveiling epigenetic instability in pluripotent stem cells
Pluripotent stem cells (PSCs), including ESCs and iPSCs hold promise as cell sources forregenerative medicine. However, the epigenetic stability of PSCs has not been fully understood. We
conducted a comprehensive analysis of DNA methylation during somatic cell reprogramming. We
found that several imprinted genes are often de novo methylated in reprogrammed PSCs.
Mechanistically, ablation of Dnmt3a prevented PSCs from de novo DNA methylation. Notably,
similar DNA hypermethylation pattern was observed in pediatric cancers. These results may haveimportant implications in the pathogenesis of pediatric cancers and the application of PSCs. Stem
Cell Reports. 12(5):1113-1128, 2019.
２）Education Activities
Since April 2019, we accepted master course and PhD course students in Graduate School of
Medicine and Graduate School of Frontier Sciences.
３）Social Activities
Prof. Yamada is a member of Science Council of Japan, a councilor of Japanese Cancer
Association, The Japanese Society of Pathology, and The Japanese Society for Epigenetics.
４）International Activities
A joint project with Prof. Miguel Esteban at Chinese Academy of Sciences (CAS) is currently
ongoing as a JSPS-CAS joint program (Project title: Molecular roadmap of in vivo reprogrammingat the single-cell level). Our group is also collaborating with investigators at Harvard University,
UCLA, and Max Plank Institute. Prof. Yamada is a member of publication committee ofInternational Society for Stem Cell Research (ISSCR). Prof. Yamada co-organized Stem Cell
Crossroads, a Cold Spring Harbor Asia (CSHA) meeting in 2018.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
We will investigate the stem cell function at the organismal level and reveal the role of stem cell
dysfunction in the pathogenesis of age-related diseases. The ultimate goal of our research projects is
to develop a novel therapeutic approach targeting the stem cell function to treat patients. Particularly,
we will aim to rejuvenate the function of tissue stem cells to facilitate tissue regeneration.

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Division of Stem Cell Biology（１）Members
Project Associate Professor

Satoshi Yamazaki

Postdocs

2

Graduate students

3

Technicians

5

Others1（２）Research objectives
Our studies focus mainly on investigation of stem cell biology using the hematopoietic stem cell(HSC) as a research model. Recent identification of a variety of stem cell sources including embryonicand somatic (tissue-specific) stem cells has brought about substantial progress in the field of stem cellresearch.
（３）Activity Reports
１）Research Activities
Our studies focus mainly on investigation of stem cell biology using the hematopoietic stem cell(HSC) as a research model. Recent identification of a variety of stem cell sources including
embryonic and somatic (tissue-specific) stem cells has brought about substantial progress in thefield of stem cell research. The HSC represents the first stem cell for which identity and existence
were determined. Studies on HSCs have provided us with some basic concepts applying to different
types of stem cells, yet many of these concepts remain unverified. It therefore is very important tocontinue basic studies to answer many questions left unsolved and thus to permit contributions to
the field of biological research and clinical medicine. HSCs are capable of continuous supply of all
lineages of blood cells to each individual for his or her entire life. Both self-renewal andmultilineage differentiation potentials enable this task. One major advantage in HSC research liesin that established assay systems allow clonal analysis of each individual stem cell. Using a defined
assay system, we can test capabilities of self-renewal and multilineage differentiation at single celllevels using either in vitro or in vivo assays. We believe that HSC research will eventually makegreat contributions to the development of safe and efficacious regenerative medicine and genetherapy.
２）Education Activities
None.
３）Social Activities
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None.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
In the future, through basic research on stem cells, we will lead to clinical research to treat
diseases using stem cells.

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International Research Center for Infectious Diseases
Director Yoshihiro Kawaoka（１）Background (Missions and Features)
The COVID-19 pandemic continues to kill many people and affect economics and our daily lives,
reminding us of what infectious diseases can do. To control infectious diseases, we need to understandpathogens and develop diagnostic tools and countermeasures such as drugs and vaccines. To this end,
the International Research Center for Infectious Diseases was established in 2005 at the Institute ofMedical Science, the University of Tokyo. Because the current governmental financial support for thiscenter has been reduced by 75% compared to that in 2005, we now have only two research departments
and the “Pathogenic Microbe Repository Unit”.
（２）Organization
Department of Special Pathogens
PI, Yoshihiro Kawaoka, DVM, PhD [concurrent appointment] [2005-to date]
PI, Chieko Kai, DVM, PhD [concurrent appointment] [2005-2018]
Department of Infectious Disease Control
PI, Yasushi Kawaguchi, DVM, PhD [concurrent appointment] [2005-to date]
Division of Viral Infection (PI, Takeshi Ichinohe, PhD [2012-to date])
Division of Bacteriology (PI, Hitomi Mimuro, PhD [2011-2018])
Division of Systems Virology (PI, Kei Sato, PhD [2018-to date])
Pathogenic Microbes Repository Unit
（３）Activity Reports
１）Research Activities
Researchers in our centers study herpes viruses, influenza viruses, Ebola viruses, HIV, Nipah
virus, and Helicobacter Pylori and have made major contributions to the field and reported theirfinding in high profile journals, specifically: 1 in Nature (IF 43.070); 1 in Cell (IF 36.216); 1 in
Nature Biotechnology (IF 31.864); 1 in Nature Immunology (IF 23.530); 1 in Cell & Host Microbe(IF 15.753); 5 in Nature Microbiology (IF 14.300); 6 in Nature Communications (IF 12.353); 4 in
the Journal of Clinical Investigation (IF 12.282); and 1 in Nature Protocols (IF 11.334).
２）Education Activities
The number of students who received degrees is: 7 doctors and 4 masters in FY2016; 3 doctors
and 5 masters in FY2017; 7 doctors and 3 masters in FY2018; and 6 doctors and 5 masters in
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FY2019.
To help our students to be international researchers, we encourage them to give presentations atinternational conferences. The number of the students who presented at international conferences
is: 6 in FY2016, 7 in FY 2017, 6 in FY 2018, and 5 in FY2019.
Graduate students and postdoctoral fellows received the following awards:
Feb 2017 The 45th Annual Meeting of the Japanese Society for Immunology, Best presentation
award winner (Postdoc H.U.)
Mar 2017 IMSUT Outstanding student publication award FY 2016 (D3 S.N.)
Jun 2017

UT Graduate Program for Leaders and Life Innovation, General Meeting 2017, Best
Poster Award (D2 M.S.)

Sep 2017 The Japanese Society of Veterinary Science, the 8th Vet. Microbiology Best
presentation award winner (D3 M.W., D3 T.N, D2 K.T.)
Mar 2018 The 28th Molecular Immunology Forum Tokyo Research Incentive Award (D3 M.M.)
Mar 2018 IMSUT Outstanding Student Publication Award (D3 M.M.)
Apr 2018 Japanese Society for Immunology, Tadamitsu Kishimoto International travel award
winner (Postdoc H.U.)
Sep 2018 The 27th Annual Meeting of the Bioimaging Society of Japan BIOIMAGING, Bestimaging Carl Zeiss award winner (Postdoc H.U.)
Mar 2019 The 47th Annual Meeting of the Japanese Society for Immunology, Best presentation
award winner (Postdoc H.U.)
Mar 2019 Most outstanding student publication award FY 2018 (D3 A.Y.)
Apr 2019 Best presentation award, General Meeting of Japanese Society of Bacteriology (D2
R.T.)
Mar 2020 Outstanding student publication award FY 2019 (D4 K.T.)
３）Social Activities
Every summer, we hold a public seminar "LOVE LABO" for high school and university students.
In addition, we conduct the "LOVE LABO Laboratory Tour", which includes a laboratory tour andspecial lectures for high school students, and a one-day laboratory experience course for university
students. Some of the students who participated in these activities later joined one of our labs asgraduate students.
４）International Activities
We are conducting international joint research with 24 institutions in 7 countries. We havepublished the following international co-authored papers: FY2016, 11 papers; FY2017, 15 papers;
FY2018, 20 papers; and FY2019: 20 papers.
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In addition, we held the following international symposia:
06-09 Sep 2016: 15th Awaji International Forum on Infection and Immunity
05-08 Sep 2017: 16th Awaji International Forum on Infection and Immunity
04-07 Sep 2018: 17th Awaji International Forum on Infection and Immunity
19-20 Feb 2019: Influenza and Other Infections
10-13 Sep 2019: 18th Awaji International Forum on Infection and Immunity
５）Other matters to be noted
In the Pathogenic Microbes Repository Unit, we distributed pathogenic bacterial strains touniversities, national public research institutes, nationwide sanitary laboratories, hospitallaboratories, food laboratories, and corporate laboratories. We distributed 25 strains in FY2016, 14
strains in FY2017, 15 strains in FY2018, and 11 strains in FY2019. Thus, we contributed to
infectious disease and medical microbiology education and research in Japan.
In addition, we held the following symposia:
17 Feb 2017: FY2016 Rising Stars in Cutting Edge Immunology Research
14 Mar 2018: Symposium on 4 Universities Infectious Diseases Collaborative Research
Education Union
31 Jan 2019: FY2018 Rising Stars in Cutting Edge Immunology Research
27 Jan 2020: FY2019 Rising Stars in Cutting Edge Immunology Research（４）Challenges and Future prospects
At the end of March 2019, Professor Kai (concurrent appointment) retired and Associate Professor
Mimuro (concurrent post) moved due to Osaka University. Due to continued government budget cuts,
we are unable to increase the number of faculty members in our center. The limited number ofscientists in our center impedes our ability to respond to emerging pathogens such as SARS-CoV-2.
We hope that the Japanese government will increase our budget in the future.

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Division of Viral Infection（１）Members
Associate Professor

Takeshi Ichinohe

Graduate students

1（２）Research objectives
We focus on understanding how influenza virus is recognized by innate immune systems and how
the innate recognition receptor controls the virus-specific adaptive immune responses. Our recent
focus also includes the study of how microbiota regulates adaptive immune responses to influenza
virus infection. Our ultimate goal is to utilize the knowledge we gain through these areas of researchin the rational design of effective intranasal vaccines.
（３）Activity Reports
１）Research Activities
1. Recognition of influenza virus by cytosolic DNA sensors
Cytosolic mitochondrial DNA (mtDNA) activates cGAS-mediated antiviral immune responses,
but the mechanism by which RNA viruses stimulate mtDNA release remains unknown. Here weshow that viroporin activity of influenza virus M2 or encephalomyocarditis virus (EMCV) 2B
protein triggers translocation of mtDNA into the cytosol in a MAVS-dependent manner. Although
influenza virus-induced cytosolic mtDNA stimulates cGAS- and DDX41-dependent innate immune
responses, the nonstructural protein 1 (NS1) of influenza virus associates with mtDNA to evade the
STING-dependent antiviral immunity. The STING-dependent antiviral signaling is amplified inneighboring cells through gap junctions. In addition, we find that STING-dependent recognition of
influenza virus is essential for limiting virus replication in vivo. Our results show a mechanism bywhich influenza virus stimulates mtDNA release and highlight the importance of DNA sensing
pathway in limiting influenza virus replication (Moriyama et al. Nat Commun. 2019).
2. Effects of ambient temperature in the induction of antiviral immunity
Although half of the world’s population could face severe food crisis as a result of global warmingby the end of this century, the effects of environmental temperature and host nutritional status inhost defense to viral infection in vivo are less clear. Here, we demonstrated that exposure of miceto the high ambient temperature of 36 °C reduced their food intake and impaired adaptive immune
responses to influenza virus infection. In addition, we found that administration of glucose or dietary
short-chain fatty acids restored influenza virus-specific adaptive immune responses in high heatexposed mice. Our results imply possible public health problems and concerns that outside
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temperature and host nutritional status may be critical determinants of viral pathogenesis or vaccine
efficacy (Moriyama et al. Proc Natl Acad Sci U S A. 2019).
3. Pathogenesis of SARS-CoV
Nod-like receptor family, pyrin domain-containing 3 (NLRP3) regulates the secretion ofproinflammatory cytokines interleukin 1 beta (IL-1β) and IL-18. We previously showed that
influenza virus M2 or encephalomyocarditis virus (EMCV) 2B proteins stimulate IL-1β secretion
following activation of the NLRP3 inflammasome. However, the mechanism by which severe acuterespiratory syndrome coronavirus (SARS-CoV) activates the NLRP3 inflammasome remains
unknown. Here, we provide direct evidence that SARS-CoV 3a protein activates the NLRP3
inflammasome in lipopolysaccharide-primed macrophages. SARS-CoV 3a was sufficient to cause
the NLRP3 inflammasome activation. The ion channel activity of the 3a protein was essential for
3a-mediated IL-1β secretion. While cells uninfected or infected with a lentivirus expressing a 3aprotein defective in ion channel activity expressed NLRP3 uniformly throughout the cytoplasm,
NLRP3 was redistributed to the perinuclear space in cells infected with a lentivirus expressing the
3a protein. K+ efflux and mitochondrial reactive oxygen species were important for SARS-CoV 3ainduced NLRP3 inflammasome activation. These results highlight the importance of viroporins,transmembrane pore-forming viral proteins, in virus-induced NLRP3 inflammasome activation(Chen et al. Front Microbiol. 2019).
4. SFTS viral strategy that inhibits host antiviral immunity
Recognition of viruses by host innate immune systems plays a critical role not only in providing
resistance to viral infection but also in the initiation of antigen-specific adaptive immune responses
against viruses. Severe fever with thrombocytopenia syndrome (SFTS) is a newly emerging
infectious disease caused by the SFTS phlebovirus (SFTSV), a highly pathogenic tick-borne
phlebovirus. The 294-amino-acid nonstructural protein (NSs) of SFTSV associates with TANKbinding kinase 1 (TBK1), a key regulator of host innate antiviral immunity, to inhibit interferon beta
(IFN-β) production and enhance viral replication. Here, we demonstrate that two conserved aminoacids at positions 21 and 23 in the NSs of SFTSV and heartland virus, another tick-borne
phlebovirus, are essential for association with TBK1 and suppression of IFN-β production. Our
results provide important insight into the molecular mechanisms by which SFTSV NSs helps tocounteract host antiviral strategies (Moriyama et al. J Virol. 2018).
２）Education Activities
A Ph.D. student published six papers as a first author in high impact factor journals including
Nature Communications, PNAS, and Journal of Virology. After graduation, she got a postdoctoral
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fellowships from Japanese government to extend her research in Fukuoka University. Recently, shestarted a new research project as a postdoctoral fellow in Yale School of Medicine (Prof. Akiko
Iwasaki’s laboratory).
３）Social Activities
I attended several outreach activities for high school and undergraduate students to introduce ourrecent findings. In addition, I hold a short-term training program for undergraduate students to teachthem laboratory works.
４）International Activities
I continue international joint research with 3 institutes including Yale University, National Taiwan
University, and Korea Advanced Institute of Science and Technology.
５）Other matters to be noted
2011 The Commendation for Science and Technology by the Minister of Education, Culture, Sports,
Science and Technology, Japan: the Young Scientists' Prize (T.I.)
2014 Sugiura Incentive Award of the Japanese Society for Virology (T.I.)
2015 Research Incentive Award of the Kao Foundation for Arts and Sciences (T.I.)
2017 Takahashi Incentive Award of the Japanese Society for Vaccinology (T.I.)
2020 Research Incentive Award of the Intestinal Microbiology Society (T.I.)（４）Challenges and Future prospects
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the infectious disease
COVID-19. Despite the tremendous efforts to control the disease, COVID-19 has now spread to over
100 countries and caused a global pandemic. Therefore, there is an urgent and important public healthneed to develop effective vaccines against SARS-CoV-2. Thus, we will develop an intranasal vaccinethat induce protective mucosal immune response at upper respiratory tract and protect against SARSCoV-2 infection.

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Division of Bacteriology (-2019.3)（１）Members
Associate Professor

Hitomi Mimuro

Graduate students

1（２）Research objectives
We are investigating the pathogenicity of gastrointestinal infection pathogenic bacteria. We will
elucidate the dynamics of Helicobacter pylori (H. pylori) in the intestinal tract by 2018. By 2020, we
aim to clarify the mechanisms of persistent infection of H. pylori based on bacterial genome sequencevariation.
（３）Activity Reports
１）Research Activities
We have been conducting researches to elucidate the infection mechanisms of pathogenic
gastrointestinal infectious pathogenic bacteria such as H. pylori, which is a causative agent of gastricdiseases such as gastric cancer. Our goals from April 2016 to March 2019 were to elucidate themechanisms of H. pylori infection in the intestinal tract and to elucidate genomic mutations in H.
pylori that persistently infect the stomach.
When H. pylori invade the body along with foods and drinks during childhood, they adhere to
gastric epithelial cells, establish long-term infection, and after decades, develop gastritis and gastriccancer. We have previously reported that the uptake of bacterial antigens at the immune system
Peyer's patches in the intestinal tract is essential for the induction of H. pylori-induced gastritis.
However, unlike the microaerobic environment in the stomach, bacterial dynamics in the anaerobic
intestinal tract is unknown. In addition, it is considered that in the process of persistent infection, H.
pylori enables to change the protein expression pattern by introducing mutations into its genome
sequence under the environment, thereby enabling persistent infection. Graduate students in ourlaboratory successfully found that H. pylori change its morphology in an anaerobic environment
such as the intestinal tract, and its growth decreases, but when it is returned to the optimum
environment, the morphology and growth ability are restored. She reported this finding in a paper(Hirukawa et al., Microbial Immunol, 2018), and she received a degree. Besides, we constructed arodent infection model of H. pylori, isolated colonized bacteria that established persistent infection
from the stomachs and performed whole-genome analysis using a next-generation sequencer. As aresult, we have found several specific mutations that changed the expression of multiple novel
pathogenic genes that were acquired during host adaptation [Kinoshita-Daitoku et al., Biochem
Biophys Res Commun (2020), Microbiol Resour Announc (2020)]. Among these novel genes, we
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analyzed the effects of small RNA, which have particularly significant changes in the pathogenicity
of bacteria (Kinoshita-Daitoku et al., bioRxiv, 2020). Based on these achievements, graduate
students obtained his degree.
From these, it is considered that the results in our laboratory have been sufficiently achieved fromthe viewpoint of research execution. We will carry out additional experiments necessary for therevision in the future, and publish a paper as soon as possible.
２）Education Activities
The goal from April 2016 to March 2019 is to obtain a doctoral degree for four graduate students
and one master's degree.
In fact, with regard to doctoral programs, a total of four people, two completed in March 2017,
one completed in March 2018, and one ended in March 2019, received a degree. Also, one master's
degree student received a degree in March 2018.
As a result, we were able to achieve the results in terms of educational activities and the numberof students with a degree. Among the degree-obtained students, the first author's papers were
accepted after graduation. Unpublished contents will be published as soon as possible.
３）Social Activities
None.
４）International Activities
None.
５）Other matters to be noted
2019 Best presentation award, General Meeting of Japanese Society of Bacteriology (D2 R.T.)
2018 Uehara H. pylori Award, The Japanese Society for Helicobacter Research (H.M.)（４）Challenges and Future prospects
It is a problem in our laboratory that it takes time to publish a paper on research results. In the future,
we aim to realize more prompt research presentations.
This Division has completed and closed as of March 31, 2019.

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Division of Systems Virology（１）Members
Associate Professor

Kei Sato

Postdocs

1

Graduate students

1

Technicians

3（２）Research objectives“Systems Virology” is a scientific field to understand “viruses” from multiple aspects in the
combination of experimental virology and a variety of sciences such as bioinformatics, molecular
evolution, phylogenetic, paleobiology, and mathematics. We consider the virus-host interaction andthe events triggered by virus infections as a “mutualism” and “conflict” and aim to address thesevirological issues through multiple scientific approaches. Followings are our current projects:
1. Evolutionary episode of viruses and hosts
2. Mechanisms of viral cross-species transmission
3. Impact of endogenous viruses
4. Understanding of the viruses living with humans
5. Virus infections at “multi-omics” viewpoint（３）Activity Reports
１）Research Activities
1. Evolutionary episode of viruses and hosts
2. Mechanisms of viral cross-species transmission
We revealed that mammalian APOBEC3 proteins can be species barriers to restrict lentiviralcross-species transmission, while lentiviral Vif protein antagonize the antiviral actions of host
APOBEC3 proteins (Konno et al., J Gen. Virol., 2018 [IF 2.8] *corresponding author; Konno et al.,Retrovirology, 2019 [IF 3.7] *corresponding author). Also, we identified a novel anti-HIV-1 protein,
N4BP1, that triggers viral genomic RNA degradation (Yamasoba et al., Nat. Microbiol., 2019 [IF14.3]). Moreover, through comprehensive transcriptome analysis, we revealed the difference oninterferon responses in a variety of HIV-1-targeting cells (Aso et al., Front. Microbiol., 2019 [IF4.1] *corresponding author)
3. Impact of endogenous viruses
APOBEC3 genes are members of the AID/APOBEC gene family that are found exclusively inmammals. APOBEC3 genes encode antiviral proteins that restrict the replication of retroviruses by
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inducing G-to-A mutations in their genomes, and have undergone extensive amplification anddiversification during mammalian evolution. Endogenous retroviruses (ERVs) are sequences
derived from ancient retroviruses that are widespread mammalian genomes. In this study wecharacterize the A3 repertoire and use the ERV ‘fossil record’ to explore the long-term history ofco-evolutionary interaction between A3s and retroviruses. We examined the genomes of 160
mammalian species and identify 1,420 AID/APOBEC-related genes, including representatives ofpreviously uncharacterized lineages. We showed that APOBEC3 genes have been amplified in
mammals and that amplification is positively correlated with the extent of germline colonization by
ERVs. Moreover, we demonstrate that the signatures of APOBEC3-mediated mutation can bedetected in ERVs found throughout mammalian genomes, and show that in mammalian species withexpanded APOBEC3 repertoires, ERVs are significantly enriched for G-to-A mutations. Finally, weshow that APOBEC3 amplification occurred concurrently with prominent ERV invasions inprimates. Our findings establish that conflict with retroviruses is a major driving force for the rapid
evolution of mammalian A3 genes (Ito, Gifford and Sato, PNAS, 2020 [IF 9.4] *corresponding
author). We also revealed that endogenized human herpesvirus 6 may associate with immune
activation (Kumata, Ito and Sato, Virus Genes, 2020 [IF 1.6] *corresponding author).
4. Understanding of the viruses living with humans
Human-resident microbes can influence both health and disease. Investigating the microbiome
using next-generation sequencing technology has revealed examples of mutualism and conflict
between microbes and humans. Comparing to bacteria, the viral component of the microbiome (i.e.
the "virome") is understudied. Somatic tissues of healthy individuals are usually inaccessible forthe virome sampling, therefore, 1) which viruses infect which tissues in healthy individuals and 2)
how virus infection associates with human gene expression and perturbs immunologicalhomeostasis remains unclear. To characterize the human virome in a tissue-specific manner, here
we performed meta-transcriptomic analysis using the RNA-sequencing dataset from the GenotypeTissue Expression Project. We analyzed the 8,991 RNA-sequencing data obtained from 51 somatic
tissues from 547 individuals and successfully detected 39 viral species in at least one tissue. We
then investigated associations between virus infection and human gene expression and humandisease onset. To our knowledge, this study is the first comprehensive investigation of the human
virome in a variety of tissues in healthy individuals through meta-transcriptomic analysis (Kumata
et al, BMC Biology, 2020 [IF 6.7] *corresponding author).
5. Virus infections at “multi-omics” viewpoint
For eradication of HIV-1 infection, it is important to elucidate the detailed features andheterogeneity of HIV-1-infected cells in vivo. To reveal multiple characteristics of HIV-1-producing
cells in vivo, we used a hematopoietic stem cell-transplanted humanized mouse model infected with
GFP-encoding replication-competent HIV-1. We performed multiomics experiments using recently
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developed technology to identify the features of HIV-1-infected cells. We described multiple
characteristics of HIV-1-producing cells in vivo, which could provide clues for the development of
an HIV-1 cure (Aso et al, Cell Rep., in press [IF 7.8] *corresponding author)
２）Education Activities
We have weekly progress meeting (on Thursday) and journal seminar (on Monday). We routinely
have web meetings with the colleagues in the other laboratories via webcast.
３）Social Activities
As outreach activities, our laboratory joined "Lab-Labo", held in IMSUT in 2018 and 2019. The
PI joined an outreach seminar "NEKKEN summer school" in NEKKEN, Nagasaki University, 2019.
４）International Activities
To proceed multi-disciplinary research projects, our laboratory have a variety of international
collaborations with the scientists in University of Glasgow (UK; Drs. Robert Gifford, Sam Wilson,
David Robertson, and Massimo Palmarini), Ulm University (Germany; Drs. Daniel Sauter andFrank Kirchhoff), University of Minnesota (USA; Dr. Reuben Harris), and University ofPennsylvania (USA; Dr. Kotaro Sasaki).
５）Other matters to be noted
Apr 2020 The Commendation for Science and Technology by the Minister of Education, Culture,
Sports, Science and Technology, The Young Scientists’ Award (Kei Sato)（４）Challenges and Future prospects
In the last two years since the PI joined the IMSUT in April 2018, our laboratory published sevenscientific papers with correspondence, indicating that our scientific activity is high and goes
successfully. To expand our scientific activity, recruiting and educating graduate students would be
essential. Also, to address more important and complicated issues in the field of virology, moresophisticated approaches and productive international collaborations would be required. Since April
2020, our laboratory has started projects focusing on SARS-CoV-2, the causative agent of COVID-19.
This is one of the most important issues in the current world. We plan to elucidate the molecularmechanisms of COVID-19 pathogenesis and cross-species transmission of SARS-CoV-2 from bats tohumans.

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International Research and Development Center for Mucosal Vaccines
Director Hiroshi Kiyono (-2018)
Director Ken J. Ishii (2019-)（１）Missions and Features
Humans have evolved together with a wide variety of microorganisms through life phenomenon"Symbiosis and Elimination". The immune system that serves as its foundation for harmonizing with
beneficial microorganisms and attempting to eliminate it as harmful pathological microorganisms. The
development of antibiotics and vaccines and the advancement of public health care systems haveprovided means to prevent and contain infectious diseases, thus contributing to the welfare ofhumanity and social progress in the 20th century. However, we are now facing new challenges
including 1) The emergence of an entirely new range of problems including drug resistances,
immunocompromised hosts, and hospital-acquired infections; 2) Serious problems in developing
countries that repeat a vicious cycle of poverty and the spread of infectious diseases; and 3) The
occurrence of emerging/reemerging infectious diseases such as AIDS, tuberculosis, and malaria. In
advanced countries, the main serious problems include allergic diseases, such as pollen and foodallergies, cancer, and severe infectious diseases including influenza and COVID-19. It is now known
that a flexible but precise mucosal immune system exists and serves as an interface between in-andout-side environments. After infection, allergies and cancer often occur in mucosal tissues, such as the
respiratory, digestive, and urogenital organs. Both basic investigations to clarify the role of themucosal immune system from a physiological state to pathogenesis, and the development offundamental technology to induce and modulate mucosal immunity artificially, are essential for thedevelopment of new preventative treatments and therapies.
In these circumstances, it is important to take the initiative in the development of ‘mucosal vaccines’
as a next-generation strategy for the prevention and treatment of illness in our country and the rest ofworlds, which has taken the lead in the promotion of immunological research based on our
understanding of “ Symbiosis and Elimination”. In 2011, The Institute of Medical Science at The
University of Tokyo (IMSUT) initiated the establishment of an International Research andDevelopment Center for Mucosal Vaccine (IMV), to promote cooperation between international
researchers in integrating accumulated intellectual discovery and technology including immunology,
microbiology, oncology, genome medical science, regenerative medicine and systems biology in across-disciplinary manner. The center will develop an innovative academic field, termed ‘Mucosal
Vaccinology’, by promoting basic research on mucosal immunology and vaccinology for thedevelopment of the new generation of mucosal vaccines to form an international hub to foster nextgeneration researchers. Molecular and cellular bases of an integrated understanding of “Symbiosis
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and Elimination” will lead to the opening of a new era for the development of next-generation of
mucosal vaccines.

Director/Professor
Ken J Ishii

Professor
Cob an Cevayir（２）Organization
Division of Mucosal Barriology
Division of Innate Immune Regulation
Division of Clinical Vaccinology
Division of Mucosal Vaccine
Division of Mucosal Symbiosis（３）Activity Reports
１）Research Activities
Each division has its own task and goal for their research including publication, presentation at
the meeting, and patent application. Please see the reports of individual divisions for the details
described in the following pages.
２）Education Activities
Each division has its teaching activity for graduate students. Thus, faculty members of individual
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divisions are involved in didactic and research mentorship education.
３）Social Activities
Each division has collaborative projects with companies. Please see the reports of individual
divisions for the details described in the following pages.
４）International Activities⚫

The IMV has a research agreement with the Pasteur Institute in order to develop the joint
research unit in each institute. Dr. James DiSanto agreed to serve as the director of the joint
research unit at Pasteur Institute. As a part of this joint research project, we have been assessed
microbiota of the nasal cavity of allergic patients.

⚫

Dr. Kiyono possessed a position of Professor at The University of California, San Diego.

⚫

Dr. Kiyono as the principal investigator obtained a new research grant from the AMEDSATREPS program entitled “Surveillance and Laboratory Support for Emerging Pathogens of
Public Health Importance.

⚫

Dr. Ishii promoted international clinical study and got budget by GHIT fund.

５）Other matters to be noted
None.
（４）Challenges and Future prospects
Since Dr. Kiyono (Director) has been retired, Dr. Ken J. Ishii took over the director’s position of
IMV in April 2019. Dr. Ishii is currently planning a new organization of the center and preparing a
new budget proposal for the renewal at 2021.

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Division of Mucosal Barriology（１）Members
Professors

Hiroshi Kiyono (2016-2018), Kensuke Miyake (2018-2019),
Ken J. Ishii (2019), Cevayir Coban (2019-)

Visiting Professor

Koji Hase

Visiting Associate Professor

Shintaro Sato (2016-2019)

Project Associate Professors

Takako Negishi-Koga, Taketoshi Mizutani（２）Research objectives
Division of Mucosal Barriology is conducting research on understanding homeostasis between themucosal tissues and the immune barrier system. We will also focus on their pathological changes that
occur during microbial infection and/or other immunological disorders, that novel intervention andprevention are needed. In addition, another goal of our research is to explore antigen uptake receptors
on specialized epithelial M cells to identify potential targets for mucosal vaccine delivery. Thus, thisdivision aims to develop novel mucosal vaccines by taking advantage of the conjugation of M-cellreceptor ligands with various vaccine antigens. To accomplish our goals, we are fully employing our
evolutionally novel and fusion technics using molecular biology and bioengineering science.
（３）Activity Reports
１）Research Activities⚫

Visceral fat accumulation as observed in Crohn's disease and obesity is linked to chronic gut
inflammation, suggesting that accumulation of gut adipocytes can trigger local
inflammatory signaling. Thus, it is important to investigate direct interactions between
intestinal epithelial cells (IECs) and adipocytes. We originally established intact, polarized,
and cytokine responsive IEC monolayers from primary or induced pluripotent stem cellderived intestinal organoids by simple and repeatable methods. When these physiological
IECs were co-cultured with differentiated adipocytes in Transwell, pro-inflammatory genes
were induced in both cell types, suggesting reciprocal inflammatory activation in theabsence of immunocompetent cells. These inflammatory responses were blocked by NF-κB
or signal transducer and activator of transcription 3 inhibition and by anti-tumor necrosis
factor- or anti-IL-6-neutralizing antibodies. Our results highlight the utility of thesemonolayers for investigating IEC biology. Furthermore, this system recapitulates theintestinal epithelium–mesenteric fat signals that potentially trigger or worsen inflammatory
disorders such as Crohn's disease and obesity-related enterocolitis.

⚫

Gut epithelial organoids are routinely used to investigate intestinal biology; however, current
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culture methods are not amenable to genetic manipulation, and it is difficult to generatesufficient numbers for high-throughput studies. Here, we present an improved culture
system of human-induced pluripotent stem cell (iPSC)-derived intestinal organoids
involving four methodological advances. We adopted a lentiviral vector to readily establish
and optimize conditioned medium for human intestinal organoid culture. We obtained
intestinal organoids from human iPSCs more efficiently by supplementing WNT3A andfibroblast growth factor 2 to induce differentiation into definitive endoderm. Using 2D
culture, followed by the re-establishment of organoids, we achieved efficient transductionof exogenous genes in organoids. We investigated suspension organoid culture without
scaffolds for easier harvesting and assays. These techniques enable us to develop, maintain,and expand intestinal organoids readily and quickly at low cost, facilitating the highthroughput screening of pathogenic factors and candidate treatments for gastrointestinal
diseases.
⚫

Worldwide, human norovirus (HuNoV) is a major cause of intestinal infectious
gastroenteritis leading to morbidity and mortality in children and the elderly and thus having
major social and economic influences. Neither an effective vaccine nor an effective
treatment is currently available. One of the biggest reasons for the lack of an appropriate
prevention or treatment strategy is the unavailability of methods for culturing HuNoV.
Therefore, the recent development of a HuNoV replication system in human primary
intestinal epithelial cells (IECs) has spawned advances in HuNoV characterization andopened up new strategies for HuNoV vaccine development. However, this techniquecurrently requires human tissue cells and supplementation with bile, which contains
unidentified components. Here, we report the replication of HuNoV in human induced
pluripotent stem cell-derived IECs without bile. Furthermore, we provide evidence thatvaccination with not only GII.4 but also GII.17 virus-like particles can induce neutralization
antibodies against the predominant type of HuNoV, GII.4.

⚫

During this reporting period (April 2016 to March 2019), we have published more than 50
peer-reviewed papers and 14 of which are closely related to the projects described above.

⚫

We have filed one patent application: No. 2018- 152166, Shintaro Sato, Yoshikazu Yuki,
Hiroshi Kiyono, “Human norovirus-like particles and the usages”, 2018/ 8/13

２）Education Activities
The members participate in the annual event, “Future of Immunology” organized by the JapaneseSociety of Immunology (JSI) to enlighten the immunology to the general public including children
and students at The National Museum of Emerging Science and Innovation in every August.

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３）Social Activities
None.
４）International Activities
The 10th Probiotics, Prebiotics and New foods, Nutraceuticals and Botanicals for Nutrition and
Human and Microbiota Health /1st Science and Business Symposium, Rome, Italy５）Other matters to be noted
None.
（４）Challenges and Future prospects
We have accomplished our primary goals during this period. Since the divisions of theInternational Research and Development Center for Mucosal Vaccines (IMV) have been reorganized in 2019, we will put our efforts to investigate the roles of the mucosal barrier system
together with other divisions of the IMV including Mucosal Immunology, Mucosal Vaccine, andClinical Vaccinology. To do this, we will continue to apply for outside funding, including theGrant-in aids for Scientific Research announced by Japan Society for the Promotion Science (JSPS),
Japan Agency for Medical Research and Development (AMED) as well as others.

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Division of Innate Immune Regulation（１）Members
Project Professor

Satoshi Uematsu

Project Assistant Professor

Kosuke Fujimoto

Technician

1

Others2（２）Research objectives
1. Clinical application of our novel vaccine technology that can efficiently induce pathogen-specificsIgA on mucosal surface
2. Functional analysis of innate immune cells in the intestinal lamina propria
3. Development of new treatments for radiation-induced mucositis（３）Activity Reports
１）Research Activities
The innate immune system senses the invasion of pathogens, induces an inflammatory response,
and activates adaptive immunity. Since the innate immune system plays a role in initiating an
immune response, it is thought that regulation of this mechanism enables control of various diseases
related to the immune response. In particular, the innate immune system of the intestinal tract has avery unique function because it helps to ingests food safely and to coexist with commensal bacteria
in itestine. In the division of innate immune regulation, we have established a technique to isolate
innate immune cells from the lamina propria of the intestinal tract. Based on the findings obtained
from the functional analysis of intestinal innate immune cells, we will develop new mucosal
vaccines, treatment for various intestinal inflammation and the method to regulate intestinal bacteria.
1.

Development of a new mucosal vaccine

There is a need for the development of a next-generation vaccine that induces systemic and potent
pathogen-specific IgG and Th1 responses and high-titer pathogen-specific secretory IgA (sIgA) on
the mucosa. Our division identified the unuque dendritic cells (DC) in the intestine, which induce
IgA-producing B cells. We further found that the expression of retinoic acid synthase Raldh2 in DC
was essential for IgA induction. As a result of the screening of microbe components, β1,3-glucan
was found to induce Raldh2 in DC. By using CpG DNA and β1,3-glucan as mucosal adjuvants inintramuscular vaccination, we could induce antigen-specific IgG (in blood) and sIgA Induced (infeces). After the priming, high titer of antigen-specific sIgA was induced for a long period byboosting orally, respiratory tract, or vagina with only the antigen. Now, we are performing vaccine
experiments in monkeys for clinical application.
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2.

Functional analysis of innate immune cells in the intestinal lamina propria

CD11cintCD11bint MFs express CX3CR1. We are analyzing on the MFs about expression patternsof TLRs, cytokine production, regulatory function and roles in inflammation and infection. It is wellknown that large numbers of eosinophils reside in small intestinal lamina propira. However, thefunction of intestinal eosinophils is yet to be elucidated. We are analyzing on the eosinophils about
the activation mechanism and roles in inflammation, parasite infection and food allergy.
3.

Analysis of innate immunity in radiation syndrome

High-dose ionizing radiation induces severe DNA damage in the epithelial stem cells in small
intestinal crypts and causes gastrointestinal syndrome (GIS). Although the tumour suppressor p53
is a primary factor inducing death of crypt cells with DNA damage, its essential role in maintaining
genome stability means inhibiting p53 to prevent GIS is not a viable strategy. Here we show thatthe innate immune receptor Toll-like receptor 3 (TLR3) is critical for the pathogenesis of GIS.
Tlr3−/− mice show substantial resistance to GIS owing to significantly reduced radiation-induced
crypt cell death. Despite showing reduced crypt cell death, p53-dependent crypt cell death is not
impaired in Tlr3−/− mice. p53-dependent crypt cell death causes leakage of cellular RNA, which
induces extensive cell death via TLR3. An inhibitor of TLR3–RNA binding ameliorates GIS by
reducing crypt cell death. Thus, we propose blocking TLR3 activation as a novel approach to treat
GIS (Takemura N, et al. Nat Commun. 2014.). In addition, Radiation-induced intestinal fibrosis isa serious complication after abdominal radiation therapy for pelvic tumors or peritoneal metastases,
causing significant fibrosis, especially in the submucosa of the small intestine. This condition was
associated with excessive infiltration of activated eosinophils in the submucosa. After irradiation of
the abdomen, chronic cell death was induced in the intestinal crypt, causing adenosine triphosphate(ATP) leakage outside the cell and activating myofibroblasts directly under the crypt. This activatedmyofibroblast was found to infiltrate and activate eosinophils under the mucous membrane.
Activated eosinophils under the mucus membrane have been shown to stimulate collagenproduction from myofibroblasts through the production of TGF-β and induce significant fibrosis
under the mucosa. In collaboration with Kyowa Hakko Kirin Co., Ltd., we have developed a new
eosinophil-removing antibody targeting mouse interleukin (IL) -5 receptor (R) α. This antibody
abolished intestinal eosinophil infiltration and markedly improved radiation-induced intestinal
fibrosis. Based on the above, we were able to demonstrate a new treatment strategy for radiationinduced intestinal fibrosis by performing antibody treatment targeting eosinophils (Takemura N, etal. Sci Trans Med. 2018.). We believe that administration of eosinophil-removing antibody can
suppress fibrosis of the intestinal tract, prevent complications in patients after radiation therapy, andavoid a decrease in quality of life (QOL). We are now analyzing the mechanism of oral mucositis
after radiation to develop a new therapy.

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２）Education Activities
We accept 3 PhD students at the dual post.
３）Social Activities
We are collaborating with EA Pharma Co., Ltd and Meiji Co., Ltd.
４）International Activities
Our center has signed an agreement with the Pasteur Institute to create a joint unit for both parties.
Prof. James Di Santo, the counterpart of the other party, made this joint research contract together
with us. We are now conducting a joint research project to analyze the nasal microflora of allergic
patients in France.
５）Other matters to be noted
We made a patent application for our developed immunization method as a new vaccination in2016 (PCT / JP2016 / 67403). This was patented in 2019.
（４）Challenges and Future prospects
The granted patent has been licensed to Mitsubishi Tanabe Seiyaku Pharmaceutical Co., Ltd. and
we are developing a pneumococcal vaccine and COVID-19 vaccine by using this method. The future
prospect is to bring it into a formulation as a new mucosal vaccine.

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Division of Clinical Vaccinology（１）Members
Project Professor

Kohtaro Fujihashi

Project Associate Professor

Yosuke Kurashima

Technicians

1

Others1（２）Research objectives
To explore new avenues for mucosal vaccine development, investigators have begun to employ
novel adjuvants and targeting mucosal tissues and immune cells for vaccine delivery. Despite recently
advanced sciences, it still remains to develop effective mucosal vaccines for human use. To this end,
our main task is to define the effectiveness and safety of novel mucosal vaccines including adjuvantand delivery system-development and bring them from bench-top to practical applications. In order toaccomplish our goals, we are fully employing evolutionally novel and fusion technics using agriculture
and bioengineering science including botany and engineering knowledge.
（３）Activity Reports
１）Research Activities
In order to develop a new generation of oral vaccines which elicit mucosal immunity in the entire
mucosal surfaces including respiratory and reproductive tracts, we have been studied to discovernovel molecules which could use potential oral adjuvant for inducing global protective mucosal
immunity by using single-cell mRNA sequencing approach. We have successfully established andanalyzed several DNA libraries from nasopharyngeal associated lymphoid tissues and Peyer’s
patches of naïve mice as well as mice given the oral or nasal vaccine. We currently testing several
candidate molecules for their ability to elicit antigen-specific immunity in the entire mucosal tissues.
We have studied to better define the cellular and molecular mechanisms of dendritic cell-targeting
nasal adjuvant, i.e., plasmid encoding Flt3 ligand and CpG ODN for the induction of protective
secretory IgA (SIgA) antibody responses against respiratory pathogens in aged mice. We are
exploring the roles of Foxp1 and microRNA in the activation of naïve or memory CD4+ T cells forthe induction of mucosal immunity in the elderly. The successful outcome of our approaches would
lead to facilitate the development of novel mucosal vaccines for the elderly.
During this reporting period (2018 to present), we have published 8 peer reviewed original papers
and one review, and 5 of which are closely related to the projects described above. In addition, we
have 3 papers in preparation.

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２）Education Activities
None.
３）Social Activities
Collaborative research project with Astellas Pharmaceutical Inc to develop MucoRice-based neworal vaccines by using a novel oral adjuvant system.
We have been collaborative with Dr. Tomonori Nochi at Tohoku University to study the
relationship between gut microbiota and Peyer’s patch-dependent maternal IgA antibody responses.
This study is supported by Joint Research Project of the Institute of Medical Science, The Universityof Tokyo (IMSUT).
４）International Activities
We have two international collaborative researches with Dr. Peter B. Ernst at the University ofCalifornia San Diego (UCSD, Intratissue cohabitation of commensal bacteria for immunity andsymbiosis) and Dr. Catherine Tsai at University of Auckland (Development of M2e-based intranasal
universal influenza vaccine utilizing PilVax platform) supported by IMSUT International Joint
Research Program.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
We will keep up our high performance in research in a comparable fashion to the last 2 years. In
this regard, we will continue to study the projects showing above in order to understand the cellularand molecular regulation of mucosal immunosenecence and mucosal vaccines for the elderly by
evolutionally novel and fusion technics using agriculture and bioengineering science including
botany and engineering knowledge. The outcomes of studies will contribute to establish a healthy
aging society and subsequently fill the gap between the actual life span and healthy life.
In order to maintain our research activities as well as to be involved and contribute to IMSUT, it
will be essential to obtain new outside funding supports. We will continue to apply for outsidefunding, including the Grant-in aids for Scientific Research announced by Japan Society for the
Promotion Science (JSPS), Japan Agency for Medical Research and Development (AMED) as wellas others.

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Division of Mucosal Vaccine（１）Members
Professor

Ken J. Ishii

Visiting Professor

Jun Kunisawa

Visiting Associate Professor

Tomonori Nochi

Project Assistant Professor

Rika Nakahashi

Postdocs

3

Technicians

8

Others2（２）Research objectives
Division of Mucosal Vaccine is conducting research and development for mucosal vaccines. The
mucosal vaccine is a prospective strategy for vaccine development against pathogens invading throughmucosal tissues. We have examined the immunological functions of commensal and pathogenic
microorganisms as well as diets and applied them to the development of adjuvants and antigen delivery
for the efficient immune responses against mucosal vaccines. These findings also could be extended
to the development of mucosal immunotherapy against cancer, allergic, inflammatory, and infectious
diseases. To accomplish our goal, we are fully employing our evolutionally novel and fusion technics
using the agriculture and bioengineering science including botany and engineering knowledge.
（３）Activity Reports
１）Research Activities
Food poisonings caused by Clostridium perfringens, Shiga toxin (Stx)-producing Escherichia
coli (STEC), and cholera occur frequently worldwide; however, no vaccine is currently available.
Therefore, we aimed to develop a bivalent vaccine against C. perfringens, STEC, or cholera
infections. The fusion of the C-terminal region of C. perfringens enterotoxin (C-CPE) with Stx2 B
subunit (Stx2B) or cholera toxin B subunit (CTB) induced T cell-mediated high levels of C-CPE-,
Stx2B- or CTB-specific neutralizing IgG antibody responses which were sufficient for protective
immunity. These findings collectively indicate that C-CPE-based fusion protein could be efficientagainst C. perfringens, STEC, and cholera infections.
We have developed cationic types of cholesteryl group-containing pullulan (cCHP) nanogels asa novel drug delivery system that adhere to the epithelial layer of the nasal cavity after nasal
immunization and elicit the effective immunity by sustained antigen release. Using the cCHP
nanogel system, we are currently developing a universal nasal vaccine for all serotypes ofpneumococcal infection. Based on the findings, we plan to conduct a double-blind, randomized,
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placebo-controlled phase I study to evaluate the safety, tolerability, and efficacy of the cCHP
nanogel nasal vaccine. Further, we have been testing the effectiveness of cCHP nanogel-based nasal
vaccines for human papillomavirus and RSV in murine experimental models.
MucoRice-CTB (line 51A) has been developed as a rice-based oral vaccine against diarrheal
diseases. Line 51A was self-pollinated for five generations to fix the transgenes, and the seeds ofthe sixth generation produced by T5 plants were defined as the master seed bank (MSB). T6 plants
were grown from part of the MSB seeds and were self-pollinated to produce T7 seeds (next seedbank; NSB), and were compared to the whole genomes and proteomes of MSB and NSB samples.
Our results showed that NSB is essentially identical to MSB in terms of the genetic, protein contents,
and their functionality.
During this reporting period (April 2016 to present), we have published more than 50 peerreviewed papers which are closely related to the projects described above. In addition, we havepublished 15 review papers. Further, 5 manuscripts were submitted for the publication and 4 of them
are currently under the revision process.
２）Education Activities
None.
３）Social Activities
None.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
We will keep up our high performance in research in a comparable fashion to last 5 years. In thisregard, we will continue to study the projects showing above in order to understand the cellular andmolecular regulation of mucosal immunology and mucosal vaccine by evolutionally novel and fusion
technics using the agriculture and bioengineering science including botany and engineering knowledge.
In order to maintain our research activities as well as to be involved and contribute to IMSUT, it
will be essential to obtain new outside funding supports. We will continue to apply for outside funding,including the Grant-in aids for Scientific Research announced by Japan Society for the Promotion
Science (JSPS), Japan Agency for Medical Research and Development (AMED) as well as others.
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Division of Mucosal Symbiosis（１）Members
Project Professor

Tetsuro Matano

Project Associate Professor

Yoshiyuki Goto

（２）Research objectives
In the division of Mucosal Symbiosis, the following goals are set every year.
1. Publish at least 2 international journals
2, Submit at least 1 patent application
We will also investigate and clarify the scientific objectives as described below.
3. Elucidate the interplay between gut resident microorganisms and host epithelium and immune cells.
4. Isolate and identify intestinal microorganisms that contribute to boost host immunity and regulate
host diseases.
5. Clarify the mechanism of immune activation by intestinal microorganisms and develop novel
therapeutic technology to optimize the effect of vaccine.
6. Elucidate induction and regulation mechanism of α1,2-fucose of intestinal epithelial cells.
（３）Activity Reports
１）Research Activities
In our laboratory, we aim to develop new prophylactic, therapeutic, and diagnostic methods for
infectious diseases and other host diseases by conducting the research using immunological andbiological techniques. In particular, we isolate and identify useful gut microorganisms for humanand propose novel therapeutic approaches against various host diseases. Our research aim fromJanuary 2018 to March 2019 was to publish at least two international original articles and to apply
for at least one related patent. In fact, we published 6 original papers in international journals,
including 3 papers that are IF>10 in this period, and one more original article was accepted. We also
submitted one patent related to detecting gut inflammation. From these results, the progress of
research of Mucosal Symbiosis is satisfactory in this period.
２）Education Activities
None.
３）Social Activities
None.

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４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
We will continue to carry out the research stated in the above goals. As a potential problem, it isnecessary to develop research that is associated with clinical research on human diseases in addition
to the basic research using experimental animals. We plan to promote research directly linked tocontrol human disease by accelerating the corroboration with clinical researchers and promoting theanalysis and isolation of microorganisms in feces and tissue samples from patients with specificconditions. In addition, we will continue the isolation, identification, and management of
microorganisms that regulate human diseases and create a biological bank of disease-related
microorganisms in the future. At the same time, we aim to apply various patent by establishing amethod for creating a microorganism cocktail that contributes to the regulate multiple diseases. We
will create a cooperative system in our laboratory for an accomplishment of early acceptance of papers
that were submitted or ready to submit.

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Health Intelligence Center
Director Seiya Imoto（１）Missions and Features
Health Intelligence Center aims to promote data science and personalized genomic medicine forpredicting and preventing diseases and maintaining health by using supercomputers to analyze big
data combined with genome-related data, health and medical data.
（２）Organization
Division of Health Medical Data Science
Division of Health Medical Computational Science（３）Activity Reports
１）Research Activities
We have developed statistical data analysis technologies for prediction and prevention of diseases
and maintenance of health by analyzing whole genome, transcriptome, epigenome, and commensal
microbial metagenome data (e.g., intestinal and oral microbiome) together with big data on healthand medical care such as health insurance claims and specific health checkup information.
In April 2020, Health Intelligence Center was merged to Human Genome Center in order toincrease its research activity and promote new dimension genomic medicine. This integration
provided a stronger research center with genomic and health medical big data analysis researches.
２）Education Activities
The OJT (On the Job Training) utilizing supercomputer SHIROAKNE is provided to not only
students of computer science department, but also experimental laboratories’ students in IMSUT
and young researchers such as postdocs. We also provide guidance to undergraduate students whowish to become a data scientist in health medical researches.
３）Social Activities
Science Café (The Takeda Foundation), Education Course (lectures about AI in medical
researches) at the Japanese Society of Rheumatology and the Japanese Medical AI Society.
４）International Activities
We participated and contributed to the International Cancer Genome Consortium and
TCGC/TCGA PanCancer Analysis of Whole Genomes.
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５）Other matters to be noted
Together with members of Human Genome Center, we managed SHIROKANE supercomputerat Human Genome Center and improved its service. The number of users, which had been hovering
around 500 in the past, has exceeded 1,500. We analyzed over 10,000 whole genome sequencing
data through collaborative research with other universities and other organizations. over 10,000 We
created an information infrastructure that enables us to analyze the sequence data of human wholegenome, intestinal microbiota and oral flora with health check-up data and medical records.
（４）Challenges and Future prospects
By the integration of Health Intelligence Center into Human Genome Center, reorganization of thecenter that enables to create personalized medicine in the Society 5.0 era ahead of the world is theprimary issue. Based on this integration and renewal, we will address the following four areas.
(1) The challenge of addressing important issues in cancer genomics, such as the unveilingmechanisms of generating cancer heterogeneity, and the development of fundamental infrastructure
for genomic data and data sharing.
(2) Promoting artificial intelligence research for clinical translation of new dimensional genomic
information (integrated genomic information from human genome, commensal bacteria and virus
genomes).
(3) Proceeding medical informatics research, which organizes, analyzes, and interprets new
dimensional genomic, medical, and health-related information and training researchers and physicians
who translate it for personalized medicine.
(4) ELSI research addressing a variety of issues, which arise at the contact point between medical
research such as advanced medicine including new dimensional genomic medicine and society.

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Division of Health Medical Data Science（１）Members
Professor

Seiya Imoto

Assistant Professor

Takanori Hasegawa

Graduate students

3（２）Research objectives
By integrating human genome-derived data such as whole genome sequencing (WGS) data andtranscriptome data to medical data like blood tests and time-series health-related data from wearable
devices using IoT, we develop big data analysis technologies and create an information infrastructure
for the analysis using supercomputer. Furthermore, using the analysis results of big data and personaldata, we aim to establish an informatics method that enables us to provide health-medical action plansthat improve personal health condition and realize personalized precision medical care.
（３）Activity Reports
１）Research Activities
As the datasets of whole genome sequencing, we collected 3,000 samples from BioBank Japan(BBJ), about 6,000 samples of normal and tumor from ICGC/TCGA PanCancer, and about 1,500
samples from Hirosaki University Center-of-Innovation Program and analyzed them integratingwith RNA-sequencing data. We also started a collaborative research with researchers of Monash
University to develop a method for the integrative analysis of pathological image data and genomic
sequencing data. We use TCGA data of multiple types of cancers for this purpose. We have received
15 years of health checkup data (approximately 30,000 records, WGS, intestinal and oral flora,
health checkup information, lifestyle habits, etc.) from Hirosaki University, and we are developing
a risk prediction model for lifestyle-related diseases. In addition, in an effort to return analysis
results to individuals, we are working with a company that conducts direct-to-consumer genetic
testing to analyze SNP information from approximately 100,000 users. In order to analyze such big
data and personal data and apply them to health/medical care, we have been working on a projectin collaboration with IMSUT Hospital, Advanced Clinical Research Center and Human Genome
Center to realize WGS-based cancer genomic medicine for hematological and gastrointestinal
cancers. In this context, we were one of the pioneer groups in the world to implement an artificial
intelligence system to clinically interpret genomic mutations of cancer genomes, proceeding thelearning and developing new AI, which now allows us to complete the process of receiving consent
for genomic analysis from patients and returning the results to the physician in charge in about five
days.
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２）Education Activities
Accepting graduate students from Department of Computer Science (2 in 2019 and 3 in 2018);
and we provide research guidance related to bioinformatics. We also provide training to motivated
graduate students who want to study bioinformatics in experimental laboratories (several students
each year). We provided several bioinformatics related lectures to graduate and undergraduate
students in the University of Tokyo. Undergraduate students at the University of Tokyo who areinterested in data science are asked to visit the laboratory on a regular basis for guidance. Lecturer
for the 2019 Japan Rheumatology Society's "Medical Education Project to Foster the Interface
between AI Technology and Rheumatology held in Tokyo, Osaka and Fukuoka. We also provide theJapanese Society of Internal Medicine's Educational Lecture Series for 2020.
３）Social Activities•

The Takeda Foundation, Science Café “Changing medicine and health care by genomic
information” (All 6 sessions in the series)•

Host of JST Sakura Science Program (Central Asian countries for 2019, Chinese
Academy of Sciences for 2018, governmental officers of China (ministry of health) for
2017, Rajiv Gandhi Centre for Biotechnology, India for 2016)４）International Activities•

ICGC/TCGA PanCancer Analysis of Whole Genomes (PCAWG)•

Collaborative research with Center for Research and Advanced Studies, Mexico (Prof.
Martha Espinosa-Cantellano) was accepted and supported by the IMSUT International
Joint Research Center’s project (2019 and 2020)•

Collaborative research with China Medical University, Taiwan Genome Project (Dr. RoTing Lin) was accepted and supported by the IMSUT International Joint ResearchCenter’s project (2020)•ollaborative research with Monash University (Assc. Prof. Jiangning Song) for Image andGenome Analysis was started.

５）Other matters to be noted•

Presentation and Panel Discussion at Tokyo Forum 2019’s session “Healthy Aging
Society”•

Press Releases➢

with Riken about the Nature paper of PanCancer project in Feb 2020➢

with Fujitsu Laboratory about AI for genomic medicine in Nov 2019
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•

➢

with Kao about microbiome research in Nov 2019➢with BrightPath Bio about the launch of joint research in Dec 2018
Prof. Imoto was served as a member of committee "Studying a vision of how doctors,
nurses and other professionals work based on a new way of medical care” Ministry of
Health, Labour and Welfare in 2016. Research on "Survey of Physicians' Working
Conditions and Work Style" (a survey of 100,000 physicians) was conducted as theprincipal investigator. This is the largest survey for physicians’ working style in Japan.
The result was published in the Press Office of the Ministry of Health on April 6, 2017. It
was covered by various media such as newspapers, TV and the web.

（４）Challenges and Future prospects
Recent studies have shown that our commensal microbes are linked to our health and disease. It is
not only limited to bowel disease, but also affects mental illnesses such as depression and evenneurodegenerative diseases. It's called "alter ego". Integrating the microbe information is essential forthe future of genomic medicine. We will promote the development of information analysis techniques
and artificial intelligence for this purpose.

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Center for Gene and Cell Therapy
Director Keiya Ozawa (-FY2017)
Director Arinobu Tojo (FY2018-FY2019)
Director Takashi Okada (FY2019-)<Members>
Professors

Arinobu Tojo, Tomoki Todo, Toshio Kitamura, Fumitaka Nagamura

Invited Professor

Koji Tamada

Project Professor

Hideaki Tahara

Visiting Professor

Shin-ichi Muramatsu

Associate Professors

Satoshi Takahashi, Tokiko Nagamura-Inoue

Project Associate Professor

Hiroaki Uchida（１）Missions and Features
IMSUT hospital has been playing a crucial role in clinical gene therapy and stem cell transplantationin Japan. In order to reinforce this clinical development even further, IMSUT established the Center
for Gene & Cell Therapy (CGCT) in 2014. CGCT particularly focuses on the development of genetherapy and cell therapy for intractable cancer and chronic diseases, such as oncolytic virus therapy,
engineered T cell therapy, gene therapy for neurological disorders using AAV vectors, T cell therapy
for post-transplant viral infections, and cell therapy using mesenchymal stem cells.
（２）Organization
Division of Molecular and Medical Genetics（３）Activity Reports
１）Research Activities
CGCT has promoted the development and trial of oncolytic virus therapy, engineered T celltherapy, gene therapy for neurological disorders using AAV vectors, T cell therapy for posttransplant viral infections, and cell therapy using mesenchymal stem cells. With the aim of massproducing high-quality GMP/GCTP-compliant gene therapy products that are needed to promotefurther trials, CGCT is working with domestic companies to conduct development research for
manufacturing processes. In addition, CGCT has conducted collaborative research on gene therapy
and related technologies with various facilities in Japan and abroad. The research results are
published in journals such as Science, Nat Biotechnol, Nature, J Immunol, J Exp Med, Stem Cells,
J Virol, Cancer Res, Sci Rep, J Biol Chem, Circulation, Proc Natl Acad USA, J Clin Invest, Mol
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Ther, EMBO Rep, Leukemia, Blood, and Nat Commun. The followings are the total numbers of theoriginal papers published in the peer reviewed international journals in each fiscal year: 79 in 2016,
95 in 2017, 106 in 2018, 70 in 2019, and 16 in 2020.
２）Education Activities
In the process of our research, we have educational programs for graduate students interested inpursuing a career in the field of gene and cell therapy. The faculties of various divisions teach awide range of courses in graduate school of medicine and graduate school of frontier sciences.
Through graduate seminar series, researchers from various academic backgrounds domestically andinternationally, interact with one another making interdisciplinary research which provide an ideal
educational environment. Between 2016 and 2018, more than 10 graduate students received degrees,
some were accepted as JSPS Research Fellowship for Young Scientists and some were to study
abroad. There were also graduate students who started their professional careers at major
pharmaceutical companies.
３）Social Activities
There are high expectations for the development of gene therapy products. However, theconstruction and operation system of domestic GMP/GCTP compliant manufacturing facilities are
not sufficient. In fiscal year 2018, proposals from IMSUT-CGCT for AMED's Program to Develop
Fundamental Technologies for Industrialization of Regenerative Medicine and Genetic Treatment
were accepted. We expect that the domestic academia will be organized and have at its center on
IMSUT, Jichi Medical University, and Osaka University.
４）International Activities
A CGCT Seminar was held on Apr. 8, 2016. We invited R. Michael Linden, Ph.D. (Vice President,
Gene Therapy Head, Genetic Medicine Institute Pfizer Inc.) as the senior lecturer to give a talk on“Open innovation for development of therapeutic agents against intractable diseases and its future
directions.” Taking the situation in the United States as an example, we exchanged views on
regulatory compliance and development strategy schemes.
５）Other matters to be noted
The 3rd IMSUT-CGCT Symposium was held on Mar. 13, 2017, the 4th on Jun. 27, 2017 and the
5th on Jan. 30, 2018. Well-known researchers in the field of gene therapy not only from Japan but
from various countries and regions were invited to have lively discussions.
（４）Challenges and Future prospects
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As a nationwide inter-university research hospital, the Institute of Medical Science is characterized
by accepting seeds from outside the university, and is widely used as a place to promote clinicaldevelopment of excellent projects in Japan. With regard to gene and cell therapy, clinical development
toward commercialization is activating in Japan due to the marketization in Europe and the UnitedStates, and TR promotion at IMSUT-CGCT is required as a base for gene and cell therapy in Japan. In
the future, in order to actively promote gene and cell therapy research and clinical trials for intractable
cancers and hereditary diseases, it is required to build a cooperative system with TR supporting
sections such as IMSUT Hospital Center for Translational Research, Department of Cell Processing
and Transfusion, Therapeutic Vector Development Center, and Department of Biopharmaceutical
Safety Inspection.

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Division of Molecular and Medical Genetics（１）Members
Professor

Takashi Okada

Postdocs

6

Technicians

1

Others2（２）Research objectives
Division of Molecular and Medical Genetics has been continuously carrying out research into thedevelopment of fundamental gene therapy techniques with the adeno-associated virus vectors and celltherapeutic modalities. The main research theme is the development as well as clinical application ofgene and cell therapies using viral vectors and MSCs for the treatment of diseases where fundamental
therapies are still difficult, such as various neuromuscular diseases. We promote international
contribution by developing the world's most advanced technology and industrial power by gathering
academia and companies with original technology.
（３）Activity Reports
１）Research Activities
Since the division opened in July 2019, we have been continuously carrying out research into thedevelopment of fundamental gene therapy techniques. Our main research theme is the development
and clinical application of gene and cell therapies using viral vectors as well as mesenchymal
stromal cells for the treatment of illnesses where fundamental therapies are still difficult, such as
muscular dystrophy, stroke, and cancer. The research achievements are published in journals suchas Hum Gene Ther Methods, Glia., Mol Pain, Calcif Tissue Int, Int J Lab Hematol, Exp Anim., Mol
Ther Methods Clin Dev., Mol Ther Methods Clin Dev., Glycobiology. The total numbers of theoriginal papers published in the peer reviewed international journals in each fiscal year are 4 in2019, and 7 in 2020.
Overall findings of the research were also presented at the scientific symposiums includingInternational Gene & Cell Therapy Symposium, The 25th Annual Meeting of Japan Society of Geneand Cell Therapy, The 61st Annual Meeting of Japanese Association of Oral Biology, The 64th
Annual Meeting of the Japan Society of Human Genetics, and the Gunma Univ Initiative forAdvanced Research Viral Vector Core Start-up Symposium.
We also presented our findings at the academic conferences held by American Society of Geneand Cell Therapy, Japan Society of Gene and Cell Therapy, Japan Neuroscience Society, JapaneseSociety for Neurochemistry, Japan Muscle Society, Japanese Pharmacological Society, Molecular
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Biology Society of Japan, and Japanese Pharmacological Society.
Research grant proposals for Ministry of Education, Culture, Sports, Science and Technology(MEXT) and Japan Agency for Medical Research and Development (AMED) were accepted suchas Grant-in-Aid for Scientific Research (B), Program to Develop Fundamental Technologies for
Industrialization of Regenerative Medicine and Genetic Treatment, Acceleration Transformative
Research for Medical Innovation, Translational Research Grant (B, preB).
２）Education Activities
We develop global human resources who will play a leading role in the next generation withdiverse academic backgrounds. With the opening of the postgraduate course, we started recruiting
graduate students at the Graduate School of Medicine. We also gave lectures at the School of
Medicine and research guidance for graduate students at Nippon Medical School.
Educational lectures were provided through the programs prepared by Manufacturing
Technology Association of Biologics and Japan Biological Informatics Consortium.
３）Social Activities
In cooperation with the AMED and the Manufacturing Technology Association of Biologics, wewould like to contribute to the elimination of trade deficits and economic growth in the domestic
medical field, whereas fostering the gene and cell therapy as an academic discipline.
Various cooperative research programs toward social implementation have been actively
conducted with academia and companies such as National Center of Neurology and Psychiatry,
Osaka University, and Nippon Medical School.
４）International Activities
We are seeking for the way to establish the next generation vector manufacturing process
technology and reform import-dependent medical structure. In addition to publicizing research
activities at the international conferences, such as annual meetings of the American Society of Gene
& Cell Therapy as well as the Bioprocessing Summit, we have routinely exchanged opinions amonginternational communities toward future advances. Furthermore, we gave a course lecture of
Introduction to Medical Science at the International Course, the School of Advanced Science andEngineering, Waseda University.
５）Other matters to be noted
As a member of the Center for Gene and Cell Therapy, we are establishing a major international
medical research center that will lead the world in this field by establishing advanced technologies
and fields by using the background and unique achievements of gene and cell therapy. Our unique
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research activity was introduced in the media.
（４）Challenges and Future prospects
We would like to continue the research carried out to present into fundamental vector techniques,
stromal cell techniques, molecular pathology analysis, and the gene therapies that make use of these.
Additionally, so that these results can make it to clinical use, we would like to guide the standardizationof gene and cell therapies for the treatment of neuromuscular disorders and cancer.

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Laboratory Animal Research Center
Director Chieko Kai (-FY2018)
Director Tomoji Mashimo (FY2019-)（１）Missions and Features
Laboratory Animal Research Center (LARC) was founded in 1965 as the ﬁrst modern animal
facility in Japan. Mice and rats are strictly maintained in the SPF condition for many scientificexperiments. We also provide several services for mouse embryo manipulation and generating
genetically modiﬁed animals with genome editing technologies.
In addition, we are developing novel genome editing tools such as CRISPR-Cas3 and (CombiCRISPR) knock-in strategies in mice and rats, which can be widely applied in laboratory rodents. We
are also focusing on generating "humanized animals" or "immunodeficient animals". These valuable
animal models can be used for xenotransplantation of human cells/tissues including human iPS cells.
（２）Organization
Laboratory Animal Research Center (Kai Laboratory) (-FY2018)
Division of Animal Genetics
Animal Center（３）Activity Reports
１）Research Activities
Genome engineering technologies achieve a "revolution" in life science and medical science.
These techniques allow us to manipulate genes of interest for multiple purposes. Using thosetechnologies, we have developed many useful strains in mice and rats. We are now focusing on
generating

andoptimizing"humanizedanimals"or"immunodeficientanimals"forxenotransplantation of various human cells/tissues including human iPS cells. We are also
developing therapeutic strategies such as cell therapy and gene therapy with genome editing tools.
２）Education Activities
We have an annual training course for all researchers and technical staffs who use our animal
facility.
３）Social Activities
None.

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４）International Activities
By utilizing our efficient genome editing technologies, we generate immunocompromisedtransgenic rats with the suicide gene to induce apoptosis of rat hepatocytes. We are collaboratingwith the University of Pittsburgh in the USA to develop in vivo proliferation strategy of humanhepatocytes for clinical application.
５）Other matters to be noted
Nowadays, the technologies of genome editing enable us to generate various animal model.
Different from mice, the laboratory rats have larger size and more relevance to human diseases andattract more attention in many fields, such as Pharmacology and Toxicology. Among numerous rat
models, the immunodeficient rats have large applicability and potential in multiple researches
including cancers, stem cells, organ transplantation, etc. As a participant of NBPR-RAT project, we
breed SCID rats and provide them to worldwide institutes.
（４）Challenges and Future prospects
We will continue devoting to improve the breeding space and experimental environment to meetthe needs of more researchers. As the experiments related to the tumor transplantation and infection
are increased in these years, we will expand the special space for the increasing requirement. We will
also continue the support of making SPF mice, embryos preservation and generation of advanced
animal models. In addition, we are also developing novel diagnosis strategy and more clinicalapplication by using CRISPR-Cas3 technology.

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Laboratory Animal Research Center (Kai Laboratory) (-2019.3)（１）Members
Professor

Chieko Kai

Associate Professor

Misako Yoneda

Project Senior Assistant Professor

Hiroki Sato

Assistant Professors

Tomoko Fujiyuki, Shotaro Uchida

Project Assistant Professor

Akihiro Sugai

Postdocs

3

Graduate students

1

Technicians

1

Others10（２）Research objectives
Goals as of April 2016;１）To advance the preclinical study for the novel measles virus for cancer therapy that we havebeen developing for the past three years to completion by the end of FY 2019, leading toclinical studies from FY 2020.
２）To conduct a collaborative study toward practical application of the candidate of therecombinant vaccine against Nipah virus that we have developed.
３）To identify factors associated with growth of Morbillivirus in the study to elucidate its
mechanism of pathogenesis.
４）To identify factors associated with growth of Nipah virus in the study to elucidate its
mechanism of pathogenesis.
（３）Activity reports
１）Research activities
1. The preclinical study was supported by AMED for the second time in FY 2017, and was
successfully continued. We conducted 4 animal safety tests, and applied for face-to-face advice
on safety tests with the PMDA. The production of GMP-compliant viruses for clinical studies
was completed using the GMP-compliant cells for virus replication that had already been
generated, and quality assurance testing was completed. We started individual consultations forface-to-face advice with the PMDA on pharmaceutical product manufacturing. Applicability
testing also revealed new efficacy of the novel measles virus for cancer therapy in the otherfour carcinoma cell lines. A number of other preclinical study procedures are going smoothly,
and thus the goal of completing the preclinical study by the end of FY2019 will be achieved.
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2. We started a collaborative research with countries where Nipah virus is epidemic. We madevarious attempts to obtain the substantial amount of research funds required to conducttranslational research leading to clinical study. As the international organization CEPI wasestablished in January 2017 to support grants dedicated to the development of vaccines against
emerging infectious diseases, we have set up a consortium for international collaboration with
the institutions from EU, the US and Bangladesh. We applied to the CEPI's first public offeringand accepted first from Japan in February 2019. We are now promoting developmental research
to reach a phase II clinical trial in the next 5 years with the aim of putting it to practical use,
and we have reached and significantly exceeded our goals.
3. In the study to elucidate the mechanism of pathogenesis of Morbillivirus, we showed that gene
expression dynamics in various organs interact with each other by viral infection as a factor
associated with its growth.
4. In the study to elucidate the mechanism of pathogenesis of Nipah virus, we identified two factors
associated with its growth. We identified two of the mechanisms involved with them.
２）Education Activities
We provided lectures and practical training in the Department of Computational Biology andMedical Sciences of the Graduate School of Frontier Sciences, and the Department of Pathology,
Immunology and Microbiology of the Graduate School of Medicine.
３）Social Activities
None.
４）International Activities
To develop the vaccine against Nipah virus infection described above, we have set up aninternational consortium with the institutions of EU, the US and Bangladesh, and are promoting alarge developmental study to achieve the practical use of the vaccine.
５）Other matters to be noted
None.
（４）Challenges and future prospects
We believe that we have reached and significantly exceeded our goals, which can be evaluated.
Although the two large projects are still on the way, the activities in this laboratory were terminated in
IMSUT because of the mandatory retirement of the professor. These projects are going to be continued
in another institute.
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Division of Animal Genetics（１）Members
Professor

Tomoji Mashimo

Senior Assistant Professor

Kazuto Yoshimi

Project Assistant Professor

Tomoaki Fujii

Postdocs

1

Technicians

2

Others1（２）Research objectives
Genome engineering technologies achieve a "revolution" in life science and medical science. These
techniques allow us to manipulate genes of interest for multiple purposes. Using those technologies,
we have developed many useful strains in mice and rats. We are now focusing on generating andoptimizing "humanized animals" or "immunodeficient animals" for xenotransplantation of various
human cells/tissues including human iPS cells. We are also developing therapeutic strategies such ascell therapy and gene therapy with genome editing tools.
（３）Activity Reports
１）Research Activities
We have established several useful animal mice and rats by genome editing tools. Especially, we
generated a Severe Combined. Immunodeficiency (SCID) rat model, which carry homozygous
mutation in both Il2rg and Rag2 gene. The immunodeficiency animals are valuable experimental
models, not only in the studies of immunodeficiency related diseases, they also have good
performances in the application of grafting various tissues. We also established photoactivatableCre(PA-Cre) knock-in mice at safe harbor locus for the spatial and temporal regulation of Cre
recombinase activity. The PA-Cre knock-in mice can facilitate spatiotemporal control of genetic
engineering and promise a useful resource to elucidate gene function in vivo with Cre-loxP.
２）Education Activities
None.
３）Social Activities
None.
４）International Activities
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By utilizing our efficient genome editing technologies, we generate immunocompromisedtransgenic rats with the suicide gene to induce apoptosis of rat hepatocytes. We are collaboratingwith the University of Pittsburgh in the USA to develop in vivo proliferation strategy of humanhepatocytes for clinical application.
５）Other matters to be noted
Nowadays, the technologies of genome editing enable us to generate various animal model.
Different from mice, the laboratory rats have larger size and more relevance to human diseases andattract more attention in many fields, such as Pharmacology and Toxicology. Among numerous rat
models, the immunodeficient rats have large applicability and potential in multiple researches
including cancers, stem cells, organ transplantation, etc. As a participant of NBPR-RAT project, we
breed SCID rats and provide them to worldwide institutes.
（４）Challenges and Future prospects
To generate humanized rat models, we will modify other genes in these SCID rats, to improve theefficiency of xenograft and alleviate acute xenogeneic graft-versus-host disease (GVHD) in therecipient SCID rats. These valuable animals can be used for xenotransplantation of human cells/tissues
including human iPS cells. We are also developing the efficient genome editing strategies with genome
editing tools in mice and rats to generated humanized animals.

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Animal Center (-FY2018)（１）Members
Professor

Chieko Kai

Technicians

5

Others9（２）Mission and features
We provide technical assistance for research using laboratory animals in IMSUT; husbandry andhousing of laboratory animals; maintenance of cleanliness and cleaning in contaminated rooms;
monitoring; freezing, cryopreservation and thawing of embryos and sperm; embryo manipulation in
genetically modified animals; maintenance and provision of genetically engineered mice and their
biological genetic resource bank. We house animal species including mice, rats, rabbits and hamsters,
all of which are SPF animals. About 30,000 mice are being raised at any given time, accounting forthe highest percentage of the animals in the center. The numbers of mice used in FY 2016, 2017, and2018 were 26,061, 29,192, and 17,599. We have P2 and P3 animal infection laboratories, which areprovided to researchers who wish to use them for experiments of infection and tumor transplantationby lending them for each experiment term. We are also equipped with analytical instruments including
MRI and IVIS, to contribute to various animal experiments performed in the institute. This center wasused by 36 laboratories, had 346 researchers registered on average and around 22,000–30,000 users intotal annually.
Microbial monitoring is conducted each month in the SPF animal breeding areas, and no viral orsignificant bacterial infections have occurred in the last three years. Although about 2 cases of minor
contamination per year occurred in the past, SPF cleanliness has been kept by killing all infectedanimals followed by cleanup of the contaminated rooms and a cleaning support system in which clean
SPF animals are produced from embryos or sperm. The biological genetic resource bank contributes
to preservation of biological resources by opening itself to both Japan and other countries to share its
information, and collecting and providing mice. The number of strains deposited in the biologicalgenetic resource bank is 184 at present.
（３）Activity reports
１）Research activities
None.
２）Education Activities
None.
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３）Social Activities
The animal center has established a biological resource bank to respond to the international needfor preservation and provision of biological genetic resources.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and future prospects
Animal experiments are essential for research in the field of medical science, and thus the animal
center is highly significant as it maintains a high level of cleanliness and addresses the diverse needsof researchers in IMSUT. The animal center is highly rated because it has and maintains excellent
functions as a center for supporting animal experiments in medical science studies; for example, it has
an embryo manipulation room and cleaning methods that can be implemented immediately so that it
has experienced no serious contamination by infectious diseases in the last 20 years, and it is equippedwith laboratories for infection and tumor transplantation and analytic instruments including MRI and
IVIS for laboratory animals. The IMSUT biological genetic resource bank was established to meet theneeds of the institute to preserve and share biological resources and to support long-term preservationand provision of genetically modified animal embryos, responding to international needs. Although
there still remain issues to be improved, the animal center should be maintained and improved further
for its high user-friendliness.

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Animal Center (FY2019-)（１）Members
Professor

Tomoji Mashimo

Senior Assistant Professor Kazuto Yoshimi
Technicians

4

Others1（２）Research objectives
The Laboratory Animal Research Center (LARC) was founded in 1965 as the first modern animal
facility in Japan. Currently about 30,000 mice are housed for different researches in IMSUT, andstrictly maintained in the SPF condition. The Animal Center building of LARC was improved in 1998
to perform genome engineering in animals, make infectious experiments (P2A, P3A), and housebigger animals, such as rats and rabbits. Techniques of mouse embryo manipulation and generating
genetically modified mice, including genome editing technologies, have been introduced into the
LARC.
（３）Activity Reports
１）Research Activities
The Animal Center building is a centralized facility designed, constructed and maintained to meet
regulatory standards required for the operation of research animal facilities. The barrier housingrooms to support the production and use of genetically-engineered mice, biohazardous experimentsarea and equipment room which has X-ray Irradiator, MRI and IVIS imaging system were provided
in this facility.
Our Barrie housing rooms are strictly maintained in the SPF condition, therefore, we provide IVF
mouse derivation service for all mice shipped to LARC from other institutions or non-approved
vendors to keep mice in SPF grade. We make frozen embryo for reducing number of using animals
and laboratory space. In addition, it is useful for making back up of the strains
２）Education Activities
We have an annual training course for all research and technical staffs who use our animal facility.
３）Social Activities
None.
４）International Activities
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None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
We will continue devoting to improve the breeding space and experimental environment to meetthe needs of more researchers. As the experiments related to the tumor transplantation and infection
are increased in these years, we will expand the special space for the increasing requirement. We will
also continue the support of making SPF mice, embryos preservation and generation of advanced
animal models.

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Amami Laboratory of Injurious Animals (-FY2018)
Director Chieko Kai（１）Members
Professor

Chieko Kai

Assistant Professor

Shinichi Yokota

Postdocs

1

Technicians2（２）Mission and features
Amami Laboratory of Injurious Animals was originally established as Oshima branchlaboratory to study endemic tropical diseases in 1902, at the time of the National Institute for Infectious
Diseases when Dr. Shibasaburo Kitasato was the director. It was taken over the Medical Science
Institute of the University of Tokyo, and yielded excellent results, including from the studies thatformed the basis for the eradication of filariasis in Japan and from those on bites by the venomous
Habu snake, which made a great contribution to the study of tropical diseases. From 2005, as a basefor primate experiments, the laboratory was equipped to be a rare facility where infection experiments
can be carried out using primates for national universities in Japan. Now, as a base for collaborative
studies, it has many users in the field of basic medicine not only with laboratories in IMSUT but alsowith a number of other universities, national institutes and other research institutes. It also houses andbreeds precious biological resources, squirrel monkeys and owl monkeys, which are useful primatesfor experiment but cannot be purchased in Japan at present, and also conducts studies to preserve thosebiological resources.
（３）Activity reports
１）Research activities
Collaborative studies were conducted with 8 institutes in FY2016, 8 in FY2017, and
8 in FY2018 except laboratories in IMSUT. We worked on projects including studies in variation of
Habu venom by islands and Habu venom inhibitor in serum, morphogenesis of Habu’s pit organ,development of methods of controlling vivax malaria using owl monkeys, analysis of pathogenesisof measles virus, safety analysis of measles virus vector vaccine, elucidation of biologicalcharacteristics of New World monkeys, analysis of pathogenesis of novel animal pathogens inprimates, and wound healing using autologous cells of squirrel monkeys and cynomolgus monkeys.
２）Education Activities
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We held public seminars and provided hands-on experience on the activities in IMSUT and Amami
Laboratory of Injurious Animals.
３）Social Activities
None.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and future prospects
There are only two other experimental facilities affiliated with universities under the
Ministry of Education, Culture, Sports, Science and Technology that are allowed to use primates forexperiments. Further, the pathogens they are allowed to use are limited. Amami Laboratory of
Injurious Animals is the only facility affiliated with the university where P2 and P3 infection
experiments with primates can be carried out without limitation on the pathogens. This laboratory is
open to institutes and universities in Japan, serving as the Joint Usage/Research Center affiliated an
institute of the university, and thus its maintenance as a valuable facility is significant.

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Amami Laboratory of Injurious Animals (FY2019-)
Director Tomoji Mashimo（１）Members
Professor

Tomoji Mashimo

Project Assistant Professor

Shin-Ichi Yokota

Technicians

3（２）Research objectives
Amami Laboratory of Injurious Animals is the unique International Joint Usage and ResearchCenter capable of infection experiment using non-human primates. We are maintaining the colonies
of New World monkeys and providing them for medical research in non-human primates to assess thepathogenicity of various pathogens, including viruses, bacteria, and protozoa, together with various
domestic and foreign research institutions. In addition, research such as regenerative medicine,
reproductive engineering, etc., in which our monkeys become suitable experimental models are also
conducting at our laboratory.
（３）Activity Reports
１）Research Activities
As FY2020 adopted IMSUT Joint Research Project, we are conducting research related to thedevelopment of a malaria vaccine using squirrel monkeys with external research institutes such as
Kyoto University, Nagasaki University, National Institute of Infectious Diseases, etc.
２）Education Activities
None.
３）Social Activities
None.
４）International Activities
None.
５）Other matters to be noted
None.

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（４）Challenges and Future prospects
This facility is the only university-affiliated research institute capable of primate infection
experiments up to BSL3 without limiting the kind of pathogens. It is extremely important to continue
to open this facility to universities and other institutions and maintain it as a Joint Usage and ResearchCenter. Also it is important to keep colonies of squirrel monkeys and owl monkeys, whose trading isseverely restricted by the CITES, from the viewpoint of biological resource conservation in Japan.

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Medical Proteomics Laboratory
Acting Director Yuji Yamanashi（１）Members
Professors

Yuji Yamanashi, Kouhei Tsumoto

Project Professor

Koichi Tanaka

Associate Professors

Masaaki Oyama
Makoto Nakakido (Graduate School of Engineering)

Project Assistant Professor Hiroshi Sagara
Technicians

3

Graduate students

20

Others17（２）Research objectives
The mission of our laboratory is to develop advanced technologies for antibody engineering, small
molecule screening, mass spectrometry and electron microscopy to perform an integrative proteomic
analysis of disease-related protein-protein interaction networks from a physicochemical, structural,and bioinformatical point of view.
Our main goal regarding research activities is to publish more than 20 research papers ininternational journals each year. We also encourage graduate students to make presentations at
academic conferences to be awarded at least 3 prizes annually. For industry-academia collaboration
activities, we aim to set up a corporate sponsored research program in cooperation with domestic andforeign companies.
In addition, our laboratory is widely involved in many collaborative research projects to facilitate
the utilization of these medical proteomics technologies inside and outside the institute. In our mass
spectrometry/electron microscopy facilities, we plan to establish an integrative platform for mass
spectrometry-based comprehensive identification and quantification of multiple protein modifications
and easy section-preparation methodology for serial ultrathin section scanning electron microscopy.
（３）Activity Reports
１）Research Activities
We published 20 (FY2016), 31 (FY2017), 26 (FY2018), and 25 (FY2019) research papers ininternational journals based on a wide range of advanced technologies as noted above. Regarding
antibody engineering and small molecule screening platform, Dr. Tsumoto’s group have developed
a variety of novel biophysical based strategies for antibody engineering and compound screening to
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modulate protein-protein interactions. For the mass spectrometry facility, Dr. Oyama’s group
established a highly sensitive proteomic workflow for integrative analysis of protein
phosphorylation, ubiquitination, acetylation and methylation. For the electron microscopy facility,
Dr. Sagara’s group developed a widely available technology for serial preparation of ultrathin
sections and is now involved in methodological sophistication for picking up these sections.
２）Education Activities
The young researchers in Dr. Tsumoto’s group received 3 (FY2016), 6 (FY2017), 6 (FY2018),
and 7 (FY2019) awards at various academic conferences. Dr. Oyama’s group conducted 13(FY2016), 8 (FY2017), 11 (FY2018), and 12 (FY2019) outreach scientific programs for junior andsenior high school students.
３）Social Activities
Dr. Tsumoto’s group has started a project division of advanced biopharmaceutical science with
Tosoh Corporation since 2017.
４）International Activities
Dr. Oyama’s group has initiated a clinical proteomics project with Abbott Laboratories under
IMSUT-Abbott strategic research collaboration agreement since 2017.
５）Other matters to be noted
Dr. Tsumoto’s group published 3 press releases regarding the outstanding research achievements.
（４）Challenges and Future prospects
Continuous and cumulative improvement of mass spectrometry-based analytical workflow for
sample preparation, comprehensive measurement, and subsequent bioinformatic analysis, is crucial as
technological advancement at each step is very rapid. We will forward establishment of a nextgeneration analytical and computational platform based on proteomic big data-oriented drug discovery
and disease diagnosis. For the electron microscopy facility, we consider that a novel device toautomatically pick up ultrathin sections is needed for constantly applicable sample preparation. Basedon the draft by Dr. Sagara’s group, a prototype model is under development to be introduced in ourfacility within a few years.

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Research Center for Asian Infectious Diseases（１）Members
Professors

Yasushi Kawaguchi, Yoshihiro Kawaoka

Project Professor

Mitsue Hayashi

Project Associate Professors

Seiya Yamayoshi, Jin Gohda

Project Senior Assistant Professor

Mizuki Yamamoto

Assistant professors

Akihisa Kato, Naoto Koyanagi, Yuhei Maruzuru（２）Research objectives
The Research Center for Asian Infectious Diseases, in addition to establishing and operating anoverseas base in the People’s Republic of China, the country that recorded the first cases of Severe
Acute Respiratory Syndrome (SARS) and avian influenza, and facilitating in recent years numerous
personnel interactions of great significance for advancing efforts to control infectious diseases in Japan,
is currently conducting research on emerging and reemerging infectious diseases in collaboration with
the Institute of Medical Science, the University of Tokyo. With the support of the Japan Agency for
Medical Research and Development (AMED) the Center advanced its “China-Japan Research
Collaboration on Defense against Emerging and Reemerging Infections” project from April 2016 to
March 2019. In addition, in collaboration with the National Institute of Infectious Diseases, the Center
conducted research projects targeting the Middle East Respiratory Syndrome (MERS) coronavirus
strain, HIV-1, flavivirus, influenza virus, drug-resistant viruses, and infectious diarrhea virus,
published the results in various papers (more than 20 reports per year), and obtained related patents.
Through these Japan-China joint research activities, we will cultivate the next generation of infectious
disease researchers and contribute to amicable relations between Japan and China.
（３）Activity Reports
１）Research activities
Through the support of the Ministry of Education, Culture, Sports, Science and Technology’s(MEXT) “Program on Founding Research Centers for Emerging and Reemerging Infectious
Diseases” as well as the “Japan Initiative for Global Research Network on Infectious Diseases” (JGRID), the Research Center for Asian Infectious Diseases has established and currently operates
laboratories at the Institutes of Biophysics and Microbiology at the Chinese Academy of Sciencesin Beijing, China’s most advanced research institution, in which Japanese researchers are assigned
to permanent positions. This support has also allowed the Center to establish a joint research
program with the Harbin Veterinary Institute of the Chinese Academy of Agricultural Sciences(CAAS). Additionally, from April 2016 to March 2019, the Center conducted in cooperation with
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Japanese medical research institutes: ① basic and applied research on the control of envelope virus
infection, ② research on dormant HIV-1 infections to develop curative treatment, ③ basic
research and epidemiological studies on influenza virus, and ④ activities to establish a collection
system for epidemiological information related to drug-resistant bacteria. The major achievementsof these activities are detailed below.
① Basic and applied research on the control of envelope virus infection
A cell-based quantitative method capable of high-throughput screening of candidate inhibitors
against MERS coronavirus, HIV-1, Dengue virus, and Zika virus not requiring use of infectious
virus samples was established as a result of collaboration between the Institute of Biophysics at
the Chinese Academy of Sciences in Beijing and Japanese institutions. In addition, Nafamostat
was identified from a library of drugs for clinical use as a specific inhibitor of the MERS
coronavirus, and various other agents acting to inhibit Dengue and Zika viral activity were also
found. Nafamostat also strongly inhibited the fusion activity of SRAS-CoV-2, which is acausative virus of coronavirus disease 19 (COVID-19). Further, a parallel search of compound
libraries yielded multiple agents capable of inhibiting the membrane fusion activity of HIV-1,
MERS coronavirus, and Dengue virus.
② Research on dormant HIV-1 infections to develop curative treatment
At the Institute of Microbiology in Beijing, an HIV-1 dormant infection model cell line wasestablished, after which two compounds each with the ability to reactivate dormant viral
infections were identified. Three compounds able to act synergistically with existing reactivationinducers were also identified. These drug candidates are thought to be effective in inducing
activation of dormant HIV-1 as part of a treatment strategy designed to cure HIV-1 infections
known as “Shock and Kill”.
③ Basic research and epidemiological studies on influenza virus
Through its collaborative efforts with the China CDC, Taiwan CDC, and the National Instituteof Infectious Diseases, the Center was able to produce monoclonal antibodies targeting H7N9
influenza virus isolated from humans in China and develop a rapid diagnostic kit for H7 subtype
influenza virus in collaboration with CAAS-Harbin Veterinary Institute and Japanese facilities.
In addition, between late-2016 and 2017, we obtained two strains of highly pathogenic H7N9
virus, which were transmitted to mammals through droplets, indicating that infections
originating from exposure to even a small amount of virus can become severe, highlighting theneed for caution. Our results also showed that a mutation in the H7N9 viral polymerase could
enhance polymerase activity and contribute to pathogenicity.
The H5N1 virus was determined to be enzootic in Indonesia in 2016, whereas the H7N9 virus
was not isolated. Three of nine isolates of the H5N1 virus that was enzootic in Egypt from 2014
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to 2015 transmitted via respiratory droplets in ferrets with one fatality. No droplet transmission
was observed during three follow-up experiments. Nonetheless, our data suggest that theseviruses have pandemic potential.
To date, a database maintained by Hokkaido University has catalogued 4 highly pathogenic
strains of H5N1 avian influenza virus isolated from Vietnamese birds, 9 highly pathogenic H5N1
avian influenza strains isolated from Egyptian birds between 2014 and 2015, and 6 strains of
seasonal influenza virus isolated from Japanese patients (3 hCK cell isolates, MDCK cell isolates,
and AX4 cell isolates). This not only enables comparisons with virus strains isolated in othercountries, but also allows for sharing of information on nucleotide sequence mutations that differ
for each cell line used for virus isolation; it is therefore expected to be useful for future
epidemiological research.
④ Establishment of a collection system for epidemiological information related to drugresistant bacteriaWith the participation of researchers from the Department of Bacteriology II and
Antimicrobial Resistance Research Center of the National Institute of Infectious Diseases, theCenter conducted a survey to gather epidemiological information concerning drug-resistantbacteria in China. In China, the National Health and Family Planning Commission (equivalent
to Japan’s Ministry of Health, Labour and Welfare) operates the China Antimicrobial Resistance
Surveillance System (CARSS) which monitors over 1,000 hospitals, and maintains oversightover the management of this system by researchers at Peking University. We exchanged
information with these researchers and conducted a comparative study with Japan. As a result,it was determined that the rate of development of drug resistance in many bacterial species tends
to be higher in China compared to Japan. Moreover, with particular regard to the issue of
nosocomial infections caused by K. pneumoniae, although in Japan this species has a <1% rateof resistance to carbapenem, the current “trump card” of antibiotic drugs, the rate has been
rapidly rising in China in recent years. In a 2018 study examining bacteria isolated from target
hospitals, 10.1% of all samples were resistant, and 21.9% of samples taken from ICUs wereresistant.. Although it can be said that the prevalence of drug-resistant bacteria in Japan at present
is relatively low, there is a high possibility that these resistant strains could spread to Japan via
importation. Accordingly, continued surveillance and care as well as taking sufficient
precautions is believed to be necessary.
The above research results were published in various journals (29 reports in 2016, 23 reports in
2017, 31 reports in 2018, 28 reports in 2019), patent applications were filed (2 claims in 2016, 3
claims in 2019), and we believe overall that the Center has been successful in achieving its goals
related to information dissemination and acquisition of intellectual property.
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２）Education Activities
Our staff actively contribute to activities to educate young people interested in infectious diseaseresearch by giving regular laboratory tours (1 in 2016, 1 in 2017, 1 in 2018, 2 in 2019) and lectures
geared towards high school students and teachers (2 in 2016, 2 in 2017, 1 in 2018, 1 in 2019).
３）Social Activities
Our staff have contributed to initiatives to raise awareness of infectious disease activities bygiving public talks at various venues in Japan (1 in 2016, 1 in 2018, 2 in 2019) as well as
presentations at the Japanese Embassy in China (2 in 2017).
４）International Activities
In addition to the above collaborative research activities, the IMSUT-CAS Workshops on
Infectious Diseases was held at the Institute of Biophysics at the Chinese Academy of Sciences on
April 17, 2017, at the Institute of Medical Science, the University of Tokyo on October 9, 2018 andat the Institute of Microbiology Chinese Academy of Sciences on December 17, 2019. These events
served as a platform for presentation of the latest research results as well as constructive interaction
between researchers in Japan and China.
５）Other matters to be noted
We are continuing our efforts to nurture young Chinese researchers in the field of infectious
diseases by locally hiring a total of 9 dispatch researchers, with 2-3 people at each of the JapanChina collaborative laboratories at our Beijing bases (Institutes of Biophysics and Microbiology).
We continue to cultivate the next generation of researchers at Japanese sites as well, and during thisperiod two specially-appointed professors were promoted to succeeding Assistant Professors, wehave had three postdoctoral students dispatched overseas, one Special Assistant Professor was
promoted to Special Associate Professor, and two staff members accepted more senior positions atother institutions.
（４）Challenges and Future prospects
With the recent revisions to Chinese Japanese laws, it has become more difficult for foreign
nationals to obtain epidemiological information as a result of protections placed on genetic andepidemiological information related to pathogens. In order to facilitate epidemiological research in
China in the future, we will further strengthen our cooperative initiatives with infectious disease
specialists and epidemiological researchers in China. Supporting the development of the next
generation of human resources in China through programs such as those supporting students in Beijing
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has been difficult based on research funded by AMED alone. To solve this problem, we will utilize theinternational joint use and joint research center program launched in fiscal 2019, invite humanresources including students from China to Japan, and promote joint research activities in infectious
diseases and other fields.
In addition to frequent interactions between Japan and China-based researchers, the Center regularly
holds a Japan-China steering committee meeting each year through our Beijing office to review theoperation of our China base as well as maintain productive and amicable relations with the relevant
research institutes and our two countries. In the future, we plan to continue to encourage young
researchers to participate in this project as we work to cultivate the next generation of researchers.

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Laboratory of Molecular Genetics (-FY2016)（１）Members
Professor

Izumu Saito

Assistant Professor

Saki Kondo

Assistant Professor

Tomoko Nakanishi

Postdocs

1

Graduate students

1

Technicians

2

Others3（２）Research objectives
The research aims of our laboratory are to develop adenovirus vectors and provide powerful tools
for biomedical research including gene therapy, to promote pathophysiological research on hepatitis
B virus, and to support gene-recombination experiments and biohazard experiments in IMSUT as aconsultation counter.
（３）Activity Reports
１）Research Activities
In this laboratory, we developed useful adenoviral vectors and support biomedical research bothwithin and outside Japan under at least five collaboration s in a year. The results have been publishedin several peer reviewed international journals. In 2016, we developed a novel single-typeadenoviral vector with which more than two independent shRNAs are simultaneously andeffectively expressed. This vector could be utilized in a therapy for hepatitis B virus. Hepatitis B
virus genome contains both pregenomic RNA and covalently-closed circular DNA. Using an above
adenoviral vector, we could reduce the level of pregenomic RNA in an infected liver throughsimultaneous expression of three distinct shRNAs for the hepatitis B genome. However, thereduction of covalently-closed circular DNA was not apparent. In future, we will try to overcome
this problem.
In order to eradicate hepatitis B, the hepatitis B genome has to be completely destroyed. In thisrespect, CRISPR-Cas9 genome editing technology can digest and destroy the intrinsic hepatitis B
genome. However, constitutive expression of Cas9 might undergo a harmful consequence throughoff-target digestion of the host genome. Therefore, its transient expression or activation is desired.
For this purpose, in 2016, we developed an adenoviral system with a circular DNA in which theexpression of Cas6 could be regulated by Cre recombinase.
These research achievements had been published in 3 peer reviewed international journals and235

G4_Hospitalthus we believe that we achieved our research missions. In addition, we collaborated with more thanten research subjects in a year.
２）Education Activities
In 2016, one PhD student received their PhD from Graduate School of Medicine, University ofTokyo.
３）Social Activities
Many of the adenoviral vectors we developed have been supplied to many laboratories within
and outside Japan and have led to substantial contribution to advances in medical sciences as wellas other basic biology.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
Expanding our research by integrating all members in our laboratory as well as materials,
equipments, and technologies.

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Laboratory of Molecular Genetics (Frontier Research Unit)（１）Members
Acting Director, Professor

Yuji Yamanashi

Associate Professor

Kazuo Tatebayashi（２）Research objectives
The aim of this unit is to address how cells appropriately respond to various environmental stresses
such as high osmolarity. Our research focuses on the stress-sensing mechanisms as well as theregulatory mechanisms of stress-activated MAP kinase (MAPK) signaling pathways. Our final goal is
to understand the molecular bases of cellular stress responses, for developing the technology to confer
environmental stress resistance to animals and plants to survive in severe environmental conditions
caused by global warming, and also for developing methods of treating human diseases such as cancer
and autoimmune diseases caused by dysregulation of the stress response machinery.
（３）Activity Reports
１）Research Activities
Since 2017, this unit has conducted researches to elucidate the mechanisms of how cells respond
appropriately to extracellular stress stimuli including high-osmolarity stress using budding yeast
with cell biological, biochemical, and molecular genetic approaches. We have focused on two
issues of the osmoregulatory Hog1 MAPK pathway of Saccharomyces cerevisiae: 1) the sensing
mechanism of high osmolarity by osmo-sensors, 2) the regulatory mechanisms of intracellularsignaling. Our research achievements of these three years are as follows. First, we identified theinteraction sites of the transmembrane osmo-sensors Sho1 and Opy2 in the Hog1 MAPK pathway
by biochemical and genetic analyses, and found that the interaction between the transmembrane
domains of Sho1 and Opy2 enhances the signaling efficiency of the Hog1 MAPK cascade. This
study was published in PLOS ONE (Takayama et al. 2019).

Next, we found that osmostressenhances activating phosphorylation of Hog1 MAP kinase by mono-phosphorylated Pbs2 MAP2K.
The lack of the osmotic enhancement of the Pbs2-Hog1 reaction suppresses Hog1 activation bybasal MAP3K activities and prevents pheromone-to-Hog1 crosstalk in the absence of osmostress.
This study was published in The EMBO Journal with an impact factor of 11.2 (Tatebayashi et al2020). These findings highly contributed to our research goal: the understanding of the full pictureof how cells appropriately respond to environmental stresses.
The unit member got research funding from JSPS Grants-in-Aid for Scientific Research (B)(2016-2019), The Salt Science Research Foundation (2017), and the Japan Foundation for Applied
Enzymology (2017).
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The unit member organized a symposium at Annual meeting of the Japanese Biochemical Society
in 2019, and presented the achievements at the symposiums (Annual meeting of the Japanese
Biochemical Society (2019), Kyushu Regional Meeting of the Japan Transporter Research
Association (2019)). These activities contributed to the academic societies.
Based on the research accomplishments described above, the goal of this unit has been largely
achieved.
２）Education Activities
The aim of this unit for education is to train talented personnel who will play active roles as future
leaders in the field of life sciences. The unit member contributed to the education of graduate
students at the graduate school of Science, the University of Tokyo by giving the lectures ofmolecular and cellular biology (especially on cellular stress response and signal transduction), andalso by serving as a member of the evaluation committees for the assessment of PhD or MA theses
and dissertations every year. In addition, the unit member has been engaged in health and safety
education for the students of this institute as a manager of the health and safety office.
３）Social Activities
None.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
Our recent research contributed to an understanding of the mechanisms for cellular adaptation toenvironmental stresses. Especially, the newly discovered regulatory mechanism of the MAP kinase
pathway will be useful in human diseases, because many are caused by excessive or deficient activities
of MAP kinase pathways. Therefore, we can anticipate development of treatments and therapeutics
for human diseases such as cancer and autoimmune diseases in the future. To achieve this goal, it will
be necessary to promote interdisciplinary collaborations for application of our findings to biomedical
area.

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IMSUT Hospital
Director Keiya Ozawa (-FY2017)
Director Arinobu Tojo (FY2018-)（１）Missions and Features
IMSUT Hospital is the only one hospital affiliated with a national university research institute inJapan and has 122 beds including a unique ward organized for translational research and early clinical
trials such as a F-I-M study, an outpatient clinic, and operating rooms. Currently, IMSUT Hospital
focuses diseases such as hematological malignancies, solid tumors, infectious diseases, andautoimmune disorders and is conducting research on their pathophysiology and promoting
translational research (TR), such as gene, viral, and cell therapy of cancers as well as novel vaccine
treatment. IMSUT Hospital aims to be a core facility for clinical application of excellent outcomes bydomestic and international collaborative research, especially in close association with Advanced
Clinical Research Center and other centers/departments in IMSUT. IMSUT hospital is still setting up
its infrastructure for better clinical practice.
（２） Organization
Medical Care Unit
Department of Hematology/Oncology
Department of Infectious Diseases and Applied Immunology
Department of Rheumatology and Allergy
Department of General Medicine
Department of Applied Genomics
Department of Radiology
Department of Palliative Medicine
Department of Diagnostic Pathology
Department of Surgery
Department of Anesthesia
Department of Joint Surgery
Department of Surgical Neuro-Oncology
Care Support Unit
Department of Medical Informatics
Department of Radiological Technology
Department of Cell Processing and Transfusion
Surgical Center
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Department of Medical Supply Center
Department of Laboratory Medicine
Department of Pathology
Department of Clinical Genomics
Department of Clinical Nutrition
Radiation Control Office
Regional Medical Liaison Office
Clinical Safety and Infection Control Unit
Center for Clinical Safety and Infection Control
Clinical Research Support Unit
Center for Translational ResearchCenter for Antibody and Vaccine Therapy
Therapeutic Vector Development Center
IMSUT CORD
Department of Nursing
Department of Pharmacy
Department of AIDS Vaccine Development（３）Activity Reports
１）Medical Activities
Medical activities in FY 2016 - 2018 has remained lower compared to preceding years mainly
due to gradual decrease in the number of inpatients. Actually, over the past three years, inpatient
occupancy rates have revealed a worsening trend, as shown in the table below. This trend is mainly
attributed to temporary closure of one ward for renovation and human factors including lack ofyoung resident doctors and retirement of experienced doctors.
2016

2017

2018

Average daily number of inpatients

62.5

52.0

46.2

Average daily number of outpatients

114.4

98.9

98.5

Average length of hospital stay

11.4

11.1

11.7

%Ratio of nursing needs

41.6

43.7

39.9

%Ratio of medical care

66.2

68.6

72.1

２）Research Activities
Five distinct physician-initiated or company-based early clinical trials including herpes virus
therapy of brain tumors, peptide vaccine therapy against solid tumors, and rice-based oral cholera
vaccine were conducted in 2016. Clinical study of viral therapy of mesothelioma were approved by
240

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IRB in 2017. Two physician-initiated clinical trials, WT1-expressing artificial adjuvant vector cell(aAVC-WT1) therapy for AML and cord-derived MSC therapy for refractory GVHD were started,and a physician-initiated clinical trial for melanoma using another recombinant herpes virus wasapproved by IRB in 2018.
３）Education Activities
Since there are no undergraduate students and few residents in IMSUT Hospital, educational
activities for physician are very limited. However, we have over 15 years’ experiences of hospitalinternship program for non-MD master's and doctoral students (Graduate School of Frontier
Sciences) and undergraduate students of Bunkyo University. This program is designed to provide
students with lessons on ethical considerations and practical training in translational research. Morethan 50 people participate in the curriculum every year. There appears a favorable impact on theirreaffirmation of the dignity of life, motivation for medical research, and post-graduate career
selection.
４）Social Activities
Based on a partnership agreement with Minato City, we bimonthly hold an open medical seminarfor citizens, which provide useful medical information to help them stay healthy and prevent
diseases. Around one hundred people attend each seminar from inside and outside of Minato City,and the total number of participants in 2016 was 522, 384 in 2017 and 566 in 2018.
５）International Activities
None.
６）Other matters to be noted
In order to realize genomic medicine, we are promoting clinical research termed as AI medicine
in which artificial intelligence (AI) is applied to interpret enormous data from NGS analysis ofcancer genome and to find therapeutic options deduced from driver mutations. Our trial for AI
medicine was introduced by various media including newspapers and TV program with a significant
impact.
（４）Challenges and future prospects
Within FY2018, the 5th floor ward was restarted after renovation. This ward is specified to be used
for translational research and early clinical trials, and also to accept VIP and patients from overseas
for medical check-up and/or care. Therefore, this ward is mainly consisted of private rooms andequipped with ICU-mimetic rooms. To revitalize outpatient clinic, second opinion clinic and travel241

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clinic with vaccination were open in 2017 and 2018, respectively. Furthermore, the main laboratory
room was relocated to B1F of the Building 1 East and simultaneously, several laboratory testingmachines were updated in 2018.
In order to recruit young doctors, we made partnership agreements between more than 10 general
hospitals and at the same time, we are making efforts to appeal our unique training program via our
website and other media. In 2019, we plan to expand both rehabilitation room and outpatientchemotherapy unit.

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Department of Hematology/ Oncology（１）Members
Professor

Arinobu Tojo

Associate Professors

Yoichi Imai, Satoshi Takahashi, Tokiko Nagamura-Inoue

Project Associate Professor

Hiroshi Yasui

Assistant Professors

Tomohusa Fukuyama, Seiko Kato, Takaaki Konuma,
Toyotaka Kawamata, Kazuaki Yokoyama, Aki Sato,
Muneyoshi Futami, Masamichi Isobe（２）Research objectives
We are challenging to cure intractable hematological disorders such as leukemia and lymphomawith the aid of hematopoietic stem cell transplantation (HSCT). Our major stem cell source forrecipients without suitable family donors is unrelated cord blood, with which no less than 20 adultpatients receive cord blood transplantation (CBT) annually. Since 1998, we have performed around360 cases of CBT, which appears a distinguished experience in the world. Recent advances in
identification of tumor-specific therapeutic targets resulted in a series of rationally designed
therapeutic agents. In the field of hematological malignancies, we have already experienced
remarkable clinical efficacies of molecular targeted drugs including tyrosine kinase inhibitors for
Philadelphia-chromosome positive leukemia, monoclonal antibodies (MAb) for CD20+ B cell
lymphoma and CCR4+ adult T cell leukemia/lymphoma (ATL), and proteasome inhibitors,
immunomodulatory drugs for multiple myeloma (MM), respectively. Additionally, novel therapeuticmodalities including anti-CD319 and anti-CD38 MAb are available for MM. We extensively apply
these molecular targeted therapies for in- and out-patients. Furthermore, our department is one of the
hub facilities in Japan for clinical practice and clinical research in ATL and Langerhans cellhistiocytosis (LCH), both of which are rare and intractable tumors.

（３）Activity reports
１）Medical Activities
Outpatient clinic is staffed by physicians above the rank of assistant professor on weekdays. The
annual number of new patients has been varying around 120, most of which are those with leukemia,
lymphoma, and myeloma. Hospitalized patients in our department are mainly held in a clean ward
on the seventh floor of the hospital building, which include an average of 20-25 patients per day.
Since the mid 1980s, our department has been a core facility of allogeneic stem cell transplantation
243

G4_Hospital(SCT) in Japan, and in recent years, we have performed around 25 allogeneic SCT per year. Morethan 90% of stem cell source are unrelated cord blood, and their clinical outcomes are among thebest in the world. Our unique projects of clinical practice include specialized outpatient clinic forpatients with HTLV-1 infection/adult T cell leukemia (ATL) as well as patients with adult
Langerhans cell histiocytosis (LCH). We are also conducting a number of physician-initiative orcompany-based early clinical trials, which include various types of cell therapies using
mesenchymal stem cells (MSC) for therapy-resistant GVHD, WT1-expressing artificial antigenpresenting cells (aAVC-WT1) for relapsed/refractory AML, and CD19-targeted CAR-T cells for
intractable B-ALL.
２）Research Activities
We have been conducting two types of physician-initiated phase I clinical trials; (1) aAVC-WT1
therapy for relapsed/refractory AML (started in 2017) and (2) cord-derived (MSC) therapy forsteroid-resistant acute GVHD (started in 2018). In addition, many peer-reviewed articles were
published according to well-organized clinical database for allogeneic cord blood transplantation(CBT). In the field of HTLV-1 infection and ATL, we developed a HAS-Flow method to analyze
dynamics and malignant progression of HTLV-1-infected cells by flow cytometry. Moreover, weare promoting AI-guided precision medicine approach to hematological malignancies throughclinical sequencing of patients’ samples and actually analyzed about 180 cases between 2015 and2018. We have also demonstrated the significance of circulating tumor DNA (liquid biopsy) inclinical outcome after allogeneic SCT in AML/MDS. We published a number of peer-reviewed
original articles every year; 2 papers in FY2016, 8 in FY2017, and 10 in FY2018.
３）Education Activities
In clinical departments, education and instruction to residents is achieved as On-the-Job-Training(OJT). We supervised 4 senior residents in 2016, 3 in 2017, and 2 in 2018 according to the clinicalhematology program. All these residents were qualified to be board certified hematologists ofJapanese Society Hematology (JSH).
４）Social Activities
Several physicians in our department regularly cope with consultations and/or give a lecture atpatient meetings.
５）International Activities
None.

244

G4_Hospital６）Other matters to be noted
In order to realize genomic medicine, we are promoting clinical research termed as AI medicine
in which artificial intelligence (AI) is applied to interpret enormous data from NGS analysis ofcancer genome and to find therapeutic options deduced from driver mutations. Our trial for AI
medicine was introduced by various media including newspapers and TV program with a significant
impact.
（４）Challenges and future prospects
Human resources are important in the field of clinical hematology, especially in SCT. Since IMSUT
hospital is small-sized and has a limited number of departments, junior residents have been notavailable so far, and we cannot accept senior residents under the novel specialist system which started
in 2018. Lack of young physicians is a critical obstacle to maintain clinical activity. We need iminent
personnel exchange through inter-hospital network.

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Department of Infectious Diseases and Applied Immunology（１）Members
Professor

Hiroshi Yotsuyanagi

Associate Professor

Takeya Tsutsumi

Assistant Professors

Eisuke Adachi, Michiko Koga, Makoto Saito

Technicians

2

Others5（２）Research objectives⚫

We will carry out clinical research while inheriting and developing the tradition of HIV treatment/ international infectious disease treatment, which is our tradition.

⚫

A travel outpatient department is opened to facilitate medical care for international infectious
diseases.

⚫

We will develop an environment for conducting research, including translational research, incooperation with researchers within the institute.

⚫

We will actively provide hepatitis virus treatment in cooperation with general medical
departments.

（３）Activity Reports
１）Medical Activities⚫

HIV medical care
IMSUT hospital, the Institute of Medical Science is a medical institution with the longest historyof HIV treatment in Japan and is closely related to the AIDS Research center, National Center for
Global Health and Medical Research. (1) Observing the long-term progress of infected people bymaking use of this characteristic, (2) constructing a database, making necessary ethicalapplications, preparing research seeds, and (3) actively reporting cases. The target was set when
the classroom was established (July 2016).

⚫

Regarding (1), most patients continue to visit our hospital, and there are 20-30 new visits annually,
achieving the target.

⚫

Regarding (2), the target has been achieved.

⚫

Regarding (3), we were able to prepare four case reports. I was also able to report a paper on theconstruction of a Care Cascade for HIV-infected persons, which has been ongoing since mypredecessor.

⚫

International infectious disease medical care➢

The outpatient clinic started in May 2018 with the full cooperation of hospital staff. We also246

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prepared imported vaccines and prepared a system to deal with consultations before
traveling abroad and health problems after traveling abroad. Currently, there are 30-40
medical examinations per month. In the future, we are considering improving the researchsystem in addition to the summary of medical records.
⚫

Medical care for viral hepatitis➢

While taking over the patient who was being treated in the general medical department, heis actively accepting patients from other medical institutions. Consideration is being given
to medical treatment so that patients can continue to go to the hospital, and it has been doing
well so far.

２）Research activity
Wet research is carried out in the field of infectious diseases, and research in the field of infectious
immunology aims to report the experience in cases as described above and link it to further research.
As described above, four case reports have been made. Of these, cases of HIV/HBV co-infection
have led to current research in the field of infectious diseases.
３）Education Activities
Every year, about 2 early trainees and 2 late trainees are accepted.
In May 2018, we held a May festival emergency plan for university students-to protect young
people from sexually transmitted diseases-and provided information and discussion centered on theoutbreak of syphilis infection.
４）Social Activities
None.
５）International Activities
None.
６）Other matters to be noted
As activities of the Department of Internal Medicine for Infectious Immunology, we held public
lectures, a social gathering for medical cooperation, and a medical seminar at the Institute ofMedical Research, the University of Tokyo Hospital, to raise awareness about overseas travel. We
also opened a travel outpatient department.
（４）Challenges and prospects
For the two and a half years until March 2019, the emphasis was placed on the establishment of a247

G4_Hospitaltravel outpatient facility that also served as a hospital. I am thinking that the outpatient will go on track
and carry out research based on the outpatient.

248

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Department of Rheumatology and Allergy（１）Members
Professor

Hirotoshi Tanaka

Project Associate Professor

Motohisa Yamamoto

Senior Assistant Professor

Noritada Yoshikawa

Assistant Professor

Hiroki Yamazaki

Postdocs

1

Others3（２）Research objectives
Our department is founded in 2001 to tackle systemic autoimmune inflammatory diseases including
rheumatoid arthritis, systemic lupus erythematosus, vasculitic syndromes and IgG4-related disease.
We provide patients personalized and evidence-based medical service. Moreover, we challenge cuttingedge science of autoimmune, rheumatic and allergic diseases and novel treatments for patients withthese disorders.
Our specific aims are
・Developing a novel therapy preventing glucocorticoid-induced muscle atrophy in patients withrheumatic diseases
・Developing a novel therapy to improve abnormal fat distribution in patients taking GC therapy
・Development of novel therapeutic modalities against metabolic syndrome targeting the skeletal
muscle-liver-fat signalling axis
・ Clarification of functional crosstalk between GR and sex hormone receptors for bodycomposition and metabolic regulation
・Clarification of the effect of ageing for regulation of energy storage in skeletal muscle andadipose tissues
・Translational Research and Clinical Trial of Division of Rheumatology（３）Activity reports
１）Medical Activities
We vigorously conducted patient management at outpatient clinic (4 days per week) and ward
(over 100 patients).
Rheumatologic services offered at IMSUT Hospital include:•

Outpatient consultations•

Outpatient specialty care for patients with chronic rheumatic diseases•

Hospital consultations
249

G4_Hospital•

Diagnostic and therapeutic intra-articular and soft tissue injections and aspirations•

Diagnostic ultrasonography•

Education on rheumatologic diseases and treatments•

Clinical trials２）Research Activities
We published 9 original research papers in peer-review journals, and reported 39 research papers
in various academic meetings from 2017 to 2018.
３）Education Activities
We took charge of 4 lectures for graduate students every year.
４）Social Activities
We published 7 review articles in Japanese medical journals from 2017 to 2018. We performed
one collaboration with Japanese pharmaceutical company (3-year contruct).
５）International Activities
We are promoting international collaborative research for IgG4-relared disease with Wuhan
University Medical Center in China.
６）Other matters to be noted
None.
（４）Challenges and future prospects
We will develop novel therapeutic approach for intractable diseases in the field of rheumatology
and allergy. Currently, we are heavily involved in clinical research for IgG4-related disease andrheumatoid arthritis. Moreover, we, through our longstanding basic research, are working to renovate
glucocorticoid therapy.

250

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Department of General Medicine（１）Members
Professor

Hiroshi Yotsuyanagi

Project Professors

Kenzaburo Tani, Takayuki Morisaki

Associate Professors

Takeya Tsutsumi, Yoshihiro Hirata

Senior Assistant Professor

Yasuo Matsubara

Project Senior Assistant Professor

Yasuki Hijikata

Project Assistant Professor

Koichi Kimura（２）Research objectives- Perform general medical examinations for gastrointestinal disorders, including endoscopy for
general consumers. The target number of endoscopic examinations by the local government is 150
cases a year, and the number of new cases including referrals for outpatients of Helicobacter pylori is
40 cases a year.
- In addition to standard treatment for patients with solid tumors, advanced treatment is performed incollaboration with various departments within the institute.
- Provide medical treatment as one of the centers for diseases such as Marfan syndrome and muscular
dystrophy.
- Actively provide viral hepatitis treatment in collaboration with Department of Infectious Disease
and Applied Immunology.
（３）Activity reports
１）Medical Activities- Medical treatment of digestive diseases
Helicobacter infection is one of the main targets of medical treatment for digestive organs.
Regarding gastrointestinal tract diseases in our hospital, inflammatory bowel disease is morecommon than other medical institutions. Department of general medicine focuses on the treatmentof these diseases. The number of endoscopic examinations in the upper digestive tract is 60 to 70
per month, and the number is increasing gradually. Considering the number of hospital beds, thenumber is quite large.
- Treatment of solid tumors
We accept patients who are considered to have only Best Supportive Care at other medical
institutions, and offer the possibility of treatment based on histopathological findings and gene
analysis. Some patients are receiving treatment out of insurance coverage.
- Cardiovascular disease medical treatment
251

G4_HospitalIn addition to supporting cardiovascular medical treatment for patients who are hospitalized, we
also provide medical treatment support for rare disease patients from all over the country.
２）Research Activities
Taking advantage of the characteristics that rare diseases are often dealt with, a summary of thepathophysiology and clinical aspects of various diseases, genetic analysis and biomarker search arebeing conducted.
３）Education Activities
None.
４）Social Activities
None.
５）International Activities
None.
６）Other matters to be noted
We deal with rare diseases, and conducted awareness-raising activities through a public medical
conference on tumors.
（４）Challenges and future prospects
We deal with rare diseases, and cooperation with other facilities is important, and it is necessary to
improve the system.

252

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Department of Applied Genomics（１）Members
Professor

Yoichi Furukawa

Associate Professor

Tsuneo Ikenoue

Technicians

1

Others1（２）Research objectives
Our department has been working on the application of human genome information in clinics. As aclinical service, we provide genetic counseling, genetic tests for human malignancies such as leukemia
and cancer, and a surveillance program for patients with hereditary colorectal cancer. In addition, we
have been carrying out two research projects; 1) determination of genetic alterations in human tumors,and elucidation of the mechanisms underlying their development, and 2) clinical sequence for the
implementation of genomic medicine（３）Activity reports
１）Medical Activities
As a part of clinical service, we have been performing genetic analysis of human neoplasms suchas leukemia and colorectal cancer. In 2019, a total of 539 genetic analyses were performed in our
department. The results were utilized for the precise classification of neoplasms, evaluation of
disease status, selection of therapeutic drugs, and evaluation of the response to treatment.
Additionally, we provided genetic counseling and genetic tests to clients who visited ourcounseling clinic. In 2019, we had a total of 42 counseling cases including hereditary breast andovarian cancer, familial adenomatous polyposis, Lynch syndrome, Li-Fraumeni syndrome, tuberous
sclerosis, adrenoleukodystrophy, hemophilia A, spinal and bulbar muscular atrophy, spinocerebellar
degeneration, Huntington’s disease, developmental disorders, and achondroplasia. In the counseling,
we provided appropriate information about hereditary diseases and took psychological care of theclients in collaboration with a clinical psychologist. Genetic testing was performed in five caseswith informed consent after thoughtful discussion about its merit and demerit.
Systematic surveillance programs are provided for the clients susceptible for hereditary tumors.
Patients with familial polyposis visited our hospital to undergo clinical checkup and endoscopic
colonoscopy.
２）Research Activities
For the implementation of precision medicine for patients with rare or intractable cancer, we have253

G4_Hospital

carried out whole exome sequencing/whole genome sequencing of cancer genome and analyzed thesequencing data using IBM Watson for Genomics (WfG). Patients with colorectal, breast, uterine,
gallbladder, pancreatic cancer, lymphoma, prostate cancer, liposarcoma, glioblastoma, andhepatoblastoma were enrolled in the study after written informed consent was obtained. WfG
selected driver mutations from the somatic mutations in the tumors and suggested actionable drugs.
These data were discussed in the Tumor Board meetings every two weeks.
３）Education Activities
As a training hospital authorized by Japanese Board of Medical Genomics and Clinical Genetics,
we provide a practice and seminars course of genetic counseling in the hospital. In 2019, six medical
doctors participated in this course.
４）Social Activities
None.
５）International Activities
None.
６）Other matters to be noted
None.
（４）Challenges and future prospects
To develop better medical service, we would like to promote the precision medicine project incollaboration with clinical departments in our hospital and other domestic hospitals.

254

G4_Hospital

Department of Radiology（１）Members
Director/Associate Professor

Akira Kunimatsu

Senior Assistant Professor

Hiroyuki Akai

Assistant Professor

Koichiro Yasaka（２）Research objectives

To hold the eligibility to claim the reimbursement for managing the quality of diagnostic imaging

To publish three articles in international journals every year（３）Activity reports
１） Medical Activities
Our department offers a radiology service at the IMSUT hospital. We conduct radiologicalexaminations and report the results of the exams. Computed tomography (CT), magnetic resonanceimaging (MRI), and radioisotope scans are available at our department. We made 9,480 reports from2016 to 2018. The local bureau of health and welfare has authorized the high quality of our service.
２）Research Activities
Using CT and MRI, we sought novel imaging findings of disease and performed statisticalmachine learning on imaging features. We also performed basic research using mouse models on asmall animal MRI and reported the pharmacokinetics of MRI contrast agents. From 2016 to 2018,
we published 52 articles in international peer-reviewed journals.
３）Educationl Activities
Medical school: a lecture for the radiology section of systematic lectures in medicine (A.K.)
Post-graduate: a lecture for clinical radiology in the master course in bioscience (A.K.), a hospital
visit program (H.A.)
The residency program at the IMSUT hospital: short clinical lectures in diagnostic imaging (A.K.
and H.A.)
４）Social Activities
None.
５）International Activities
None.
255

G4_Hospital６）Other matters to be noted
We would be honored to accept requests for radiological examinations from family medicine
doctors in the neighborhood. More than 300 patients visited our department from 2016 to 2018.
（４）Challenges and future prospects


Medical image analyses using statistical machine learning

Basic research using the small animal MRIA rise in profit for radiology service through business cooperation with the University of Tokyo
Hospital256

G4_Hospital

Department of Palliative Medicine（１）Members
Professor

Arinobu Tojo

Project Senior Assistant Professor

Yasumoto Hijikata

Others2（２）Research objectives
The Department of Palliative Medicine is committed to providing evidence-based treatment, andresearch to create evidence for palliative medicine with multidisciplinary collaboration. Throughdomestic and international activities, we promote palliative medicine.
（３）Activity reports
１）Medical Activities
Consultation activities: (1st Apr.2017-31st May 2019): 728cases (33 patients)
２）Research Activities
Aug 2018

Comprehensive exploration of monoclonal autoantibodies against tumor

Shimada, Fujiwara

cells from lymphocytes of cancer patients

June 2017

Exploratory research on determinants of place of death by a large scale of

Shimada, Fujiwara

cohort study: the JPHC study

July 2018

Development of precision palliative medicine based on genetic

Shimada, Fujiwara

polymorphisms

2018

Association between the degree of supporting patients’ decision-making andFujiwara

nurses’ perception of the degree of importance of their role in supporting
patients’ decision-making of whether to participate in cancer clinical trials

2018

A prospective observational study to evaluate the effect of rehabilitation for

Fujiwara

cancer patients in palliative care units in Japan: a pilot-feasibility study

2018

The efficacy of specialized rehabilitation using the Op-reha Guide for

Fujiwara

cancer patients in palliative care units: protocol of a multicenter,randomized controlled trial

2018-2020

Development of a practice guide to support clinical nurses in patient

Fujiwara

decision-making in cancer clinical trials.

257

G4_Hospital【Publications】
1.

Ishiki H, Kinkawa J, Watanabe A, Watanabe C, Chiba T, Yasui H, Shimada N, Ariyoshi K,
Nojima M, Iwase S, Tojo A, Imai K. Prevalence of myofascial pain syndrome in patientswith incurable cancer. J. Bodyw Mov Ther. 22(2):328-32, 20182.

Shimada N, Ohno N, Tanosaki R, Yuji K, Uchimaru K, Tojo A. Therapy-related acute
myeloid leukemia after the long-term administration of low-dose etoposide for chronic-typeadult T-cell leukemia/lymphoma: A case report and literature review. Intern Med.
56(14):1879-84, 20173.

Shimada N, Ishiki H, Iwase S, Chiba T, Fujiwara N, Watanabe A, Kinkawa J, Nojima M,
Tojo A, Imai K. Cancer transitional care for terminally ill cancer patients can reduce thenumber of emergency admissions and emergency department visits. Am J Hosp Palliat Care.
34:831-7, 20174.

Noriko F, Ryota O, Yuki S, Yuko S, Fumitaka N, Satoru I, Keiko K, Qualitative analysis ofclinical research coordinators' role in phase I cancer clinical trials. Contemporary Clin Trials
Commun. 8 :156–61, 2017

5.

Iwase, S Ishiki H, Watanabe A, Shimada N, Chiba T, Kinkawa J, Tojo A. Mapisal versus urea
cream as prophylaxis for capecitabine-associated hand-foot syndrome. J Clin Oncol,
34(4):391, 2016

【Invited speaker】
1.

Fujiwara.N. Palliative Care; Japanese experience, 17th Binenial meeting of the International
Gynecologic cancer Society. Kyoto, Japan Nov14-16.2018

2.

Fujiwara.N.UK study visit;Manchester. Panel Discussion: International Research ExchangePerspectives from a UK Study Visit Experience.10th Annual meeting of International
Association of clinical research Nurses. 2018.10.16. Arlington, VA, USA

3.

Fujiwara.N.. Belinda Fazekas. The Clinical Trial Life Cycle. Australia-Japan Palliative Care
Trials Project, 20171119, Tokyo, Japan

4.

Fujiwara.N.. What is Clinical Research Nursing? Australia-Japan Palliative Care Trials
Project, 20171119, Tokyo, Japan

5.

Fujiwara.N. Research Ethics and Good Clinical Practice, at The Global Academic Program
conference at the university of Texas, MD Anderson Cancer Center.May.9.2017, Houston,
TX, USA３）Education Activities
ShimadaLecture for Graduate students of Graduate School of Frontier Sciences, The

Fujiwara

University of Tokyo.

258

G4_Hospital

Fujiwara

Lecture for nurses regarding narcotic and psychotropic drugs
Supervise for research nurse working group
Supervise for nurses to conduct research
A part‐time instructor: Kawasaki University of Medical Welfare, Okayama, JapanA part‐time instructor: Tokyo Medical and Dental University, Tokyo, Japan４）Social Activities
Collaboration with UI KEA MINATO in Minato-city, Tokyo, Japan
５）International Activities
Collaboration with Palliative Care Clinical Studies Collaborative (Australia research group) toheld research forum, Tokyo, Japan
６）Other matters to be noted
None.
（４）Challenges and future prospects
While continuing international collaboration and research, treatment, and education activities witha multidisciplinary team approach, we will promote cooperation between the University of Tokyo
Hospital and the IMSUT Hospital, to provide palliative care for patients with terminal cancer.

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Department of Diagnostic Pathology/Department of Pathology（１）Members
Project Associate Professor

Yasunori Ota

Clinical Laboratory Technologist

Yukihisa Tanaka

Others1（２）Research objectives
To publish 10 articles in English scientific journals every year to report study findings of ourdepartment.
To “improve quality” of diagnosis. To prepare “beautiful” specimens.
To write reports that clinicians can understand easily.
To develop diagnosis into research. To acquire new technologies and apply them to diagnosis.
To develop medical doctor and technicians who will become leaders of the next generation.
（３）Activity reports
１）Medical Activities
In 2016, 1,594 cases of histological examination, 216 cases of cytology, 14 cases of autopsy, and12 cases treated in the Pathology Core Laboratory
In 2017, 1,493 cases of histological examination, 200 cases of cytology, 4 cases of intra-operative
histology, 2 cases of intra-operative cytology, 11 cases of autopsy, and 16 cases treated in the
Pathology Core Laboratory
In 2018, 1,255 cases of histological examination, 127 cases of cytology, 5 cases of intra-operative
histology, 8 cases of autopsy, and 41 cases treated in the Pathology Core Laboratory
In 2019, 1,199 cases of histological examination, 141 cases of cytology, 5 cases of intra-operative
histology, 4 cases of intra-operative cytology, 5 cases of autopsy, and 25 cases treated in the
Pathology Core Laboratory
２）Research activities
Original articles published in international journals written in English;
9 articles in 2016, 19 in 2017, 9 in 2018, and 9 in 2019３）Education Activities
1. Lectures for undergraduate students
One lecture period of systemic pathology for 4th year students in the Faculty of Medicine of the
University of Tokyo260

G4_Hospital

One lecture period of systemic pathology for 2nd year students in the Faculty of Medicine of
Akita University
2. Lectures and exercises for graduate students
One lecture period in the Graduate School of the University of Tokyo
４）Social Activities
None.
５）International Activities
Cooperation in tasks of pathological diagnosis with the Moscow Regional Research ClinicalInstitute named after M. F. Vladimirsky６）Other matters to be noted
None.
（４）Challenges and future prospects
To keep trying to achieve our goals with respect to publication of our research results in English
scientific journals.
To accelerate writing reports of pathological diagnosis. We aim to reduce turnaround time of 95%
of the cases to within 4 days.

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Department of Surgery（１）Members
Professor (Directors/Concurrent Posts)

Arinobu Tojo

Associate Professors

Masaru Shinozaki

Lecturer (Deputy Director)

Giichiro Tsurita

Assistant Prof. / Hospital Lecturer

Kentaro Yazawa

Assistant Prof.

Tomohiro Kurokawa

Others3（２）Research Objectives
Our goal in medical practice is to perform 200 cases of surgery (including 130 cases of major
abdominal surgery) yearly, and to see an average of 25 hospitalized patients daily. For research, undernormal circumstances, our goal is, to participate in more than one clinical trial and to prepare five
English papers yearly. As for education, our goal is to educate new graduate students and clinicaldoctors.
（３）Activity Reports
１）Medical Activities
Our department mainly conducts surgical treatment for malignant gastrointestinal tumors, suchas colorectal cancer and gastric cancer. The goal of our department between April 2016 and March
2020 was to carry out 100 colorectal and gastric cancer procedures yearly. However, we were only
able to perform around 60 every year and did not achieve our goal. Except for a few selectinstitutions, the number of colorectal/gastric cancer surgeries being performed in hospitals
throughout Tokyo has decreased across the board; this outcome was therefore somewhat
unavoidable. Nevertheless, we continue to aim for our target number of cases and hope to achieve
it through close clinical collaborations and united, teamwork-oriented participation in medical carefrom all members. We also plan to proactively expand the indications for laparoscopic surgery andto introduce robotic surgery accordingly.
In addition, our department provides endoscopic treatment for inflammatory bowel diseases(IBD) such as ulcerative colitis and Crohn's disease, as well as anal disease, and colon polyps. From
April 2016 to March 2020, one of our goals in this field was to perform surgeries on 30 cases of
IBD and 30 cases of anal disease, which we were largely able to achieve. We were also largely able
to achieve our goals of 500 colonoscopies and 300 polypectomies yearly. Nevertheless, we continue
to strive to increase the number of these cases that we are able to treat.
In terms of the number of hospitalized individuals seen, our goal was an average of 25 per day.
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In reality, our average was around 18. We believe this is the primary reason we were unable to meet
our surgery caseload goals.
２）Research Activities
Our department also strives to carry out clinical research alongside our medical activities. From2013 to 2016, our department participated in the following joint physician-led clinical trial initiativewith Sapporo Medical University and the Kanagawa Prefectural Cancer Center: “A multi-center
double-blind parallel-group placebo-control Phase II study on the efficacy of survivin-2B peptide
vaccine therapy for patients with advanced or recurrent pancreatic cancer, and for which there is noeffective treatment.” From April 2016 to March 2020, the goal of this department was the analysis
and reporting of the results of this trial. In reality, we completed the analysis of our results and helda general meeting in March 2017, followed by a review meeting of autopsy casers in January 2018.
In June 2019, we published two English papers publicizing our results. In terms of our activities
outside of clinical trials, we also aimed to publish 10 case reports between April 2016 and March
2020 detailing medical procedures performed in our department. In reality, we only published 4such case reports, because our participation in clinical trials and work on case reports is carried out
alongside our daily medical practice; we believe these results are somewhat substantial in thiscontext. However, following the completion of the aforementioned clinical trial, we did not initiate
any new clinical trial, and we were also unable to achieve our goal in publication of case reports. In
the future, we hope for all members to work together to acquire the necessary elements to achieve
our goals from both within and outside our department, enabling us to initiate new clinical trials andengage in other clinical research, such as the publication of case reports.
３）Education Activities
A doctoral student entered our department in April 2014, and in collaboration with the
Department of Surgical Neuro-Oncology at the IMSUT Hospital, carried out research on viraltherapy for biliary tract cancers. This doctoral student was enrolled in our department from April
2016 to March 2017 and conducted the research herein. Since then, however, there are no graduate
students enrolled in our department. In the future, we aim to organize our research environment toenable us to accept new graduate students.
In terms of clinical education, between April 2016 and March 2017, we aimed to provide
specialist resident training to at least one full-time physician at all times. In reality, although theiremployment periods varied from 6 to 15 months, we were able to train a total of 4 physicians, with
1-2 being present in our department at all times, achieving our original goal. One of these physicians
was certified as a surgical specialist, while the other was certified as a digestive system surgical
specialist. The other two were able to publish English case reports while enrolled in our department.
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There is a shortage of young surgeons throughout Japan, and while we predict that our educational
goals will be difficult to achieve in the future, we plan to work together to educate the young
surgeons of the future.
４）Social Activities
None.
５）International Activities
In July 2017, one full-time physician in our hospital began studying abroad in Boston, at
Massachusetts General Hospital, and carried out joint research with our department on newtreatments for pancreatic cancer (CAR-T).
６）Other matters to be noted
None.
（４）Challenges and future prospects
The primary challenge in our medical practice is to increase the number of surgery cases we perform.
We will work to do so by increasing the number of laparoscopic surgeries and introducing robotic
surgeries. In terms of research, we will proactively participate in new clinical trials and accelerate ourefforts to carry out case reports and other types of clinical research. Finally, in terms of education, we
will recruit young physicians and promote the education of specialists. We hope that by parallel
engagement in all these efforts, we will continue to remain an active medical department.

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Department of Anesthesia（１）Members
Director/Associate Professor

Ryo Orii

Assistant Professor

Miho Asahara

Graduate students

1

Others3（２）Research objectives
We strive to perform perioperative anesthetic management carefully in cooperation with medical
staff. We provide safe, high-quality health care and services to all patients without causing medical
accidents. We participate and cooperate in facilitating the planned implementation of robotic surgery.
In addition, we strive to promote the ongoing clinical research and target to publish research results in
English journals.
（３）Activity reports
１）Medical Activities
As the system of our department, three anesthesiologists, an associate professor Orii, an assistantprofessor Asahara, and a graduate student in the Department of Anesthesiology, School of Medicine,
The University of Tokyo, are in charge of anesthesia management.
Operations of four departments; neurosurgery, surgery, joint surgery, and hematology are
performed. We strive to maintain safe and careful anesthetic management. We conduct preoperative
visit of all surgical patients and explain them about the perioperative risk. In addition, postoperativerounds are routinely performed. Our managed cases are recorded in the the anesthesia ledger system(JSA-PIMS from Japanese Society of Anesthesiologists).
The number of general anesthesia management was 149 cases in 2016. There were 135 cases ofgeneral anesthesia management, and 23 cases of local anesthesia management in 2017. There were
132 general anesthesia management cases in 2018. Over the past four years, three incidents werereported to the Japanese Society of Anesthesiologists; one in cardiac arrest, one in severe
hypotension, and one in the neurological accident associated with surgical invasion. We
immediately reported to the Medical Safety Management Committee about the incidents and all
patients were well discharged.
We are involved in respiratory management not only in perioperative patients but also in severecases of internal medicine by endotracheal intubation or non-invasive ventilation (3 cases in 2016,
5 cases in 2017, 6 cases in 2018, 2 cases in 2019).

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G4_Hospital２） Research Activities
Clinical research about “Postoperative deep vein thrombosis in hemophilia patients undergoing
total knee arthroplasty” (approval number: 26-23) and “Anesthesia management of hemophilia
patients” (approval number: 29-48) are in progress. Since hemophilia patients undergoingarthropathy surgery gather from all over the country and at risk of perioperative bleeding,coagulopathy and thrombosis, we carefully perform anesthetic management. We published onanesthetic experience of a hemophilia patients in Masui, the Japanese Journal of Anesthesiology,
and peer-reviewed English journal (Anesthesia management of arthroscopic ankle artherosis for ahemophilia patient after living-donor liver transplantation, Intractable Rare Dis Res. 2019) We also
participated in clinical trials for hemophilia patients conducted by department of joint surgery(Evaluation of the efficacy and safety of NC-0129-0000-1003 in hemophilia A and hemophilia B in
the perioperative period).
In addition, as other clinical researches, such as "Comparison of position- related changes in
respiratory status by oxygen administration via a nasal cannula during general anesthesia"(approval number: 29-34), and " Comparison of central, nasopharynx, and tympanic temperatureduring abdominal surgery using TENPLE TOUCH PRO” (approval number: 30-16) are ongoing.
We conducted a clinical research on cardiac output was undertaken at the University of Tokyo
Hospital and published a paper in a peer-reviewed English journal (Reliability of cardiac
measurements using LiDCOrapid and FloTrac/Vigileo across broad band ranges of cardiac output
values. , J Clin Monit Comput. 2017).
Since the systemic and respiratory management is one of our research themes. We have assessed
impaired controlled ventilation in the anesthetic machine due to poor control of PEEP valve
mechanism and submited a paper in English journal (Unexpected deposits in the anesthetic circuit:a possible cause of PEEP/Pmax valve malfunction, BMC Journal) .
As a retrospective study, we confirmed that a large number of perioperative blood coagulation
disorders occurred in the patients undergoing a liver donation surgery and reported at the annual
meeting of the American Society of Anesthesiologists. A graduate student is currently preparing adoctoral dissertation for this research now. We are planning to proceed with clinical research about
evaluation of the effect of new anesthetic drugs on perioperative liver function , as a joint researchwith Department of Surgery, University of Tokyo Hospital.
３）Education Activities
As an education for students of the Graduate School of Frontier Sciences, The University ofTokyo,
we provide hospital training in order to learn about the environment and outline for surgery inthe operating room and give lectures about anesthesia (5 times a year). Similarly, we conduct266

G4_Hospital

hospital training and lectures for psychology students in response to the requests from Bunkyo
University every year. In addition, the anesthesiology lecture "Postoperative complications" held atthe Hongo campus for M2 students of the Graduate School of Medicine, the University of Tokyo is
our charge. We are in charge of lectures about anesthesia for senior residents belonging to IMSUT
hospital.
As an education about clinical anesthesia, one doctor of a graduate student of anesthesiology
department at the University of Tokyo Hospital was dispatched to our hospital on the scheduled
surgery day, and provide clinical training while implementing anesthesia management.
As a medical device safety manager, I teamed up with clinical engineers and conducted inhospital education. Specifically, we planned and conducted training programs for nurses (six times
a year), training sessions for mechanical ventilator, new medical equipment briefing sessions,medical equipment training, joint staff training.
４）Social Activities
None.
５）International Activities
None.
６）Other matters to be noted
The restart the 5th floor ward was decided in 2019, and construction of two ICU beds are planned.
In mid-2018, The 5th floor ward started in May. In addition, a special project for strengthening
hospital functions, which is one of the tasks of the University of Tokyo General Project Organization,
will start operation from 2020. Since September 2018, the director has instructed us to formulate
the Da Vinci surgical system and prepare the environment of the operating room for the introductionof robotic surgery. We set up working groups and hold meetings, visits and hear opinions from otherhospitals, prepares and submits plans for medical devices and equipment.
（４）Challenges and future prospects
As a general principle of anesthesiology, it is important to protect the safety of patients and to adjust
the homeostasis of patients due to surgical invasion, to provide appropriate pain management andhigh-quality health care services. We will continue to carefully manage perioperative management incooperation with surgeons and medical staffs to provide safe and high-quality medical care to prevent
medical accidents.
As for research activities, I am working on the contents of multiple themes mentioned above. In
particular, I am planning to submit a paper on “Perioperative management of female hemophilia”
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G4_Hospitalduring this year. In addition, we will proceed with the publication of "Consideration of the inability tocontrol the PEEP valve of anesthesia machine" during the next fiscal year to be published in themagazine within the next year.
This year, a special hospital strengthening project led by the university started to operate, and it wasplanned to introduce robot surgery to our hospital. Aiming to improve the operating rate of hospitals
and increase income, assuming the addition of medical departments and securing doctors. The
expansion of surgery contents by introducing robotic surgery is premised on securing sufficientnumbers of surgical doctors, anesthesiologists, and clinical engineering technicians, and educating
operating room nursing staff. I will continue to participate in the operation room management as ananesthesiologist in the future.

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Department of Joint Surgery（１）Members
Senior Assistant Professor

Hideyuki Takedani (chief of department),

Assistant Professor

Kumino Ono

Others3（２）Research objectives
Our department was established in 2006 to treat hemophilic arthropathy surgically. There are threemajor missions, the clinical research of safety surgical and hemostatic management for hemophilicarthropathy, the development of imaging and functional evaluation methods of hemophilic arthropathy,
and development of treatment to keep and improvement of joint function and daily activities for people
with hemophilia.
As for clinical research, A) Clinical investigation of influence of viral infection such as HIV, HCV
on joint surgeries for patients with hemophilia, B) Development of safety hemostatic management
during peri-operative period of surgical treatments, C) Clinical trial participation of new concentrates,
especially surgical matter.
As for development of evaluation methods, A) planning and implement of national investigation of
QOL in people with hemophilia using questionnaire, and B) gait analysis using depth sensing camera.
As for development of treatments, A) evaluation of rehabilitation efforts with and without surgicaltreatments, and B) basic research of regenerative treatment using mesenchymal stem cell.
（３）Activity reports
１）Medical Activities
From 2006, we have performed over 200 surgeries for patients with hemophilia and othercoagulation diseases such as VWD, FVII deficiency. Many patients with joint dysfunction caused
hemophilia and other coagulation diseases are arrival at our institutes as outpatients from all overJapan and from 15 to 20 surgeries are undergone annually.
２）Research Activities
For people with hemophilia, total and conventional functional evaluation system is need because
they have many affected joints. Therefore, we are developing gait analysis system using gamegadget with depth sensing camera.
Basic pathological research for hemophilic arthropathy and regenerative research using
mesenchymal stem cell are going, collaborated with department of orthopeadic surgery in theuniversity of Tokyo.
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G4_Hospital３）Education Activities
A couple times in a year, we speech about hemophilic arthropathy to people and family withhemophilia４）Social Activities
None.
５）International Activities
None.
６）Other matters to be noted
None.
（４）Challenges and future prospects
Development conventional gait analysis system helps to evaluate their daily functional andemotional variation at home and to detect infinitesimal joint bled (micro bleeding) for people withhemophilia.
There are two major surgical methods which are synovectomy and total joint arthropathy (TJA)
for hemophilic arthropathy. Usually synovectomy for early staged arthropathy and TJA for end
staged arthropathy are performed. Development of regenerative treatment using mesenchymal stem
cell help for patients with hemophilia who have arthropathy from early to progressive staged.

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Department of Surgical Neuro-Oncology（１）Members
Professor

Tomoki Todo

Project Associate Professor

Minoru Tanaka

Assistant Professors

Seisaku Kanayama, Hirotaka Ito

Postdocs

2

Graduate students

2Technicians

5

Others2（２）Research objectives
Our department focuses on malignant tumors of the brain, such as gliomas or metastatic brain
tumors. We are developing recombinant herpes simplex virus type I (HSV-1). Clinical trials using athird-generation, triple-mutated oncolytic HSV-1, G47Δ, is ongoing in patients with olfactory
neuroblastoma or malignant pleural mesothelioma. Recently we have started a new investigatorinitiated clinical trial using T-hIL12 for malignant melanoma.
（３）Activity reports
１）Medical Activities
Department of Surgical Neuro-Oncology was established in 2011. Our department started treating
out-patients in October 2011 and in-patients in April 2012. Glioblastoma is refractory toconventional therapies and has a poor prognosis with a 5-year survival rate of less than 5%.
Therefore, we should consider refined and personalized treatment approaches for selected patients:
high dose radiation therapy of 80Gy for newly diagnosed glioblastoma or extended field stereotactic
radiosurgery for recurrent gliomas. Four neurosurgeons treat patients with brain tumors. Standard
craniotomies, image-guided stereotactic biopsies of deep-seated lesions, and high-tech brain tumor
resections have been performed. The high-tech equipment regularly used in brain tumor resection
surgeries includes an operative microscope, a 3-D neuro-navigation system, intraoperative
monitoring with motor and sensory-evoked potential (MEP and SEP) recording, intraoperative
ultrasonography and an ultrasonic surgical aspirator.
Patients with newly diagnosed malignant glioma have been treated with high dose or standarddose radiation therapy and concomitant chemotherapy. Temozolomide was given to glioma patientsduring radiation therapy and repeated every 28 days for as long as possible. The overall survival ofpatients with glioblastoma was 30.3 months (95% confidence interval, 24.5-36.1 months. The fiveyear overall survival rate was 26.5%.
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Recurrent malignant glioma patients are treated with innovative non-standard therapies wheneverpossible. Recurrent glioma patients who have small lesions, receive extended field stereotactic
radiosurgery. To enhance the efficacy of stereotactic radiosurgery (SRS), we extended the irradiation
field with the intent to include as many tumor cells as invasive to the surrounding tissue as possible.
We demonstrated 93% local control in patients who received 20 Gy to a 0.5-1.0 cm extended field
SRS compared to 47% of patients who were treated with 20 Gy to the gadolinium-enhancing margin
only.
２）Research Activities
We are developing recombinant herpes simplex virus type I (HSV-1), which has genetic
modifications in the viral genome so that the viruses replicate selectively in cancer cells while giving
rise to an immune response against tumor-associated proteins.
We conducted a phase II clinical trial of G47Δ in patients with glioblastoma. The planned interim
analysis showed that the one-year survival rate of the 13 patients who completed the one-year
follow-up assessment was 92.3%. The independent data monitoring committee (IDMC)
recommended terminating the trial because the one-year survival rate was tremendously higher than
the set control value based on the meta-analysis of historical data. Daiichi Sankyo Company willsubmit a Marketing Authorization Application for G47Δ to the Japanese Pharmaceuticals andMedical Devices Agency (PMDA). Clinical trials using a third-generation, triple-mutated oncolytic
HSV-1, G47Δ, is ongoing in patients with olfactory neuroblastoma or malignant pleural
mesothelioma.
Recently we have started a phase 1/2 clinical trial of T-hIL12 in patients with advanced malignant
melanoma. T-hIL12 is a recombinant herpes simplex type I with IL-12 expression. This IL-12mediated antitumor immunity could be T-cell-mediated. T-hIL12 will be administered into thetumor of skin or lymph node metastases in patients with the advanced stage of malignant melanoma.
The assigned dose will be repeatedly inoculated into the metastases 2 or 4 times, with an interval of
14 (14 -28) days. The primary endpoint in phase 1 is safety, whereas, in phase 2, it is the response
rate (RECIST 1.1).
３）Education Activities
We offer various opportunities for graduate students to be involved in research activities. We also
give lectures associated with clinical issues for nurses.
４）Social Activities
We continue to educate the public about brain tumors and oncolytic virotherapy through public
lectures.
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G4_Hospital５）International Activities
We frequently exchange information through international conferences.
６）Other matters to be noted
Primary central nervous system lymphoma patients will first undergo biopsy for pathologicaldiagnosis. In addition to the standard therapy regimen using high-dose methotrexate followed byradiotherapy, an advanced treatment regimen utilizing rituximab, methotrexate, procarbazine, andvincristine (R-MPV) therapy followed by consolidation whole-brain radiation therapy and highdose cytarabine has been used as a treatment option.
（４）Challenges and future prospects
To date, immunotherapy, such as immune checkpoint inhibitors, has been shown to have the mostsignificant impact on immunogenic cancers such as malignant melanoma and renal cell cancer.
However, many immunotherapies that succeeded in immunogenic cancers have failed for glioblastoma
because the tumor microenvironment of glioblastoma is extremely immunosuppressive. G47∆ notonly selectively replicates in and kills solid tumor cells without harming healthy tissue, but also
induces antitumor immune responses. Further clinical studies are needed to understand whether G47∆,
combined with an immune checkpoint inhibitor, can break the immune tolerance in a highly
immunosuppressive tumor microenvironment.

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Department of Medical Informatics（１）Members
Director/Associate Professor

Akira Kunimatsu

Senior Assistant Professor

Hiroyuki Akai

Assistant Professor

Koichiro Yasaka

Radiologic Technologist

Nobukiyo Yoshida

Chief Clerk

Toru Sano

Others2（２）Research objectives
To operate and manage the electronic medical record system and network at the IMSUT hospital

To renew an old ordering system and implement the latest electronic medical record system（３）Activity reports
１）Clinical activities
The IMSUT hospital started to use a new electronic medical record system in October 2017. On
renewing the system, our department took the initiative, coordinating hospital members and thesystem vendor. We responded 1104 calls for system disruptions and how-to questions in 2016, 1406
in 2017 (611 before the renewal, 795 after the renewal), and 1334 in 2018. These figures suggestthat we could satisfactorily control the initial system disruptions.
２）Research activities
The IMSUT hospital is a member of the nation-wide backup program for the electronic medical
record system (the GEMINI project). Our department participated in trial runs in uploading datafrom our hospital to a designated data center and downloading stored data from the center.
３）Educational activities
For newcomers to our hospital, we held a how-to-use seminar of the electronic medical record
system every year.
４）Social activities: nothing in particularNone.
５）International joint activities: nothing in particular
None.
274

G4_Hospital６）Other matters to be noted: nothing in particularNone.
（４）Challenges and future prospetcs


To evaluate the current IT-Business Continuity Plan (BCP) at the IMSUT hospital

To implement a system upgrade periodically and improve IT-BCP when a problem is identified

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Department of Radiological Technology（１）Members
Director/Associate Professor

Akira Kunimatsu

Chief Radiologic Technologist

Tomio Inoshita

Radiologic Technologists (RT)6Technical assistants

1（２）Research objectives
To provide safe and high-quality medical careTo assist technologists who present their work

To encourage young technologists to improve their skills and knowledge

To encourage active participation in conferences and research groupsTo assist technologists who attend post-graduate courses（３）Activity reports
１）Medical Activities


Revision of operating manuals
➢

MRI

➢

Infection control manual for the department➢

Emergency operation manual for the department➢

Operating manual for emergency CTMaintenance of radiation protectors and protecting clothes (every year)Attendance to seminars held by the Society of Radiological Technology➢

2 RTs (2016), 5 RTs (2017), and 1 RT (2018)

Emergency CT and MRI (cases on average per month)➢

CT 20.5, MRI 4.5 (2017)➢

CT 18.6, MRI 3.8 (2018)

Preparing for and responding to annual audits by the Tokyo metropolitan government２）Research Activities


Publication: co-author 1

Presentation at Meetings➢

Domestic: 1st author 2, co-author 3➢International: co-author 6276

G4_Hospital３）Educational ActivitiesRadiological technologist exchange program with the University of Tokyo Hospital: 6RTs from2016 to 2018 (fiscal year)Completion of the master program: 1 RT

Attendance to conferences, study groups, and workshops (in total number)➢

17 RTs (2016), 18 RTs (2017), 9 RTs (2018)４）Social Activities: nothing in particularNone.
５）International Activities: nothing in particularNone.
６）Others matters to be noted: nothing in particularNone.
（４）Challenges and future prospects
A rise in the number of CT and MRI examinations

Continuous improvement in healthcare safety and personal skills

Improving the work environment to achieve balanced work and research activities

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Department of Cell Processing and Transfusion（１）Members
Associate Professor

Tokiko Nagamura-Inoue

Assistant Professors

Kazuaki Yokoyama, Toyotaka Kawamata

Postdocs

1

Graduate students

1

Technicians

8

Others7（２）Research objectives
The aim of our department is to support and manage the safe and appropriate use of transfusion
medicine. We also perform cell processing for cell therapy not only for clinical use but also fortranslational research. This department consists of a division of blood transfusion medicine, divisionof cell processing, and a cell resource center (IMSUT-CRC).
（３）Activity reports
１）Medical Activities(A) Division of blood transfusion medicine: We continuously tested for blood type and performed
cross-match and irregular antibody tests. To eliminate abnormal blood products, including bacterial
contamination, we established visual test methods for the identification of platelet products byplacing samples under bright lights for 10 minutes. Since September 2019, regulations regarding
radioisotopes have become stricter, and we have strengthened the monitoring of our radiation
instruments as well as have limited access to trained users.
(B) Division of cell processing: We collected peripheral blood stem cells (PBSC) and processed andcryopreserved the collected cells for patients with multiple myeloma and malignant lymphoma.
CD34+ cells were counted by flow cytometry and the patients with sufficient CD34+ cells received
PBSCT. In addition, beginning in 2018, apheresis was conducted to collect mononuclear cells forclinical trials of CAR-T cell therapy initiated by Takara Bio Inc. We also collected mononuclear
cells for a clinical trial of dendritic cell therapy.
(C) IMSUT-CRC: We maintained a clean room and sterile instruments to be able to adjust theenvironmental standards/criteria and quality tests for cell processing. We have supported severaltranslational projects including aAVC-WT-1 immunotherapy, dendritic cell therapy, and the cord
blood/umbilical cord bank (IMSUT CORD).
２）Research Activities
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Our recent projects include the IMSUT serum bank, the Research Cord Blood Bank (RCBB), theNational BioResource Project (NBRP) supported by AMED (MEXT) and CB, and the umbilical
cord-derived mesenchymal stromal cell (UC-MSC) bank for clinical use supported by AMED(MHLW). We began an investigator-initiated clinical trial in 2018 for the administration of umbilical
cord-derived MSCs in treatment-resistant severe acute graft-versus-host disease. We also studied
the immunological properties of umbilical cord-derived MSCs (UC-MSCs) for clinical applications
in graft-versus-host disease (GVHD), Hemophagocytic lymphohistiocytosis (HLH), andregenerative medicine for neonatal encephalopathy, cleft palate, and hemophilia arthropathy.
The main publications related to this work are listed below:⚫

Mukai T, Tojo A, Nagamura-Inoue T. Mesenchymal stromal cells as a potential therapeutic
for neurological disorders. Regen Ther. 2018, 9:32-37. (Review)⚫

Mukai T, Tojo A, Nagamura-Inoue T. Umbilical cord-derived mesenchymal stromal cells
contribute to neuroprotection in neonatal cortical neurons damaged by oxygen-glucose
deprivation, Front Neurol. 2018, 9:466.

⚫

Nakamura S, Yokoyama K, Yusa N, Ogawa M, Takei T, Kobayashi A, Ito M, Shimizu E,
Kasajima R, Wada Y, Yamaguchi R, Imoto S, Nagamura-Inoue T, Miyano S, Tojo A.
Circulating tumor DNA dynamically predicts response and/or relapse in patients withhematological malignancies. Int J Hematol. 2018,108:402-410.

⚫

Ikeda K, Ohto H, Okuyama Y, Yamada-Fujiwara M, Kanamori H, Fujiwara SI, Muroi K, Mori
T, Kasama K, Iseki T, Nagamura-Inoue T, Fujii N, Ashida T, Kameda K, Kanda J, Hirose A,
Takahashi T, Nagai K, Minakawa K, Tanosaki R. Adverse events associated with infusion ofhematopoietic stem cell products: A prospective and multicenter surveillance study. Transfus
Med Rev. 2018, 32:186-194.

⚫

Tanaka E, Ogawa Y, Mukai T, Sato Y, Hamazaki T, Nagamura-Inoue T, Harada-Shiba M,
Shintaku H, Tsuji M. Dose-dependent effect of intravenous administration of human umbilical
cord-derived mesenchymal stem cells in neonatal stroke mice. Front Neurol. 2018, 9:133-14.

⚫

Shintaku H, Nabetani M, Hamazaki T, Kusuda S, Tamura M, Watabe S, Hayakawa M, Sato
Y, Tsuji M, Taguchi A, Ichiba H, Oka A, Mori R, Taki A, Mukai T, Nagamura-Inoue T.
Regenerative therapy for cerebral palsy: Transplantation of umbilical cord blood stem cells
and umbilical cord mesenchymal stromal cells. J Hell Stud. 2017, 26:71.

⚫

Isobe M, Konuma T, Abe-Wada Y, Hirata K, Ogami K, Kato S, Oiwa-Monna M, Tanoue S,
Nagamura-Inoue T, Takahashi S, Tojo A. Alloimmune hemolysis due to major RhE
incompatibility after unrelated cord blood transplantation. Leuk Lymphoma. 2018, 59:10001003.

⚫

Kondo T, Nagamura-Inoue T, Tojo A, Nagamura F, Uchida N, Nakamae H, Fukuda T, Mori
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T, Yano S, Kurokawa M, Ueno H, Kanamori H, Hashimoto H, Onizuka M, Takanashi M,
Ichinohe T, Atsuta Y, Ohashi K. Clinical impact of pretransplant use of multiple tyrosine
kinase inhibitors on the outcome of allogeneic hematopoietic stem cell transplantation forchronic myelogenous leukemia. Am J Hematol. 2017, 92:902-908.
⚫

Mukai, T., Mori, Y., Shimazu, T., Takahashi, A., Tsunoda, H., Yamaguchi, S., Kiryu, S., Tojo,
A., and Nagamura-Inoue, T. Intravenous injection of umbilical cord derived mesenchymal
stromal cells attenuates reactive gliosis and hypomyelination in a neonatal intraventricularhemorrhage model. Neuroscience. 2017, 355:175-187.

３）Education Activities
We have four cell therapy specialists in our hospital. Dr. Nagamura is the chairperson of thesteering committee of Cell Therapy specialist in the education/certification system, which allows
the growth and certification for the individuals working in the clinical field of cell processing inJapan. Our facility (IMSUT-CRC) was the first certified educational and training facility to hosteducational lectures and examinations for examinees.
４）Social Activities
Our department conducted joint research studies with the companies Tsubakimoto Chain Co., Ltd.
(2013 – present), Rohto Pharmaceutical Co., Ltd. (2014-2018), Human Life Cord Inc. Stem Cell
Institute Inc. (2017-present), NIPRO Corp. (2020-), PharmaBio Inc.(2018), Kaneka (2019-present),
and Tess Inc. (2017-present). These studies were mainly focused on the research and developmentof mesenchymal cells for clinical use.
５）International Activities
We collaborated with the Chinese researcher He H.M.D., Ph.D., from the Department of
Hematology of Kunming University of Science and Technology/Yunnan Province First People'sClinic, which was supported by the Sasagawa scholarship grant, the National Natural Science
Foundation of China (NSFC-81760028), the Yunnan Provincial Basic Research (Kunming Medical
Joint Project-2018FE001-129) in 2018, and the IMSUT International Joint Research Project (2019– present) for the immunological study of UC-MSCs. Furthermore, we collaborated in aninternational research study with Dr. Coq at the France National Science Center and Dr. Tsuji at the
Kyoto Women's University supported by the MEXT grant from 2018-2019 and the IMSUTInternational Joint Research Project (2020) for the study of the efficacy and mechanisms of UCMSCs for brain developmental disorders in intrauterine fetal hypoplasia.
６）Other matters to be noted280

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Please visit our website for further information: http://www.ims.u-tokyo.ac.jp/dcpt/english/（４）Challenges and future prospects
In our department, we deal with biological resources for clinical use. We prioritize safe and qualified
blood and cell products. In near furure, because of the deterioration of the present cell processing
facility (IMSUT-CRC), we are planning to establish a new facility to serve and support cell processing
and product management.

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Surgical Center（１）Members
Professor

Tomoki Todo

Project Associate Professor

Minoru Tanaka（２）Research objectives
The IMSUT hospital gives seamless support for translational research. Our mission is the
management and operation of the surgical center to achieve a safe and organized environment where
surgical procedures can be performed in high quality. By next year we will introduce the da Vinci
surgical system, which is a robotic technology that allows surgeons to perform minimally invasive
procedures.
（３）Activity reports
１）Medical Activities
The IMSUT hospital gives seamless support for translational research. The aim is to apply
knowledge gained from the basic sciences to clinical and community health-care settings. Our
activities include the management of clean areas, the establishment of protocols for infection control,
maintenance of equipment such as astral lamps, surgical microscopes, and fiberscopes, andorganizing of daily and weekly operations. Three of four operating room is maintained at a NASAclass 1,000 clean level and specifically designed for neurosurgery and joint surgery. The others aremaintained at a NASA class 10,000 clean level. For prompt and sustained supply of sterilizedmaterials, we keep the surgical tools for each department in sets of designated purposes.
２）Research Activitiesi) Equipment in the surgical center
The center is equipped with C-arm x-ray, TV systems, surgical microscopes, ultrasonicaspirators, image guided navigation systems, intraoperative ultrasound imaging systems,
intraoperative nerve simulation monitoring systems, etc. The endoscopic procedure rooms is
located separately but adjacent to the surgical center.
ii) TV monitoring system
Each operating room is equipped with a TV camera, so that the rooms can be monitored in thecontrol center as well as by pad devices carried by managing anesthesiologists.
iii) Induction of electronic ordering system
We are accelerating the induction of an electronic ordering system for the surgical center thatallows a real time ordering by clinical departments and computerized management of operation
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３）Education Activities
None.
４）Social Activities
None.
５）International Activities
None.
６）Other matters to be noted
Facts in the fiscal year 2018
Total number of operations

161

Planned operations

149

Emergency operations

12

General anesthesia

132

Spinal1

Epidural

0

Local

28

Others0（４）Challenges and future prospects
The da Vinci system enables surgeons to perform the most complex and delicate procedures throughvery small incisions. The da Vinci Surgical System is often being used for prostatectomy and otherurologic procedures. This minimally invasive approach is ideal for delicate urologic surgery. Using
this system, surgeons have a better tool to spare surrounding nerves, which may enhance clinicaloutcomes.

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Department of Medical Supply Center（１）Members
Professor

Tomoki Todo

Others3（２）Research objectives
We manage the process of medical device distribution in the IMSUT Hospital to offer safe andhigh-efficient medical service. Medical devices directly or indirectly affect the human body andhave potential risks; therefore, quality control is especially important at all stages of the process.
The Central Sterile Supply Department provides complex services including the preparation ofsterile medical supplies for the surgery rooms and all other stations and centers of the IMSUT
Hospital. The main aim is to guarantee a high quality and level of sterilization for all medical
supplies.
（３）Activity reports
１）Medical Activities
The Central Sterile Supply Department is responsible for preparing medical-surgical supplies andequipment so that they are sterile and ready for use. Medical supplies are packed into special singleuse or reusable sterile packs. The machine-controlled washing is carried out in a closed system anduses thermal-chemical or thermal disinfection. Both chemical and biological indicators rigidly
monitor all sterilization processes. Medical devices, equipment, and surgical materials are divided
into three general categories: (1) critical items, (2) Semi-critical items, and (3) Non-critical items,
based on the potential risk of infection. Most surgical instruments are sterilized using a highpressure steam sterilizer/low-temperature hydrogen peroxide gas plasma sterilization system.
Commonly used sterilization processes have a variety of advantages and disadvantages. For
example, the high-pressure steam sterilizer is an effective sterilization process, but its hightemperature and moisture make it unusable for many of today's devices. Instead, hydrogen peroxide
gas plasma is used worldwide for the terminal sterilization of medical equipment. Sterilization
occurs in a low-moisture environment at a temperature of less than 50°C. It is suited for sterilizing
heat-and moisture-sensitive items, delicate instruments, and instruments with sharp edges. The
hydrogen peroxide gas plasma sterilization system can safely and effectively sterilize most surgicalinstruments, except for powders, liquids, devices with long, narrow lumens, linens, and othercellulosic materials.

284

G4_Hospital２）Research Activities
None.
３）Education Activities
None.
４）Social Activities
None.
５）International Activities
None.
６）Other matters to be noted
A Sterile Processing Technician who completed the skill training course for operations chief ofuse of class -1 pressure vessel works to prepare, sterilize, install, assemble, or clean all laboratoryor healthcare equipment required for surgeries, examinations, and medical procedures.
（４）Challenges and future prospects
The IMSUT Hospital will introduce the da Vinci surgical system. Before use in the operating room,
the system needs to be properly draped and the instruments and accessories sterilized. This iscomprised of the following: (1) surgeon console with an integrated 3-D display stereo viewer, (2) the
InSite vision system, and (3) surgical cart with one camera arm, and two instrument arms. There are awide range of expensive and sophisticated accessories and instruments that come along with the daVinci surgical system, that need special care and attention.

285

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Department of Laboratory Medicine（１）Members
Professor

Tokiko Nagamura-Inoue

Assistant Professor

Tomohiro Ishigaki

Head Clinical Technologist

Hiroyuki Shingyochi

Clinical Technologists

13（２）Research objectives
The department of Laboratory Medicine consists of seven divisions: clinical hematology,
biochemistry/serology, microscopy, pathology, bacteriology, physiology, and TR verificationlaboratory.
Clinical laboratory tests are necessary for all the steps of clinical practice, including diagnosis of
diseases, evaluation of stages, determination of treatments, and assessment after therapy. Our
department engages in most of the clinical laboratory examinations in our hospital under stringent
quality control and provides investigational laboratory analysis in collaboration with many otherdepartments.
Our clinical and research objective is to facilitate translational research projects in this researchhospital from the point of view of the clinical laboratory. For the purpose, we had established a special
division named TR verification laboratory, and this division has been contributing to evaluating thesafety of experimental therapeutic approaches and biopharmaceutical products for clinical trials.
As a central medical department, we are also taking part in many clinical trials and supporting
researches conducted in our hospital.
（３）Activity reports
１）Medical Activities
Our department is engaged in almost all the clinical laboratory tests except blood transfusion
screening and radiological ones in this hospital. As this institute is one of the central institutes fortranslational researches in Japan, many clinical trials and investigational studies have been
conducted in this hospital. To support such medical activities, we have been making efforts to reportlaboratory results swiftly with high precision and high accuracy. Clinical laboratory tests in our
hospital should be managed under stringent quality control. Although this hospital is not large, we
are now participating in many external quality control tests. In addition to major tests conducted by
Japan Medical Association and Japanese Association of Medical Technologists (JAMT), we are also
participating in the survey of American Society of Clinical Pathologists (CAP Survey), which is theworld's largest comprehensive proficiency testing program, to ensure the accuracy of the tests.
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As presented above, we have supported many clinical trials and researches conducted by otherdepartments in this hospital: eight main projects and more. Faculty doctors have also performed ourown basic and clinical researches about hematological malignancies (leukemia and lymphoma). Our
researches about adult T-cell leukemia / lymphoma have recently been awarded by four academic
societies: the Japanese Society of Laboratory Medicine (JSLM), the Japanese Society of
Hematology, the Japanese Society for Amino Acid Science, and the Japanese Society of HTLV-1
and Associated Diseases. Moreover, we have also developed a new laboratory management systemfrom scratch and applied it to the TR verification laboratory, which is picked up as one of therecommended presentations by the chairman of the 66th annual meeting of JSLM.
３）Education Activities
Although there are no graduate school courses such as clinical laboratory medicine courses
attached to our department, we accept students from our university and other colleges. We regularly
conduct educational activities to teach them the importance of clinical laboratory examinations. In
addition to lectures about the role of clinical laboratory testing in clinical practice, we make thestudents see the actual scene of the clinical laboratory to deepen the understanding of the clinicallaboratory department.
４）Social Activities
None.
５）International Activities
None.
６）Other matters to be noted
None.
（４）Challenges and future prospects
As a laboratory department of the only hospital attached to research institutes in Japan, we will keepon supporting translational researches from the points of view of clinical laboratory medicine. Moreactive participation of clinical technologists to researches is one of the challenges for the future. It isnecessary to create an environment and work system that will make clinical technologists be moreinterested in research activities and contribute more to clinical laboratory researches.

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Regional Medical Liaison Office（１）Members
Professor

Hiroshi Yotsuyanagi

Others6（２）Research objectives
As a hospital information desk, we work closely with local medical institutions so that patients canreceive optimal medical care smoothly. Further we announce the latest medical information at our
hospital. Social workers and nurses who support the discharge of patients support the use of the social
welfare system necessary for patients to receive medical care with peace of mind.
（３）Activity Reports
１）Medical Activities
We help with the patients introduced to the IMSUT hospital and support introduction to otherhospitals or medical facilities. Furthermore, we support patients who need social and/or financial
help.
２）Research Activities
None.
３）Education Activities
None.
４）Social Activities(a) Cooperation with regional medical institutions⚫

After accepting referral from a local medical institution, we communicate with doctors andarrange the appointment schedule.

⚫

After seeing referred patients, the reply letter from the doctor in charge is sent via the community
medical cooperation room.

⚫

“IMSUT Hospital News” is sent to the medical institutions in communication with our hospitalfour times a year.

⚫

In the fall, we invite nearby medical institutions and those who have a referral record to our
hospital to have a medical cooperation round-table conference.

⚫

We still have shortcomings in contact with regional medical institution, which are to be improved.

288

G4_Hospital(b) Patient support⚫

We introduce available social welfare services to patients and their families.

⚫

We support patient transfer, facility admission.

⚫

We introduce the social security system and medical cost subsidy to patients with financial
problems.
５）International Activities
None.
６）Other matters to be noted
None.

（４）Challenges and future prospects
As mentioned in the “Social activities” section above, insufficient attention is paid to confirm
whether all the patients referred from other medical institutions are recognized, whether the visits of
the referred patients are notified to the institutions, and whether response letters are sent to theinstitutions, all of which require further improvement. If those issues are resolved, an increase ofreferred patients can be expected.

289

G4_HospitalCenter for Clinical Safety and Infection Control（１）Members
Director of Center/Professor

Hiroshi Yotsuyanagi

Head of Medical safety Management Division/Associate Professor Yoichi ImaiHead Nurse/General Risk Manager

Hatsuko Narita

Pharmaceutical department manager/General Risk Manager

Seiichiro Kuroda

Associate Professor /Medical safety Management Division

Ayako Kamisato

Head of Infection Control Division

Hiroshi Yotsuyanagi

Assistant Professor /Infection Control Division

Eisuke Adachi

Head Nurse/Infection Control Division

Mika Kogayu

Pharmacist/Infection Control Division

Mika Yamamura

Clinical Technologist/Infection Control Division

Hiroko Shibata

Others1（２）Research objectives
The Medical Safety Management Division consisting of doctors and nurses and pharmacists wasfounded in July 2001 and is responsible for carrying out medical safety in order to prevent incidents
and accidents beforehand and deliver safe medical care to patients. Especially at our hospital, we
mainly focus on hematological malignancies, infectious diseases, immune diseases, refractory
malignant solid tumors etc, and are performing many kinds of therapies including transplantation. So,
we are keeping in mind that we can adequately respond to the things those will happen in these kindsof medical activities.
ICT（Infection Control Team）has a key role to play in educating staff and ensuring appropriate
systems to encourage infection prevention and control as part of routine practice are in place. The ICT
consists of infection control doctors, infection control nurses, pharmacists, clinical laboratory
technicians and administrative staff.
（３）Activity reports
１）Medical Activities① Reports of incident and accident in our hospital are collected and analyzed using electronic
medical record system. Based on the analysis, we are taking preventive measures for such
incident and accident.
② Monthly in-hospital inspection is performed to prevent occurrence of incident and accident③ We perform monthly report of incident and accident at the committee of Medical Safety
Management and have launched several guidelines for medical safety management in our
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G4_Hospital

hospital.
④ We hold meeting of field representative for medical safety management ten times per year tosecure the medical safety management in our hospital.
⑤ We have held emergency meeting for serious incident and accident to take measures for suchproblems (6 times in 2017, ten times in 2018, and once in 2019).
２）Research Activities
Hatsuko Narita, Annual meeting of Japan Society of Clinical Safety, March 2020, Tokyo
３）Education Activities
Hiroshi Yotsuyanagi, Seminar for Medical Safety Education, September 2019, Tokyo
４）Social Activities
Yoichi Imai, Hatsuko Narita, and Seiichiro Kuroda, the meeting for medical safety management
in National University Hospitals, twice per year５）International Activities
None.
６）Other matters to be noted
None.
（４）Challenges and future prospects
While trying to resolve the nation-wide problems concerning lacks of checking reports of CT andpathological findings, we will continue to ensure and promote clinical safety in our hospital.

291

G4_HospitalCenter for Translational Research（１）Members
Professor

Fumitaka Nagamura

Associate Professor

Masanori Nojima

Project Associate Professor

Hiroshi Yasui

Technicians

11

Others6（２）Research objectives
Center for TR is the management and support section for both pharmaceutical company initiatedand sponsor-investigator clinical trials and non-IND clinical studies like clinical trial support
organization of other hospitals. Translational Research (TR) is the clinical application of the results ofbasic research. One of the major missions of IMSUT is to promote TR. Our center is the coreorganization to support the conduct of TR from patent application to sponsor-investigator clinical trial.
University of Tokyo has been designated as a Translational Research Core Center by Japan Agency
for Medical Research and Development. As an Academic Research Organization, Translational
Research Core Centers should support the conduct of TR in both own university and other institutes.
For the support of TR, our center consists of clinical research coordinator (CRC) section, secretariat
section, data management/biostatistics section and project management section. Occupations of ourcenter include CRC, patent attorney, project manager, study manager, data manager, monitor,
biostatistician, pharmaceutical expert, and secretary. By securing these occupations, we support patentapplication, regulatory compliance, preclinical studies, manufacturing, data management,
biostatistical analysis, and conduct of clinical trials. Conducting sponsor-investigator clinical trials,
especially for First-in-Human (FIH) clinical trials, with new modality products still accompanies withmany difficulties. Our goal is to support an average of one first-in-human clinical trial based onacademia seeds per year.
（３）Activity reports
１）Medical Activities
We support industry-sponsored clinical trials, however, the main role of our center is to support
the conduct of TR, especially for FIH clinical trials. Following are FIH sponsor-investigator clinical
trials we supported:Phase I study of WT1-expressing human artificial adjuvant vector cells (aAVC-WT1) for
patients with relapsed or refractory acute leukemia. (2016)Phase I clinical trial with umbilical cord-derived mesenchymal stromal cells (IMSUT-CORD)
292

G4_Hospitalfor treatment-resistant severe acute graft-versus-host disease (GVHD) after allogeneic
hematopoietic stem cell transplantation. (2017)


A phase 1/2 clinical trial of a recombinant herpes simplex type 1 with IL-12 expression inpatients with malignant melanoma. (2018)Investigator-initiated phase 1 study of nucleic acid medicine targeting PRDM14 in patientswith breast cancer. (2019)

Followings are FIH clinical study under Clinical Trials Act (non-Investigational New Drugapplication)
A clinical study of a replication-competent, recombinant herpes simplex virus type 1(G47delta) in patients with progressive malignant pleural mesothelioma. (2018)Phase I clinical study on safety and efficacy of Ebola vaccine iEvac-Z. (2019)

All test products were entirely new modality ones. As an ARO in Japan, this achievement is
considered remarkable.
２）Research Activities
Researches as clinical research coordinator (CRC) on how to properly support TR, especially forFirst-in-Human studies and those on efficient TR related administration and regulatory complianceas secretariats have been conducted. We made two presentations at domestic conferences in 2016,
one in 2017 and 2018, and two in 2019. The contents of the research presented at conferences were:role of CRC in the review of study protocol of first-in-human clinical trials, reduction of timerequired for the beginning of clinical trials by reviewing documents processing, and so on. Research
activities of professor and associate professor are described in “Division of Advanced Medicine
Promotion”.
３）Education Activities
Education for hospital staff and investigators is indispensable. We have encouraged to participate
in graduate school lectures described in “Division of Advanced Medicine Promotion”. We have helda seminar on clinical trials and provided the e-learning developed by University Hospital Clinical
Trial Alliance (IMSUT Hospital is one of the members), and attendance and taking e-learning are
obligations as investigators and study collaborators.
４）Social Activities
As a public relation activity, we present a glossary of TR, information on ongoing clinical trials,
that of Institutional Review Board, and so on.
５）International Activities
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We have been involved in the Nipa Vaccine development project with Division Advanced
Medicine Promotion, which had adopted by CEPI (Coalition for Epidemic Preparedness
Innovation) in 2018. Our role is to handle the matters related to clinical trials. This project has been
conducted by a consortium composed of the University of Tokyo, Stanford University, European
Vaccine Initiative, and International Centre for Diarrhoeal Disease Research, Bangladesh.
６）Other matters to be noted
None.
（４）Challenges and future prospects
Many types of occupations, such as data manager, monitor, and intellectual property expert, areindispensable to carry out TR. Our challenges are to increase the number of staff and to maintain theability to support TR. Many staffs are hired using external research funding. Solutions are to obtain
more external research funding for employment, and to aggressively focus on first-in-human studies
to increase the attractiveness of our activities. Our future prospect is to secure adequate humanresources by above activities, and to support TR until regulatory approval.

294

G4_HospitalCenter for Antibody and Vaccine Therapy（１）Members
Professors

Hirotoshi Tanaka, Kohei Tsumoto

Project Professor

Yataro Daigo

Project Associate Professors

Satoru Nagatoishi, Motohisa Yamamoto

Senior Assistant Professor

Noritada Yoshikawa

Project Senior Assistant Professor

Atsushi Takano

Assistant Professor

Hiroki Yamazaki

Postdocs

1

Graduate students

3

Technicians

4

Others3（２）Research objectives
The aim of this center is to develop novel therapy for patients with various diseases including
cancers and autoimmune diseases. Moreover, attractive clinical trials are ongoing in collaboration with
IMSUT research groups and others.
Our specific projects are⚫

Developing a novel therapy preventing glucocorticoid-induced muscle atrophy in patientswith rheumatic diseases⚫

Developing a novel therapy to improve abnormal fat distribution in patients taking GC
therapy⚫

Development of novel therapeutic modalities against metabolic syndrome targeting theskeletal muscle-liver-fat signalling axis⚫

Clarification of functional crosstalk between GR and sex hormone receptors for bodycomposition and metabolic regulation⚫

Clarification of the effect of ageing for regulation of energy storage in skeletal muscle andadipose tissues⚫

Translational Research and Clinical Trial of Division of Rheumatology⚫

Novel therapeutic target discovery for solid cancers⚫

Development of therapeutic cancer vaccine⚫

Integrated genomics-based discovery of new biomarkers for cancer immunotherapy⚫

Detection of neoantigen-reactive T cell clones based on the clonal expansion using nextgeneration sequencing of TCRβ complementarity-determining region 3295

G4_Hospital⚫

Molecular characterization of tumor microenvironment molecules as diagnostic andtherapeutic targets⚫

Clinical significance of PD-L1-positive cancer-associated fibroblasts in pN0M0 non-small
cell lung cancer⚫

Identification of lung cancer susceptibility loci by genome-wide association studies⚫

Scientific Platform of Supporting Cohort Study and Biospecimen Analysis⚫

Technical Capabilities and Limitations of Optical Spectroscopy and Calorimetry Using
Water-Miscible Solvents: The Case of Dimethyl Sulfoxide, Acetonitrile, and 1,4-Dioxane⚫

Biophysical characterization of the breast cancer-related BIG3-PHB2 interaction: Effect of
non-conserved loop region of BIG3 on the structure and the interaction⚫

Structural features of methionine aminopeptidase2-active core peptide essential for binding
with S100A4⚫

Highly sensitive biomolecular interaction detection method using optical bound/free
separation with grating-coupled surface plasmon field-enhanced fluorescence spectroscopy(GC-SPFS)⚫

An epitope-directed antibody affinity maturation system utilizing mammalian cell survival
as readout⚫

Exploring designability of electrostatic complementarity at an antigen-antibody interface
directed by mutagenesis, biophysical analysis, and molecular dynamics simulations⚫

Control of Protein Adsorption to Cyclo Olefin Polymer by the Hofmeister Effect⚫

Affinity Improvement of a Cancer-Targeted Antibody through Alanine-Induced Adjustmentof Antigen-Antibody Interface⚫

Phospholipid Membrane Fluidity Alters Ligand Binding Activity of a G Protein-Coupled
Receptor by Shifting the Conformational Equilibrium（３）Activity reports
１）Medical Activities
We vigorously conducted patient management at outpatient clinic (4 days per week) and ward
(over 100 patients) in collaboration with Department of Rheumatology and Allergy at IMSUT
Hospital. Moreover, we, as a translation of our original research, are working with several clinical
trials for verification of novel treatment for various diseases.
２）Research Activities
We published 23 and 26 original research papers in peer-review journals, and reported 25 and 27
research papers in various academic meetings, in 2017 and 2018, respectively.

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G4_Hospital３）Education Activities
We take charge of at least 4 lectures for graduate students every year.
４）Social Activities
We published 10 and 11 review articles in Japanese medical journals in 2017 and 2018,
respectively. We performed 7 collaborations with pharmaceutical companies in 2 years.
５）International Activities
We are promoting several international collaborative projects for clinical development of ouroriginal research.
６）Other matters to be noted
None.
（４）Challenges and future prospects
We will continue original research and develop novel therapeutic approach for treatment of various
intractable diseases in collaboration with IMSUT research groups and other domestic or foreignlaboratories.

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Therapeutic Vector Development Center（１）Members
Professor

Tomoki Todo

Project Associate Professor

Minoru Tanaka

Technicians

2（２）Research objectives
One of the essential missions of the Institute of Medical Science is to carry out the results frombench to clinic. To achieve this, investigational drugs planned to be used in clinicals trials need to be
manufactured according to cGMP (current Good Manufacturing Practice), which is the standard for
manufacturing pharmaceuticals and quality control. The cGMP-grade manufacturing is maintained bysystematic Standard Operating Procedures (SOP) in the Therapeutic Vector Development Center. We
have obtained and maintained ISO9001 certification since 2014, which is an international standard for
quality control systems. In order to manufacture cGMP-grade oncolytic virus product, the facility andequipment are regularly validated. Therapeutic Vector Development Center also maintains a systemthat can support cGMP manufacturing of samples from outside of the university.
（３）Activity reports
１）Medical Activities
From April 2016 to March 2019, the goal of the Therapeutic Vector Development Center is to
manufacture and systematically store investigational drugs and regenerative medical products used
for gene therapy, oncolytic virus therapy, cell therapy, etc. We also support development of
manufacturing process and regulatory compliance. We are accepting two projects related to the
production of clinical-grade oncolytic HSV-1 and oncolytic measles virus. The system to support
cGMP manufacturing has been maintained and ISO9001 certification was updated. There havealways been problems to secure financial resources for fixation of the equipment deteriorated overtime of 20 years since its establishment.
２）Research Activities
None.
３）Education Activities
Lectures on SOPs, laws, and public standards are given to new project members before entering
the room, and regular re-education and training is given to those who are qualified to enter thefacility.
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G4_Hospital４）Social Activities
We can systemically support projects from outside the university.
５）International Activities
None.
６）Other matters to be noted
The TVDC consists of two units; 1) Vector Unit, the primary suite for viral vector production andex vivo transduction; and 2) Cell Unit, the suite for cell processing capable of generating therapeutic
cells such as dendritic cells for immunotherapy and gene therapy. Each unit has two independentcompartments kept as a Class 10,000 clean level.

The facility and equipment are regularly

validated to fulfill the cGMP standard.
（４）Challenges and future prospects
Although the Therapeutic Vector Development Center plays a critical role in the development oftranslational research in Japan, the current facility is too deteriorated for a further use, relocation to
Building 1, which has been scheduled since before, should be put into action promptly.

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IMSUT CORD
（１）Members
Associate Professor

Tokiko Nagamura-Inoue

Assistant Professor

Kazuaki Yokoyama

Postdocs

1

Technicians

8

Others1（２）Research objectives
The umbilical cord blood and cord tissue bank of the research hospital, The Instituteof Medical Science, The University of Tokyo (IMSUT CORD) was established in 2016.
IMSUT CORD is a biobank that supplies umbilical cord blood and umbilical cord tissue
or derived cells for regenerative medicine and immunotherapy not only forbasic/preclinical research and development, but also for cell therapy (regenerative
medicine products) in clinical use.
（３）Activity reports
１）Medical Activities
The umbilical cord (UC) is a rich source of mesenchymal stromal cells (MSCs). UC-derived
MSCs (UC-MSCs) possess many advantageous features: (1) ease of collection, storage, andtransport; (2) abundant sources with high proliferation capacity; (3) multipotency to differentiate
into various tissue cells including osteoblasts, chondrocytes, adipocytes, and neurons; (4) low
immunogenicity with significant immunosuppressive ability; (5) tissue repair potency; (6)migration ability toward inflammatory or injured sites, subsiding inflammation and repairing thedamaged tissues, and (7) no donor age-dependent variations. IMSUT CORD supplies frozen cord
blood and UC-MSCs for research purposes based on joint research and material transfer agreements
to for-profit companies and researchers in non-profit academic facilities in Japan and internationally.
The establishment of a stable supply system for the source matter of cell therapy has been supportedby the Japan Agency for Medical Research and Development (AMED) since 2018 (T angamuraInoue, principal investigator) .
We obtained the product cells of UC-MSCs, namely IMSUT-CORD, from the master cell bankand supplied them to an investigator-initiated clinical trial of treatment-resistant severe acute graftversus-host disease (GVHD) in 2018. The clinical trial for acute GVHD was supported by the
AMED (T angamura-Inoue, principal investigator).

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G4_Hospital２）Research Activities
To establish the stable supply system of CB and UC-MSCs with safe and quality assurance, we
acquired ISO9001:2015, an international standard for quality management systems, in June 2019.
We supplied UC-MSC and/or CB for research and development approved by the institutional review
board. This research includes studies on GVHD, immunological disease, cerebral palsy,osteogenesis, frail, endothelial cell regeneration, neonatal/infant chronic lung disease, and others. A
recent publication regarding this research is listed below:
1.

Nagamura-Inoue T, Nagamura F., Umbilical Cord Blood and Cord tissue bank as a source of
allogeneic use. IntechOpen. 2020. DOI: 10.5772/intechopen.91649

３）Education Activities
None.
４）Social Activities
We conducted a collaborative research study with the companies Human Life Cord Inc. Stem
Cell Institute Inc. (2017 – present), NIPRO Corp. (2020 –), and PharmaBio Inc. (2018) on research
new methods of processing samples, quality control tests, and sample banking.
５）International Activities
None.
６）Other matters to be noted
Please visit our website for more information: http://imsutcord.umin.jp（４）Challenges and future prospects
Our processing and cryopreservation technology for obtaining qualified cell products have beentransferred to companies that conduct the later phases of clinical trials and who provide
commercialization to supply the cells to the patients efficiently. We will supply master cells,
intermaediate product cells, or product cells for clinical use on demand by companies and researchers.

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G4_Hospital

Department of Nursing（１）Members
Director

Eiko Yoshii

Deputy Directors

Minayo Hisahara, Junko Izumi

Nurse Managers

8

Nurse Chiefs

11

Nurses74

Nursing assistants

14（２）Organizational goals
1. Provide nursing with grounds
1) Acquisition and thoroughness of correct skills and strengthening of assessment, 2) Improving
quality through visualization of nursing, 3) Training and support for highly specialized nurses
2. Actively promote team medical care and IPW（Inter-professional Work）
1) Promotion of multi-job collaboration, 2) Promote activities within and across-the-world
departments of full-time nurses, 3) Promotion site for participation in team medical care fornursing assistant Clark
3. Protect patient rights and support decision-making
1) Active involvement at each stage of informed consent, 2) Enhancement of ethics conferencesand death conferences, 3) Strengthen discharge support and home care support
4. Creating an environment where nurses can work lively
1) Enhance the work of nursing staff and promote work and life in harmony,2) Each nurse realizes the growth and the role of the profession, 3) Training of managers using
competency assessment and nursing management standards
5. Cooperate in hospital management（３）Activity reports
１）Medical Activities
1. Provide nursing with grounds
As a nursing team, in order to provide optimal nursing care for patients, we have established asystem for accepting new recruits, and have been working to improve the nursing practice of eachnurse by utilizing educational and training opportunities, pair systems, online education tools, etc.
Each department practices careful nursing, and patients write thanks. In addition, the pair systemprovides new recruits with a pair of nurses, are engaged in the care of patients with peace of mind,
and are an opportunity to learn from each other. However, each nurse is not able to make full useof the pair system as an advantage for medical safety and business improvement.
2. Actively promote team medical care and IPW（Inter-professional Work）
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Nurses participate in conferences such as medical care, clinical research, and discharge
support through multi-job collaboration, contributing to team medical care. In cancer
rehabilitation, we worked with physical therapists to provide support with an eye to the lives ofpatients after discharge.
3. Protect patient rights and support decision-making
In order to be involved in patient decision-making support, he has been engaged in training
sessions on medical ethics, holding multi-disciplinary ethics conferences, attending informed
consent (IC), and learning how to support decisions. As a result, information sharing with doctors
before IC and confirmation of how to understand and receive patients and their families havebecome established.
4. Creating an environment where nurses can work lively
Although we are working to create a workplace that is comfortable to work in each department,
the turnover rate of nurses has increased to 19.8% (14.8% in FY18) in FY19. The number ofpeople taking paid leave increased by 17.4 days. Nurse satisfaction situation, there is also thereopening of the 5th floor ward, night shift personnel is decreasing, in the situation that the night
shift full-time employee is always five to six people, 7-to-1 nursing arrangement is maintained.
5. Cooperate in hospital management
The nursing department cooperated with the reopening of the 5th floor ward, the establishmentof medical examinations from overseas and endoscopic health checkups in Minato Ward,clinical research on Ebola and the inactivated vaccine inlet (P1), special projects to enhance
Shirokane and Hongo, and the medical care system for the spread of new coronavirus infection.
２）Research Activities
We continuously conduct nursing research on keywords such as "daily life support for hemophilia
patients", "nursing of hematopoietic stem cell transplantation", "clinical research nursing", and"competency study group". He is continuously involved in the preparation of nursing standards andeducational programs for clinical research nursing. The Copitensy Study Group is also held on an
ongoing basis to evaluate the effectiveness of the development of managers.
３）Education Activities
As a nursing department, we accepted hospital training at the following four universities.
・the Department of Health Sciences and Nursing at the University of Tokyo
・The University of Tokyo's Medical Information And Life Sciences,
・Department of Psychology, Faculty of Human Sciences, Bunkyo University
・Faculty of Nursing，Tokyo Ariake University Of Medical And Health Sciences
And we continue to hold training as a designated training facility for clinical transfusion nurses
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certified by the Society. In addition to contributing to the development of students and nursing staff,
it is also an opportunity to train our nursing staff.
４）Social Activities
We have accepted "one-day nursing experience learning" and "return to work support training"of the Tokyo Nurse Plaza project, and cooperate in the spread and enlightenment project of thenursing profession.
５）International Activities
None.
６）Other matters to be noted
None.
（４）Challenges and future prospects
In FY20, while responding to the new coronavirus infection, we will operate the 5th floor ward,
which resumed in FY19, establish a system for accepting patients related to palliative medicine andurology, and operate the nursing department so that value can be found in the work of nursing, and wewill strive to establish nursing staff. To this end, we will continue to work on nursing practice with thechallenges of creating a comfortable working environment, medical safety and infection control,
training nursing staff, and maintaining the quality of nursing.

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Department of Pharmacy（１）Members
Pharmacy Director

Seiichiro Kuroda

Others12（２）Missions and Features
The Department of Pharmacy seeks to provide high-quality pharmaceutical care services. We
contribute to the team approach to patient-oriented medical care and provides a drug distribution
services. We are also trying to contribute to propel the right use of medicines for patients.
（３）Activity Reports
１）Medical Activities
We continue a high quality pharmaceutical approach and contribute to medical treatment in
IMSUT HOSPITAL.
２）Research Activities
We will continue to make great efforts with self-study to find and solve clinical questions inpractice and give back them to medical care in the future.
３）Education Activities
We accept to clinical trainee of the other University of Pharmacy.
We perform the bedside teaching and educate them about the knowledge and skill as clinicalpharmacist.
４）Social Activities
None.
５）International Activities
None.
６）Other matters to be noted
None.
（４）Challenges and future prospects
IMSUT hospital has a mission to confront an intractable disease.
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Therefore it is necessary for IMSUT pharmacist to manage the proper use of medicine.

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IMSUT Distinguished Professor Unit
Division of Stem Cell Therapy（１）Members
IMSUT Distinguished Professor

Hiromitsu Nakauchi

Project Assistant Professor

Hideki Masaki

Postdocs

2

Technicians

2

Others6（２）Research objectives
Our goal is to "Establish a New Frontier of Stem Cell Therapy by Connecting the Basic Science
and Clinical Medicine." We are working to uncover new diseases, elucidating the causes of disease
and developing therapeutic modalities by connecting the knowledge and methodology of basic
science such as immunology, molecular biology, cell biology and developmental engineering withclinical medicine.
We are also actively collaborating with international institutes including Stanford University in the
US and MRC Cambridge Stem Cell Institute in the UK.
（３）Activity Reports
１）Research Activities
Our department was established at April 2017, focusing on creation of fully functional humanorgan from human pluripotent stem cells in animal body by using developmental process. We are
the only group in Japan allowed to develop human-mouse chimeras in uterus at this moment. We
have provided proof-of-principle experimental data showing the advantages of organ creation
utilizing mouse-rat interspecies chimeras and blastocyst complementation technique; by injecting
normal embryonic stem cells into organ/tissue deficient embryos, we successfully created donorcell derived pancreas, thymus and kidney. In the process of creating mouse-rat interspecies chimeras,
we observed high incidence of abnormalities, such as malformation in specific organs/tissues andinflammations in various tissues. We are investigating the underlying mechanisms to cause thoseabnormalities in order to generate inter-species chimera more efficiently. Based on the experienceand knowledges we accumulated through generating intra- and inter-species chimeras, we started
human-mouse chimera development in mice uterus from September 2019, right after the approvalof our research plan from MEXT. Now we are in the process of finding the problems that prevent
formation of human-animal chimeras, and trying to solve each problem step by step.
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２）Education Activities
2017/ 5/ 27 The University of Tokyo EMP
2017/ 11/ 17 The University of Tokyo EMP
2017/ 12/ 18 Tokyo University of Science lecture
2018/ 6/ 30 The University of Tokyo EMP
2018/ 11/ 19 Tokyo University of Science lecture
2018/ 12/ １ The University of Tokyo EMP
2018/ 12/ 12 Toyo University Special lecture
2019/ 11/ 27 The University of Tokyo EMP【Facility tour】
2018/ 4/ 25 Okazaki Junior High School affiliated to Aichi University of Education
2018/ 11 /5 Keio Girls Senior High School
2019/ 6/ 19 Johnouchi High School
2019/ 9/ 5 Shimotsuma 1st High School３）Social Activities
None.
４）International Activities
Collaborating with Nakauchi lab at Stanford University for characterization of interspecies
chimeras and development of genome editing technology.
Collaborating with Smith lab at MRC Cambridge Stem Cell Institute for establishment andcharacterization of non-human primate pluripotent stem cells.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
As described above, human-mouse chimeric embryos are difficult to develop to full term. Engrafted
human cells were lost in later developmental stages, or human cells survived embryos caused
degeneration or malformation. We will clarify underlying mechanisms that prevent incorporation ofhuman engrafts, and genetically modify host animals to enable to give birth chimeric animals carrying
human organ carrying.

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Division of Mucosal Immunology（１）Members
Project Professor

Hiroshi Kiyono

Project Associate Professor

Yosuke Kurashima

Project Assistant Professor

Rika Nakahashi

Postdocs

2

Technicians

5

Others6（２）Research objectives
In higher mammals, the mucosal immune system consists of an integrated network of tissues,
lymphoid and mucous membrane-associated cells, and effector antibody molecules for providing thefirst line of defense against pathogenic microorganisms and allergens which encounter through themucosal surfaces by inhalation and ingestion. In contrast, tolerance in the mucosal immune systemrepresents the most common response of the host to its environment in order to create and maintainthe homeostasis. In this regard, the mucosal immune system establishes tolerance to continuously
ingested several thousand different food proteins as well as to our indigenous microflora colonizingin the digestive tract, which provides biological benefits to the host. Our major goals are defining thecellular and molecular mechanisms of the mucosal immune system, which is sophisticatedly regulated,elaborated, and the flexible first line of surveillance and protective system. To this end, our mission in
the research and development is to establish an infrastructure system for the prevention and treatmentof immune- and infectious-diseases by evolutionally novel and fusion strategies using agriculture andbioengineering science including botany and engineering knowledge and technologies.
（３）Activity Reports
１）Research Activities⚫

Rice expressing B subunit of cholera toxin (CT-B), MucoRice-CTB has been developed by theadaptation of rice transgenic system as a rice-based oral vaccine against diarrheal diseases. We
conducted a double-blind, randomized, placebo-controlled, three-cohort, dose-escalation
phase I study to evaluate the safety, tolerability, and efficacy of MucoRice-CTB. This phase I
clinical trial showed that MucoRice-CTB induces neutralizing antibodies against diarrheal
toxins in a gut microbiota-dependent manner, without major adverse events.

⚫

We have been studying the cellular and molecular mechanisms for the induction of antigenspecific mucosal and systemic immune responses by nasal immunization using the cationicnanogel vaccine delivery system. The outcomes of the study gain the essential knowledge ofnasal vaccination strategies and facilitate the development of effective and safe nasal vaccines
against respiratory pathogens such as Streptococcus pneumoniae and Hemophilus influenza.

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These studies are further explored to develop cationic nanogel-based nasal vaccines for SARSCoV2.
⚫

It has been shown that nasal immunization elicits antigen-specific immune responses in thefemale reproductive tract in addition to the lower and upper respiratory tracts. Thus, we havebeen examined the involvement of chemokine receptors and their ligands for CD4+ T cell
migration into the vaginal mucosa.

⚫

Our group has been elucidating roles of mesenchymal-myeloid cell interactions for the
maintenance of tissue-based homeostasis which preventing the development of intestinal
allergy and inflammation. New information obtained by these studies are contributing to ourunderstanding of the cellular and molecular interactions involving the intestinal homeostasis
and disorders, and facilitate the novel diagnostic and treatment strategies.

⚫

During this reporting period (April 2016 to present), we have published 34 peer-reviewed
original papers and 12 of which are closely related to the projects described above. In addition,
we have published 15 review papers.

⚫

We have submitted one patent application (2016-234717: Development and clinicalapplication of fibrosis-associated molecule-specific antibodies).

２）Education Activities⚫

Seven graduate students have been graduated before April 2018. Among them, three students
obtained Ph.D. degrees while 4 students graduated with MS degrees.

⚫

We have accepted three internship students from the Tokyo College of Biotechnology andprovided necessary guidance in the area of mucosal immunology to support their research
program for the graduation.

３）Social Activities⚫

We have obtained grant aid from the AMED CiCLE program together with Astellas
Pharmaceutical Inc, Asahi Kogyosha Co. LTD. and Chiba University. The main task of thisgrant is to establish a stable manufacturing system for MucoRice-CTB as an oral vaccine andtest the efficacy and safety of MucoRice-CTB in the clinical trials (Phase Ib and II).

⚫

We have established a collaborative contract with Astellas Pharmaceutical Inc to develop
MucoRice-based new oral vaccines by using a novel oral adjuvant system.

⚫

We have been developing novel nasal vaccines against respiratory infectious diseases together
with Hana Vax Inc. as a collaborative effort.

⚫

Non-disclosure agreement has been sealed with Boehringer Ingelheim and Chiba University
based on our preexisting intellectual property.

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４）International Activities
We have established a collaborative program among the University of California, San Diego,
Chiba University, and our laboratory to study mucosal immunology and allergy since 2016 until
now.
５）Other matters to be noted⚫

Under the unfortunate COVID-19 circumstances, our laboratory has initiated the project on
the adaptation of our knowledge and technology (e.g., cationic nanogel vaccine antigen
delivery system) for the development of SARS-CoV-2 nasal vaccine for the induction of dual
protections at the entry site of airway epithelium and inside of lung by secretory and serum
antibodies. This project is now being conducted with the National Institute of Infectious
Diseases under the support of AMED.

⚫

For advancing our knowledge in the mucosal immune system for the creation of homeostaticand protective environments in the digestive tract to the control of infectious diseases indeveloping countries, we have been involved in the Science and Technology ResearchPartnership for Sustainable Development (SATREPS) program offered by the Japan
International Cooperation Agency (JICA) and Japan Agency for Medical Research andDevelopment (AMED). Under the project of ”Surveillance and Laboratory Support for
Emerging Pathogen of Public Health Importance in Ghana”, we are working together with
Ghanaian scientists at Noguchi Memorial Institute for Medical Science, the University of
Ghana on the metagenome analyses of pathogens, hosts and commensal microorganisms foradvancing the genome-based host interaction with the pathogen and beneficial bacteria which
can be applied for the surveillance system in Ghana.

（４）Challenges and Future prospects⚫

We will continuously keep our high performance in the research areas of mucosal immunology
and mucosal vaccinology in a comparable fashion to last or further advancing the next 5 years.
In this regard, we will continue to press forward the projects described above in order to further
understand the cellular and molecular induction and regulation of mucosal immunity and advanceour mucosal vaccine development by continuously conducting the fusion science withintroduction of evolutionally novel ideas and technics from different scientific areas into ourlaboratory just like our group brought in the agriculture and bioengineering science including therice transgenic and nanogel engineering knowledge/technology.

⚫

In order to maintain our research activities as well as to be involved and contribute to the
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continuous advancement of IMSUT as one of the leading medical science institutes, it will beessential to incessantly seek new research supports from national and international funding
agencies. We will continuously provide our team player sprits to the rest of the IMSUT colleagues
and laboratories for creating new scientific programs which can be led to new funding
opportunities.

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Corporate Sponsored Research Program
Project Division of Molecular and Developmental Biology（１）Members
Project professor

Sumiko Watanabe

Postdocs

2

Graduate students

11Technicians

2（２）Research objectives
Our long-term goal is to understand the molecular mechanisms which coordinately regulatedifferentiation and maintenance of neural retina. As mechanisms of retinal development, we focus on
histone methylation to reveal retinal lineage specific regulatory system. We are also studying on
molecular mechanisms of photoreceptor degeneration and development to rescue photoreceptors fromdegeneration especially focusing on microglia. To clarify how microglia and other immuno-competentcells affect pathogenesis of retina, and development of new therapeutic strategy is our ultimate goal.
（３）Activity Reports
１）Research Activities
1. Analysis of roles and molecular basis of microglia in photoreceptor degeneration in the retina
Photoreceptor degeneration is a major cause of blindness. Microglia are known to play key rolesin the pathogenesis and progression of neural degeneration. We established several new system toanalyze photoreceptor degeneration in vitro by organ or primary cell culture, and human iPS cells.
In addition, using one of such systems, we made screening of effects of the naturally occurring
molecules on microglial activation and identified apigenin as a strong suppressor of microglial
activities.
2. Molecular basis and development of new therapeutic strategy for retinal photoreceptor
degeneration. We established several retinitis pigmentosa, inherited photoreceptor degenerationdisease leading to blindness, patients derived humas iPS cell lines. Using the cells and otherexperimental systems, we revealed mechanism how mutations of certain genes leads tophotoreceptor death in the retina. This work is in collaboration with Prof Bruce Conklin of UCSF.
3. NAD and lipid metabolism in the development and maintenance of the retina. Both NAD
synthesis related gene and enzymes in the lipid metabolism lead retinitis pigmentosa by mutationsin their gene loci. By using mouse-models and human iPS cells we analyze that how biochemical
disturbance of NAD and lipid metabolism lead to failure of maintenance of photoreceptor. Althoughprevious works are working on these issues individually, we hypothesize that the NAD metabolic
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circuit and lipid homeostasis affect vice versa. We found that in fact, perturbation of NAD
metabolism affects the membrane phospho-lipid contents.
4. Establishment of platform of molecular basis of the retina. We made a series of RNA-seq ofretina at various developmental stages, and fractionated retinal cells to rod/microglia/Muller
glia/other cells from normal and degenerating retinas, microglia and macrophage of normal anddegenerating retinas. In addition, several knockout mice derived retinal cells were also served toRNA-seq. As epigenetic mechanisms, ChIP-seq of several antibodies recognize histone methylated
moiety had been performed. These databases are used for almost all of our works, and published
one were referred by foreign researchers.
5. Epigenetic mechanisms of retinal development. We are analyzing enzymes related to histone
H3K4methylation, H3K27methylation, H3K36methylation on retinal development. We found allthese systems are working on cell type and stage specific manner during retinogenesis.
２）Education Activities
Research: Advising the works for students of Ph.D- and master-course (Ph.D candidate 5, mastercourse students 6)
Lectures: School of Medicine, Medical-kyotsu lecture
Soonchunhyang University(SCHU) as adjunctive professor (Sumiko Watanabe)
Gifu pharmaceutical University, special lecture
Nagasaki University school of medicine, special lecture
Thesis degree committee member; School of Medicine, School of Science
OIST (Okinawa Institute of Science and Technology)３）Social Activities
Sumiko Watanabe: Committee chair, Ethical committee (GC Lymphotec co)
Sumko Watanabe: Organizer, The emergence of Genome based drug discovery４）International Activities
Soonchunhyang University(SCHU) as adjunctive professor (Sumiko Watanabe)５）Other matters to be noted
None.
（４）Challenges and Future prospects
Currently, we are working on two main focusing epigenetic mechanisms during retinal development
and photoreceptor degeneration mechanisms. There are several projects are on-going such as microglia,
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immune-competent cells in retina, histone methylation and demethylation etc, and we use several
different systems i.e. human iPS cells, primary cultures, cell lines with diverse technologies. Although
the projects are independently performed, the results suggested the issues what we are analyzing are
related each other and orchestrated to achieve proper development and maintenance of the retina. Our
whole picture gives number of points that had not been recognized to relate each other, and we believethat the such knowledge served new insight for approach to develop drugs and therapeutic strategies.

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Project Division of Fundamental Study on Cutting Edge of Genome Medicine（１）Members
Professor

Arinobu Tojo

Project Associate Professor

Hiroshi Yasui

Postdocs

1

Technicians

2

Others1（２）Research objectives
The objectives for the period from April 2016 - June 2020 (4 years and 3 months) were: 1) to publish
six papers on genomic cancer medicine research from the Department of Hematology/Oncology, andten papers from the Division of Fundamental Study on Cutting Edge of Genome Medicine, 2) toorganize educational activities for the general public, and 3) to initiate three international collaborative
studies.
（３）Activity Reports
１）Research Activities
Goals: The Division of Fundamental Study on Cutting Edge of Genome Medicine has conductedprimary research, which aimed to establish a system for promoting the practical application of
genomic cancer medicine in Japan.
Achievements: The Department of Hematology/Oncology of IMSUT hospital has published eight
papers, reporting the results of the research on the practical application of cancer genome medicine.
The Division of Fundamental Study on Cutting Edge of Genome Medicine has published 21 papers(Annual Reports 2016, 2017, 2018, 2019). It can be considered that the Division of Fundamental
Study on Cutting Edge of Genome Medicine has achieved satisfactory results concerning the
publication of papers on the field. However, the importance of drug discovery and drug developmentin genomic cancer medicine increases year by year as the data of cancer genetic testing suggest that
there are not enough treatment options available. The division started research on drug discovery
and drug development in the second half of 2017. Since the results of this research have not yet
been published, we are trying to raise the level of translational research awareness among the faculty
members, to help further establish an appropriate research system for the development of novel
cancer drugs.
２）Education Activities
Goal: The division does not conduct educational activities for graduate students; however,
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educational activities for the public were organized in an attempt to reach out and communicate therecent developments in the field of cancer genomics.
Achievement: One lecture on genomic cancer medicine was given to university students, andthree lectures were given to the public.
３）Social Activities
Goal: In order to promote public acceptance of genomic cancer medicine in Japan, the division
aimed to conduct a survey for both experts and the public in Japan and the United States.
Achievement: Our research, entitled “Japan-US Comparative Study for Promoting Cancer
Genome Medicine,” was selected as “excellent research” by the Pfizer Health Research Promotion
Foundation at the 26th International Joint Research Grant meeting in December 2019. We
investigated and discussed the awareness of all stakeholders, including patients, physicians,
researchers, genome counselors, and the general public, on genomic cancer medicine. Hearings anddiscussions were held at the New York premises of the University of Tokyo.
４）International Activities
Goal: The division aims to start three international collaborations related to the promotion of
genomic cancer medicine.
Achievement: Four international collaborative studies have started during this period. The first,
which began in the second half of 2017, is a US-Japan comparative study to promote genomic
cancer medicine. The US-based investigators who participate in the study are Robert Nussbaum(Invitae Corp., USCF), Nikhil Munshi and Teru Hideshima (Dana-Farber Cancer Institute, Harvard
University).
The second study, which began in the second half of 2018, is research on artificial intelligence in
medicine, in collaboration with several companies in the United States and China.
The third research, which began in the second half of 2017, focuses on the development of novel
immunotherapy drugs in multiple myeloma, in collaboration with Kenneth Anderson (Dana-Farber
Cancer Institute, Harvard University). The project expanded in Asia in the second half of 2019 and
now includes joint research with Professor Hu Jianda, Fuzhou Medical University Union Hospital.
The collaboration further extended to the academic exchange between the IMSUT and the Fujian
Institute of Hematology, Fujian Medical University, in June 2020.
５）Other matters to be noted
None.
（４）Challenges and prospects
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The objectives of the research conducted by this division have evolved from the establishment of asystem for promoting the practical application of genomic cancer medicine in Japan to international
research on genomic cancer medicine and artificial intelligence. In the future, we will encourage thedevelopment of novel cancer drugs, as well as in-vitro diagnostics, to exploit the data from cancer
genetic testing.

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Social Cooperation Research Programs
Project Division of RNA Medical Science（１）Members
Project Associate Professor

Masaki Takahashi

Postdocs

1

Others6（２）Research objectives
In this division, we aim to create artificial aptamers to target proteins of therapeutic interest and to
uncover the molecular mechanism underlying the versatile interaction between nucleic acid andprotein of biological significance.
（３）Activity Reports
１）Research Activities
This division has been working on RNA science for drug discovery and basic science throughdevelopment of novel platform technologies for generating and discovering functional RNAs,
mainly RNA aptamers. Briefly, we conducted studies 1) to elucidate degradation mechanism ofendogenous mRNAs, 2) to explore microRNAs associated with human diseases for developing
another therapeutic strategy, and 3) to establish platform technologies for developing RNA aptamers
as a medical agent. As a research activity, we set the goal to publish six or more publications inpeer-reviewed journals, and to file at least one IP application for a developed product that seem topossess high potential as a pharmaceutical molecule.
In consequence, we have carried out three research themes described above and resulted in one
paper for “1)” (Hashimoto, Y. et al., Biochem Biophys Res Commun., 484(1):1-7 (2017)), one
paper for “2)” (Fukuoka M., et al., Mol Ther Nucleic Acids., 11:79-90 (2018)), and three papers for“3)” (Takahashi, M. et al., Biochimie, 131: 77-84 (2016), Takahashi, M. Biochimie. 145:63-72(2018), Imashimizu M, et al., Biology Methods and Protocols, 3(1)bpy004 (2018)), in addition to
publication of 17 peer-reviewed journals where we joined as collaborator. Regarding IP application,
we have filed one IP application for an RNA aptamer against TGF-beta by collaborating with anaptamer company, RIBOMIC Inc.
Therefore, it is considered that our set goal has been mostly achieved regarding research activity.
２）Education Activities
To contribute to education, we set the goal of engaging in at least two educational activities.
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Consequently, one lecture was delivered in 2017 as an academic frontier lecture to pre-semester
students in the College of Liberal Arts and Sciences. By introducing recent advances in nucleic acidbased therapeutic agents, it seemed to be able to contribute education to students. In addition, we
served as facilitator for two institutional seminars as part of educational activity. Thus, our aim in
education seems to be achieved.
３）Social Activities
Our division, a social cooperation research program, was established in April 2012 under a joint
research agreement between the University of Tokyo and RIBOMIC Inc that is startup fordeveloping RNA aptamer as pharmaceutical molecules. Through the social collaboration, as a goalin social activity, we aimed to file at least one IP application for a promising aptamer. Regarding an
RNA aptamer raised against transforming growth factor-β1 (TGF-beta1), we have successfully
developed and filed its IP application by collaborating with the company. We will continue to engage
in research activities aimed at realizing drug discovery based on the advantage of our social
collaboration.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
While we have generally been able to achieve various goals, the number of achievements is not
much. Given the number of staff in our division, it seems to be no wonder, but in order to improve thenumber and quality of our output, we will make efforts to secure human resources by stably raisingbudget. Then, we would like to create and disseminate our achievements more than ever before.

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Project Division of Systems Immunology Research (-2019.9)（１）Members
Project Assistant Professor

Yasumasa Kimura

Project Professor

Satoshi Uematsu

Graduate students

1

Technicians

1（２）Research objectives
1. Build an analysis pipeline that enables high-speed metagenome data analysis after the nextgeneration sequence
2. Build an intestinal virome analysis pipeline.
3. Create a database of intestinal bacteria and virus of 100 healthy Japanese people
4. Create the method to examine host-parasite association between intestinal bacteria andbacteriophages
5. To verify the probiotic effect of yogurt on aging（３）Activity Reports
１）Research Activities
1. Construction of metagenomic data analysis pipeline
In collaboration with Professor Satoru Miyano of the Human Genome Center and Professor Seiya
Imoto of the Health Intelligence Center, we have succeeded in constructing a ultr-high speed
metagenome analysis pipeline by using GHOST-MP developed by Professor Yasushi Akiyama ofTokyo Institute of Technology on Super computers SHIROKANE and Kei. We can finish thehomology search of results of Mi-seq analysis (1run) within 6 minutes. This was one of the world's
fastest analysis pipelines at that time.
2. Construction of intestinal virome analysis pipeline
Intestinal lumen contains not only bacterial flora but also resident viral flora. Most of viruses arebacteriophage (phage) that host bacteria. With the development of next-generation sequence
analysis, it has become possible to obtain the whole genome of intestinal phage without anaerobic
culture of host bacterium, which is technically difficult. However, the preparation of reference
genome data for enteric viruses has not progressed, and 99.9% or more cannot be detected. In thisarea, the difficulty of this analysis is expressed by the word “Viral Dark Matter”. The sequence
fragments obtained by the next-generation sequence analysis were assembled accurately and as longas possible, the ORFs were predicted on the created contigs, and the pseudo-cloning of the viralgenome can be performed on supercomputer. Furthermore, virus classification was performed,
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which enabled to show the composition of the intestinal virus flora. At he end of 2018, we have
implemented a pipeline that can automate the classification on the supercomputer Shirokane of theInstitute of Medical Science.
3. Creation of a database of intestinal bacteriome and virome of 100 healthy Japanese people
By the end of 2017, the feces of 100 healthy Japanese people had been collected, and the databaseof intestinal bacteriome and virome of 100 healthy Japanese people was completed during FY2018.
The database of bacterial and viral flora in the same stool is the world's first achievement and will
be published within 2020.
4. Create the method to examine host-parasite association between intestinal bacteria andbacteriophages
It is possible to search the host of intestinal phage using the results of metagenomic analysis. By
using the database of intestinal bacteriome and virome in the same feces of 100 healthy Japaneseperople, it is possible to detect the lysogenic phage that becomes prophage. In addition, byextracting the CRISPR spacer sequence from the bacterial metagenomic analysis results, it ispossible to search the sequence of phages that had been infected in the past. Based on thisinformation, it became possible to predict the infection relationship including lytic phages.
5. Verify the probiotic effect of yogurt on aging
Through joint research with Meiji Co., Ltd., we conducted an omics analysis on the effects of
LB51 yogurt on aging. This research was also a joint research with Professor Eberl of the Instituteof Pasteur in France and published the paper in 2018 (Int Immunol. 2018 Jun 26; 30 (7): 319-331.).
２）Education Activities
We provided research guidance for Yuki Usui, a graduate student at the leading graduate schoolof the Graduate School of Medicine, The University of Tokyo. One of our missions was to train
hybrid next-generation researchers who can carry out both experimental and informatics research.
In a joint research with Meiji Co., Ltd., she conducted an experiment on the aging effect of yogurt
herself, performed omics data analysis centered on informatics analysis under the guidance ofAssistant Professor Kimura, and created a dissertation. (Int Immunol. 2018 Jun 26; 30 (7): 319331.). As part of a leading graduate program, she also studied for three months at the La Jolla
Institute for Immunology in San Diego, USA. In addition, her skill in informatics analysis wasevaluated, and after graduation she was employed by Chugai. We not only trained hybrid
researchers, but also succeeded in career paths to companies.
３）Social Activities
1. Collaboration with Meiji Co., Ltd.

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"Analysis of changes in intestinal microbiota and effects of probiotics upon aging and various stressstimuli" (FY2017),"Metagenome of intestinal microbiota for healthy Japanese "Analysis" (FY2018)(the principal investigator was Satoshi Uematsu)
2. Collaboration with EA Pharma Co., Ltd.
"Identification of specific intestinal bacteriophages and enterobacteria in patients with Crohn's
disease"(the principal investigator was Satoshi Uematsu)４）International Activities
In 2015, "Research on strengthening infectious disease surveillance system and intestinal
mucosal infection protection against cholera, HIV, etc. in Ghana" was adopted in the AMEDSATREPS program with Professor Hiroshi Kiyono as the research representative. In this task, we
supported metagenomic analysis at the Noguchi Research Institute, the University of Ghana. A
technical staff dispatched from the University of Ghana was instructed how to extract nucleic acids
from feces and how to operate a next-generation sequencer. In addition, we trained two graduate
students of the University of Ghana for metagenomic data analysis, and established a system forautonomous metagenomic analysis at the University of Ghana.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
A database of intestinal flora and virus flora will be published. In the future, it will be necessary tocontrol intestinal bacteria using phages for various diseases. In addition, we believe that phage therapy
will be an indispensable treatment method against multidrug-resistant bacteria, which has become a
global problem. We think that it is necessary to carry out social implementation of phage therapy inJapan and, if possible, to establish a center in the Institute of Medical Science to practice phage therapy.

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Project Division of Advanced Regenerative Medicine (-2017.9)（１）Members
Project Associate Professor

Satoshi Yamazaki

Postdocs

2

Graduate Students

1

Technicians

3

Others1（２）Research objectives
In order to further enhance the research system of regenerative medicine, we will proceed with basic
research such as culture research using hematopoietic stem cells and mesenchymal stem cells that are
tissue stem cells, differentiation research into various tissue cells, analysis of cell function, etc. The
mission of this department is to develop advanced regenerative medicine products and develop humanresources who can play an active role internationally. In addition, because it is a social collaboration
research department with Rohto Pharmaceutical Co., Ltd., it is a project department that has thecharacteristics of combining the technology and experience of universities and companies.
（３）Activity Report１）Research Activities
Focused on mesenchymal stem cells, we developed efficient isolation and culture methods fromtissues, methods for inducing differentiation into various tissue cells, and new quality control
methods for the purpose of producing high-quality mesenchymal stem cells. Conducted the basic
research aimed at. Furthermore, we had developed and developed human resources for advanced
regenerative medicine products targeting intractable diseases, which were said to be impossible tocure with conventional drugs such as low molecular weight compounds.
２）Education Activities
None.
３）Social Activities
From joint research with Rohto Pharmaceutical Co., Ltd., we have conducted research aimed atdeveloping mesenchymal stem cell expansion technology and treatment of intractable diseases, andhave also jointly applied for patents.
４）International Activities
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None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
This Division has completed and closed as of September 30, 2017.

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Project Division of International Advanced Medical Research（１）Members
Project Associate Professor

Koichiro Yuji

（２）Research objectives
The mission of the Project Division is to apply changes in advanced medical research at the Instituteof Medical Science at the University of Tokyo (IMSUT).
（３）Activity Reports
１）Research Activities
Our activities include field research in which innovative medicine will be implemented; crossdisciplinary education of physicians, researchers, and professionals; and collaboration in innovative
projects in the Coastal Area Life Innovation Comprehensive Special Zone for International
Competitiveness Development.
The division's goal for the period of April 2016 - March 2019 was to make one or more
recommendations on bottlenecks and solutions for advanced medicine. We researched onbottlenecks and solutions for the utilization of artificial intelligence in the medical field. The resultof the study was cited in the Ministry of Health, Labour and Welfare Director's Notice in December
2018. Besides, we compiled the report on the utilization of artificial intelligence in the medical fieldby the Science Promotion Council of the Japan Medical Association.
About concerning the bottlenecks in advanced medicine, we believe we have achieved our goal.
However, we were not able to make sufficient recommendations for solutions. We aim to make atleast one recommendation for a specific solution in the future.
２）Education Activities
Training of human resources to promote advanced medicine was conducted. The division's goal
for the period of April 2016 - March 2019 was to develop one or more specialists. At IMSUT
hospital, which is a training affiliation of the Japanese Society of Clinical Pharmacology, twophysicians were certified as Board-certified Clinical Pharmacologists and one was certified as afellow by the Japanese Society of Clinical Pharmacology.
About concerning human resource training, we believe we have achieved our goal in clinicalpharmacology. However, we were unable to educate and train specialists in other fields. In the future,
we will continue to train specialists in clinical pharmacology, and aim to develop human resource
training in other fields.

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３）Social Activities
The division's goal for the period of April 2016 - March 2019 was to compile a project proposal
for the promotion of advanced medicine in the Coastal Area Life Innovation Comprehensive Special
Zone for International Competitiveness Development. However, the project proposal remains in theplanning stage. We will aim to draft an appropriate proposal with a deadline of three years or less.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
We have achieved several missions in our research and training activities, but there are stillchallenges that remain in the field of social activities, and we will aim to draft an appropriate proposal
in the future.

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Project Division of ALA Advanced Medical Research (-2020.3)（１）Members
Project Professor

Kenzaburo Tani

Project Senior Associate Professor

Yasushi Soda

Assistant Professors

Shohei Miyamoto, Yasuki Hijikata

Postdocs

1

Graduate students

1

Technicians

2

Others8（２）Research objectives
We have been heavily involved in developing gene /cell therapy and drug therapy for intractabledisease including cancers. From April 2016 to March 2019, our projects are as follows. a) Evaluationof 5-aminolevulinic acid(5-ALA) as therapeutic modality for malignancies, b) Development ofdetection methods for circulating tumor cells using 5-ALA, c) Development of therapeutic methods
for intractable hematological disorders using 5-ALA, d) Clinical development of safe and effective
Coxsackie virus type B3(CVB3) virotherapy, and e) Establishment of iPS cells using novel nontransmissible measles virus (MV) vector. We will report our new findings to international journals andalso translate these new findings to clinical field.
（３）Activity Reports
１）Research Activitiesa) Evaluation of 5-aminolevulinic acid(5-ALA) as therapeutic modality for malignancies; We
have been trying to find the combination effects of Coxsackie virus type B3(CVB3) with 5aminolevulinic acid(5-ALA) against malignancies.
b) Development of detection methods for circulating tumor cells using 5-ALA; We could flow
cytometrically detect possible protoporphyrin IX (PpIX) positive tumor cell fraction after the
coculture of peripheral blood cells with 5-ALA. We have been trying to identify these PpIX-positive
cells as real tumor cells using single cell analysis method.
c) Development of therapeutic methods for intractable hematological disorders using 5-ALA;
Sickle cell disease (SCD) is one of the most prevalent congenital hematological disorders due to the
production of mutant hemoglobin S synthesis caused by the point mutation of hemoglobin beta
chain gene. We introduced SCD model mice and have been trying to observe the possible
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therapeutic effects of 5-ALA to SCD (patent submitted).
d) Clinical development of safe and effective Coxsackie virus type B3(CVB3) virotherapy; We
have been developing CVB3 virotherapy as a new therapeutic modality for malignancy(PCT/JP2014/060988). To clinically develop the next generation safer CVB3 virotherapy, we use
miRNA technology and have developed the second generation CVB3 (Jia Y, et al., Mol Ther
Oncolytics 12:246-258, 2019). We also have been trying to translate the gene-modified CVB3 toclinical field.
e) Establishment of iPS cells using novel non-transmissible measles virus (MV) vector; We havedeveloped novel non-transmissible MV vector and successfully established iPS cells using the MV
vector. Interestingly, the MV vector could produce both of the primary and the naïve iPS cells(patent submitted, Hiramoto T, et al., Mol Ther 28:129-141, 2020). We could also develop blue lightsensitive MV virotherapy in vitro and in vivo (patent submitted, Tahara M, et al., Proc Natl Acad
Sci USA 116: 11587-11589,2019).
２）Education Activities
Mr. Jia Y, the first author of Mol Ther Oncolytics 12:246-258, 2019, obtained Ph.D. degree in the
University of Tokyo and started working in The Second Xiangya Hospital of Central South
University as a pediatrician. Prof. Tani lectured medical and/or dental students in Kyushu University,
Yamaguchi University and Miyazaki University.
３）Social Activities
We collaborated with neopharma Japan Co., Ltd, Shinnihonseiyaku Co., Ltd and Neoprecision
Therapeutics Co., Ltd.
４）International Activities
Dr. Soda collaborated with Dr. Inder Verma at Salk Institute, USA and published collaborated
data (Verma S, et al., Proc Natl Acad Sci USA 116:7363-7370, 2019).
５）Other matters to be noted
None.
（４）Challenges and Future prospects
We could publish our new findings in international journal. We, however, still need proceedclinical translation to help patients suffered from intractable diseases including cancers.
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Project Division of Advanced Biopharmaceutical Science（１）Members
Professors

Hirotoshi Tanaka, Kouhei Tsumoto

Project Associate Professor

Satoru Nagatoishi

Others2（２）Research objectives
Research activities: Publish at least 5 papers in international scientific journals, at least 10 papers at
international conferences and at domestic conferences every year. At least 10 presentations are madeeach year. Also, in the social cooperation section, we will publish a paper on joint research with acompany every year from the second year of social cooperation. We will publish at least one paper.
Educational activities: For more than a dozen graduate students in Kohei Tsumoto's laboratory, who
are also working in this laboratory, to earn their degrees.
（３）Activity Reports
１）Research Activities
Nine papers were presented in FY2017 and twelve in FY2018. We presented five papers ininternational conferences in FY2017 and three in FY2018. Domestic conferences presented 31
papers in FY2017 and 31 in FY2018. The number of papers presented each year is more than thetarget number, and we have fully achieved the results.
２）Education Activities
Two doctoral degree examinations were conducted inand six in FY 2018 (three of which were
working PhD students). Five of them were employed (two were in research positions at major
pharmaceutical companies).
３）Social Activities
We have achieved our goal with the publication of one paper in FY 2018 on the collaboration
with a company.
４）International Activities
None.
５）Other matters to be noted
Three press releases
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（４）Challenges and Future prospects
From 2019 onwards, our goal is to publish at least five papers in international scientific journals,
and to publish the results of our research in international conferences. We will present at least 10
papers every year at a national conference. In this division, we publish at least one paper on joint
research with a company every year.

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Project Division of Cancer Biomolecular Therapy（１）Members
Project Professor

Hideaki Tahara

Project Associate Professor

Hiroaki Uchida

Postdocs

5

Graduate students

1

Technicians

3

Others2（２）Research objectives
To publish two research reports from the Division of Bioengineering (transferred to the Project
Division of Cancer Biomolecular Therapy in April 2018) in European-language scientific journals
each year.
To submit an application for or obtain one patent from this division per year.
To provide all postgraduates enrolled in this division an education enabling them to obtain theirdegrees.
（３）Activity Reports
１）Research Activities
To date, the Division of Bioengineering (transferred to the Project Division of Cancer
Biomolecular Therapy in April 2018) has made progress in fundamental research aimed at clinicalapplication to cancer immunotherapy, oncolytic virotherapy, and antibody-based cancer therapy.
Between April 2016 and March 2019, the targets in this division have been cancer immunotherapy
based on understanding of immune-regulatory mechanisms by cancer cells; oncolytic virotherapy
using receptor-retargeted oncolytic herpes simplex virus (RR-oHSV); and exploration of novel
antibodies applicable to antibody-drug conjugates. The expected outcome during the relevant time
was publication of about six reports in European-language journals, application for or obtaining
three patents, and development or strengthening of academic-industrial links on the basis of theresearch results. The actual outcome has been that 19 reports of the research results have been
published in European-language journals, applications have been submitted for seven patents, fivepatents have been obtained, and academic-industrial links have been established with Ono
Pharmaceutical Co., Ltd. It is therefore considered that, from all perspectives, including publicationin European-language journals, applying for and obtaining patents, and academic-industrial links,
the outcome has been satisfactory. We see no problems during the relevant period. The teaching
staff and the graduate students will continue their effort to make progress in research.
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２）Education Activities
We have conducted the educational activities of postgraduates in this division. The target for thisdivision from April 2016 to March 2019 was to provide education such that three special research
students would be awarded PhDs, one special research student would be awarded a master's degree,
and five students would be awarded master's degrees internally. The outcome was that three special
research students were awarded PhDs, one special research student was awarded a master's degree,
and four students were awarded master's degrees internally. One of the master's students had to taketime off to recover from illness, but has continued to be supported, and it has been decided thathe/she will return to college in April 2019. It is therefore considered that the outcome of theeducational activities in this division has been satisfactory. It is not considered that there have been
any problems during the relevant period. Progress will continue to be made with educational
activities in future, centered on the professors.
３）Social Activities
This division initiated to collaborate with Ono Pharmaceutical Co. in 2017. In addition, a social
cooperation research program was set up together with Ono Pharmaceutical Co. in 2018.
Furthermore, Dr. Uchida (Project Associate Professor) has applied for a patent on the basis ofcollaboration with Daiichi-Sankyo Co., Ltd.
４）International Activities
Dr. Uchida (Project Associate Professor) has applied for and obtained patents on the basis ofachievements in the University of Pittsburgh, USA.
５）Other matters to be noted
None.
（４）Challenges and Future prospects
Taken together, it is considered that, from all perspectives, including research activities, educational
activities, social activities, and international activities, the outcome in this division has beensatisfactory. It is not considered that there have been any problems during the relevant period. The
teaching staff and the graduate students will continue their effort to make progress in research.

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G2

Project Division of Genetic Medicine and Disease Prevention（１）Members
Professor

Yoshinori Murakami

Project Professor

Takayuki Morisaki

Postdocs

1

Others4（２）Research objectives
Most human diseases, from cancer to common diseases, develop and progress through the
combinations and interactions of genetic background, acquired environmental exposure, life stylefactors and aging. Therefore, in order to promote healthy lives of citizens, it is a prerequisite to identify
health risks of individuals both at the time of birth and later in life and to provide them with appropriate
approaches to disease prevention when necessary. For this purpose, the Project Division of Genomic
Medicine and Disease Prevention was established on July 1, 2019 in cooperation with Nippon
Telegram and Telephone Cooperation (NTT). The goal of our project is to develop personalized andprecision prevention of diseases by integrating genomic information, health records and life style data
into a new predictive program of disease prevention for the healthy life of individuals.
（３）Activity Reports
１）Research Activities
Project Division of Genetic Medicine and Disease Prevention was established in July 2019 toobtain scientific evidence to develop a new predictive program for disease prevention for healthy
lives of individuals by integrating genomic information into the classic health-related information,such as individual health records, life style data and age.
The goal of the research activity in FY2019 of this Project Division is, therefore, to establish a“GenoVision” project. In this project, the employees of NTT group who got periodic physicalexaminations and provided an informed consent are recruited to a comprehensive survey programof individual SNPs. The purposes of this program are as follows. 1) To return the results of theselected SNPs to participants, which are directly involved in the activities of important biologicalenzymes for maintaining the healthy lives of individuals. 2) To obtain basic information for the
research on polygenic risk scores for establishing a next-generation approach to promoting healthy
life on the basis of the genomic information of individuals.
For this purpose, numerous relevant publications were searched comprehensively and thecandidate SNPs were selected to meet the following three criteria. 1) The SNPs are directly involvedin the enzymatic functions or expression. 2) The enzymatic activities are directly involved in
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pathological or unhealthy phenotypes. 3) The enzymatic dysfunction and the resultant unhealthy
phenotype are shown to be mitigated by behavioral changes. On the basis of these criteria, SNPs at
the MTHFR gene affecting the activity of methylenetetrahydrofolate reductase for folic acidproduction and SNPs at the ADH1B and the ALDH2 genes affecting the activity of alcohol
dehydrogenase and aldehyde dehydrogenase, respectively, for alcohol metabolism were selected as
the initial targets of this project. Recruitment of participants started in June 2020 and the individual
SNPs are being analyzed. Thus, research achievements of this Project Division in FY2019 aresatisfactory.
２）Education Activities
Since the Project Division of Genomic Medicine and Disease Prevention has been established asa Social Cooperation Research Program with NTT and has not been integrated into the graduate
school systems in the University of Tokyo, the division currently has no education activity.
３）Social Activities
Project Division of Genomic Medicine and Disease Prevention concluded a joint research
agreement with NTT Life Science Corporation and designed and constructed a collaborative“GenoVision” project as described above. This Division is also collaborating and cooperating on
the project with the Center for Disease Prevention, NTT Medical Center, Tokyo.
４）International Activities
None.
５）Other matters to be noted
None.
（４）Challenges and future prospects
The next goal of the Project Division of Genomic Medicine and Disease Prevention iscomprehensive SNP analysis of individual participants and combinatorial study with healthy records
and life-style data for establishing polygenic risk score to predict susceptibilities of diseases, which
will start after “GenoVision” system is launched. The total number of participants in the “GenoVision”
project is estimated to be around 60,000 cases, although the estimation might be changed by the
COVID-19 epidemic. Staff scientists for this project division are being recruited.

335

External Review Meeting
Date & Time: Thursday, January 21st, 2021. 9:00-11:00
Meeting style: Online meeting via the Zoom website<Schedule>
09：00 Opening declaration, Introduction of participants, Description of meeting schedule
Welcoming remarks from the Dean of IMSUT
Presentation of IMSUT’s general statement (Dean Yuji Yamanashi)
09:15

Presentation of Group 3 (Prof. Kensuke Miyake)
Presentation of Group 2 (Prof. Yoshinori Murakami)
Presentation of Group 1 (Prof. Atsushi Iwama on behalf of Prof. Mutshiro Takekawa)
Presentation of Group 0 (Prof. Seiya Imoto)Presentation of Group 4 (Prof. Toshio Kitamura)
Presentation of Group 5 (Prof. Yasuhiro Yamada)Presentation of IMSUT Hospital (Prof. Arinobu Tojo)

09:55

Q&A

10:05

Exchange of Views (External Review committee members only)

10:35

Comment from the Chairman of External Review committee
Individual Comments from each committee member

10:55

Closing declaration[Moderator: Vice-Dean Makoto Nakanishi]

336

Report of the External Review Committee
Ⅰ

Overall assessment of the state of IMSUT

1. Organization and research implementation/support/promotion system
It would be important to highlight the scientific achievement and vision of the institution for the lastand next 4 years as a story rather than individual values. There are very few female and foreign PIs
at any level. IMSUT could make a more concerted effort in the recruitment topromote gender balance and internationalization.
We can see some discrepancy between structure of Departments (G０-5）and their mission.
More simple structure of Department/Center such as Infection/Immunity, Genome/Cancer and Stemcell biology, including translational studies at each level may be efficient to show up theinternational branding in the research.
2. Research activities and dissemination of research results
IMSUT is one of the biggest institutes affiliated to University. (Fuchi-ken). The number of peerreviewed papers has been significant. In particular, it is impressive that the percent of papers of IF10
or greater reached 16% in FY2019. They demonstrated the strong research achievement in the fields
of genomics, microbiology/immunology and cancer and stem cell biology. To show the integrity inscientific vision unique to IMSUT, however, some common concept/aim should be proposed toestablish interdisciplinary science. Especially, more interdisciplinary study may be required, such as
in bioengineering and chemical biology. To do so, it is also important to collaborate within theInstitute or with the department of University of Tokyo (Hongo and Kashiwa campus).
Although they are looking to expand the translational research in the affiliated hospital, it is still
under way and is not very visible. The number of domestic and international patents also increased
over the review period; however, it is not clear how many of those are licensed to be commercialized
and resulted in revenue generation for IMSUT.
3. Education activities and development of young scientists
As a leading research Institute, they should be more international in attracting young researchers
from abroad. They should strengthen the implementation of the programs that promote exchange ofyoung researchers between Japan and overseas countries. Although each center has tried to recruit
talented young PIs, more solid tenure-track system should be introduced. It is important to articulate
all the current efforts supporting career development of students and postdoctoral fellows into an
institutional vision for training the next generation of researchers,
4. Social cooperation and contributions to academia337

It is questionable that IMSUT has distinct recognition even in Japan. The press coverage is often
about University of Tokyo. It may be advisable to try to promote IMSUT as a national leader in one
or two topics. This lack of distinctive branding is probably more of a problem from an international
point of view. Perhaps a series of internationally-recognized workshops or conferences in one or
two topics with clear IMSUT brand would help.
5. International activities
The quantity of international research activities and projects is impressive. However, the report
should single out a couple of them to elaborate on their impact, especially some big international
projects where IMSUT plays a leading role. The information on international recruitments at every
level should be addressed.
Ⅱ Assessment of the specific IMSUT departments/centers
G0 Human Genome Center：
Human Genome Center (HGC), including Health Intelligence Center before its merge into HGC,
plays a unique role in IMSUT. In addition to regular research and educational activities, HGC has a
mission to develop and maintain an informatics infrastructure for biomedical sciences in Japan with
its supercomputer system SHIROKANE. There have been significant improvements of thisinfrastructure together with new developments of AI and other informatics technologies, which resultin a large number of collaborative projects with both Japanese and overseas researchers. The missionof HGC is to promote human genome research and personalized medicine. Key to linking sequenced
genomes to any meaningful features for use in personalized medicine lies in informatics technologies.
A newly formed laboratory for ELSI (ethical, legal and social issues) can work for a unique andeffective combination of research activities.
It is unclear how artificial intelligence and each research department will be integrated with thecurrent programmatic priorities to further the goals of the institution.
G1 Department of Basic Medical Sciences：
The strength of the research is on 1) normal and malignant hematopoietic stem cells, 2) iPSCs
chimerism for organ replacement, and 3) translational research for cell replacement therapies. This
could be more strongly highlighted in the overall presentation of Group 1 and articulated as a strength
for the overall research mission of the institution.
Clarifying the intra- and inter-collaboration within Group 1 and with other departments/centers in
the institute by highlighting joint publications/projects/funding would help with the evaluation of theintegration of this group.

338

G2 Department of Cancer Biology：
Department of Cancer Biology in IMSUT has long played and is still playing a central role at thefrontier of basic life sciences, e.g., biochemistry, molecular biology, and genetics, in Japan. In addition
to the basic cancer sciences, this department is currently making stronger efforts to promotetranslational research based on original findings in each laboratory.
This is inevitably quite a small number of researchers in the very competitive area of molecularcancer research. Each group is successful in its own area. However, it may be possible to make morecombined impact by effort to focus of all the groups on particular types of cancer, or particularapproaches to therapy.
G3 Department of Microbiology and Immunology：
Department of Microbiology and Immunology is well organized to focus on the interaction between
host and pathogen. The department is composed of 5 unique divisions. They aim to develop novel
therapeutics and prophylaxis of infectious diseases. Especially, they are now playing an important rolein the basic virology and vaccine science of COVID19. However,tighter collaboration and stronger leadership will be required.
Group 3 has a track record of research successes and important contributions to science; ensuring
adequate funding and recruitment of young researchers will be critical for continued success.
G4 Advanced Clinical Research Center：
Group 4 consists of cellular therapy, infectious disease and genome medicine. Thus, it seems to bemiscellaneous. They are aiming for the translation research. Thus, affiliated hospital should be a
hospital for Experimental/Clinical research.
G5 Center for Experimental Medicine and Systems Biology：
G5 also seems to be miscellaneous. It might be time to reorganize G5 within IMSUT.
1. The long-term goal of the laboratory of Developmental Genetics has been to generate geneticallymanipulated mice. The focus has been on various developmental questions using manipulation ofmouse embryos. The laboratory has been closed in 2018.
2. The Division of Stem Cell Pathology studies epigenetic regulation with focuses on the cellulardifferentiation, the maintenance of cellular identity, and the pathogenesis including age-relateddiseases such as cancer at the organismal level. Productivity of the division has been excellent as
documented by 10 strong publications in good journals.
3.The Laboratory of Innate Immunity works on understanding molecular mechanisms controlling
pathogen sensing and TLR responses. The report lists thirteen publications in visible international339

journals.
4. The Laboratory of Reproductive Systems Biology focuses on mechanisms of germ cell
development, spermatogenesis, and fertilization. In addition, the laboratory is a core member of the"Gene Manipulated Mouse Section” and performs collaborative projects by generating genemanipulated mice with other divisions of IMSUT. They list the production of 20 gene manipulatedmouse strain per year. Productivity of the laboratory has been excellent with 14 published papers overthe last 3 years.
5. The Laboratory of Systems Biology investigates the role of certain cytokines in the developmentof allergic disorders such as asthma and dermatitis, and autoimmune disorders such as arthritis. As
judged by the publications, the laboratory is involved in numerous collaborations resulting in morethan 40 publications over the last 4 years.
6. The Division of Genome Engineering uses genome engineering technologies, such as ZFNs,
TALENs, and CRISPR-associated (Cas) nucleases and attempts to overcome limitations of current
technology. The laboratory is collaborating with a number of other groups producing geneticallymodified mice. This has resulted in 8 publications in 2019.
7. The Laboratory Animal Research Center houses mice and rats under SPF conditions andprovides services for mouse embryo manipulation and for generating genetically modified animals
with genome editing technologies. The laboratory has been successful in generating gene manipulated
mice that serve as useful models for a variety of collaborative projects.
8. The Kai Laboratory, using mouse models, is focused on research on various viruses such as Nipa
and Morbillivirus. The output of the laboratory is high with 14 publications in international journals
over the last 3 years.
9. The Division of Animal Genetics generated various engineered immune deficient mouse and rat
models for xenotransplantation. They list 9 publications that are also listed in the Division of Genome
Engineering output (both centers are directed by Dr. Mashimo).
10. The Animal Center is a centralized facility to house various animals equipped with barrier
housing rooms for biohazardous experiments, X-ray Irradiator, MRI and IVIS imaging system. The
facility provides services to derive mice by IVF and performs embryo manipulations for generating
genetically modified mice.
11. The Amami Laboratory of Injurious Animals houses non-human primates and has a BSL3 facility.
The center focuses on tropical diseases and is involved in numerous outside collaborations. Projects
include the study of Habu venom, development of methods for controlling vivax malaria using owl
monkeys, analysis of the pathogenesis of measles virus and elucidation of biological characteristics of
New World monkeys. Work from the laboratory has been published in 9 papers over the last 3 years.
They should discuss about the future plan of this laboratory.
340

Hospital：
Organization appears to be too diverse in comparison with the manpower. They should clarify theclinical focus, for example, in the cancer program and gene therapy in the hospital which could provide
some joint activities. It is essential to tightly linked with the University Hospital in Hongo or general
hospital nearby to maintain the advanced standard therapy.
Ⅲ. Comprehensive review of IMSUTThe platform of research institutes affiliated to University. (Fuchi-ken) has not been so well explainedin the web. Thus, overseas researchers could not understand the position of Fuchi-ken in the academyin Japan.
We hope IMSUT should play a role model in Fuchi-ken. IMSUT should discuss about thedevelopment/direction to World Premier International Research Center (WPI) Initiative.
In WPI, 13 research centers are tackling great challenges in order to establish “Highly visible
research centers”, which attract top-notch researchers from all over the world and further improve thequality of Science and Technology. They should discuss about the future (10-years) shape of IMSUT
from the aspect of research system in Japan. The mission of Fuchi-ken should be evaluated every 5
years, since the project may change as time goes by.
Appendix (regarding the format)

There is a lack of information on the overall number of faculty (senior/junior) within the entire
institution and its evolution (new recruit/departed members) over the last 4 years. The same is also
missing for the number of trainees (student/postdocs) and supporting staff members, making it difficult
to assess the dynamic growth of the institution. Information and the distribution between male/female
and domestic/foreigner researchers for each of those categories (faculty/trainee/staff) would also be
informative in order to assess their efforts in achieving greater integrations over the last 4 years. The
suggestion would be to share the common table in IMSUT, showing the evolution of those numbers
over the period being evaluated, and to state the objectives of the institution regarding recruitment
policy for the next evaluation period.

It is suggested for the annual faculty evaluation is to avoid an over emphasis on number ofpublications, amount of grants, etc. It is more important to ask for clear statement of both short-term
and mid-/long-term impact. For short-term: the best or most interesting result this year is. For mid/long341

term: how the results of 5 years ago now show an observable impact (e.g. citation or other forms ofusage) on the field.

342

Postscript
Through the external review process, we discovered a lot about ourselves from an objective
perspective. Prior to the committee meeting, we conducted a self-inspection and evaluation of thecurrent situation in our laboratories and departments over the past four years, and reported the results
to the committee. At the committee meeting, we also explained and discussed current and futurepressing issues with the reviewers. Despite the meeting’s online nature, we were confident that theexternal reviewers’ comments would provide essential guidance for us to improve as an internationaland multidisciplinary institute in the fields of medical science. Thankfully, the reviewers provided
their external review summary in the form of reports based on objective analysis. This report isinvaluable, because it is summarized as a consensus of leading scientists from various research fields
and nations. Finally, we would like to express our deepest gratitude to the reviewers for all their efforts
amidst the current COVID-19-imposed circumstances, and take this report seriously as a critical guidefor further strengthening our institute.

March 30, 2021
Yuji Yamanashi
Dean of IMSUT

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