HOKKAIDO

Hokkaido Division, Research Center
for Medicinal Plant Resources

OSAKA

The Headquarter of NIBIOHN
National Institute of Biomedical Innovation
National Institute of Health and Nutrition
Sennan Bioresource Research Section,
National Institute of Biomedical Innovation

IBARAKI

Tsukuba Primate Research Center
Tsukuba Division, Research Center
for Medicinal Plant Resources

2024

TOKYO

National Institute of Health and Nutrition
Tokyo Office

KAGOSHIMA

Tanegashima Division, Research Center
for Medicinal Plant Resources

National Institutes ofBiomedical Innovation,
Health and Nutrition (NIBIOHN)

A research institute committed to people s healthNational Institute of Biomedical Innovation (NIBIO)
7-6-8, Saito-Asagi, Ibaraki-shi, Osaka 567-0085, Japan
Phone: (+81)72-641-9811 (main)

Research Center for Medicinal Plant Resources• Tsukuba Division

1-2 Hachimandai, Tsukuba-shi, Ibaraki 305-0843, Japan
Phone: (+81)29-838-0571 (main)• Hokkaido Division

108-4, Ohashi, Nayoro-shi, Hokkaido 096-0065, Japan
Phone: (+81)1654-2-3605 (main)• Tanegashima Division

17007-2 Noma, Nakatane-cho, Kumage-gun, Kagoshima 891-3604, Japan
Phone: (+81)997-27-0142 (main)

Tsukuba Primate Research Center

1-1 Hachimandai, Tsukuba-shi, Ibaraki 305-0843, Japan
Phone: (+81)29-837-2121 (main)

Sennan Bioresource Research Section

2-11, Rinku, Minamihama, Sennan-shi, Osaka 590-0535, Japan
Phone: (+81)72-480-1670 (main)

Tokyo Office

3-4-2 Kasumigaseki, Chiyoda-ku, Tokyo 100-0013, Japan
Phone: (+81)3-6273-3511 (main)

National Institute of Health and Nutrition (NIHN)
Kento Innovation Park, NK Building
3-17 Senrioka Shinmachi, Settsu-shi, Osaka 566-0002, Japan
Phone: (+81)6-6384-1120 (main)

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National Institutes ofBiomedical Innovation,
Health and Nutrition

Greetings
In addition to collaboration between industry, government,
and academia, we also work together with patients toaccelerate research that will give back to society.

A research institute committed to people’s healthPresident, Yusuke Nakamura
Since the National Institute of Biomedical Innovation (NIBIO) and the National
Institute of Health and Nutrition (NIHN) merged in 2015 to form the National
Institutes of Biomedical Innovation, Health, and Nutrition (NIBIOHN), a six-centersystem, which includes the Center for Drug Design Research, has been establishedbased on the first med- to long-term plan. NIHN had been located in Tokyo, but was
relocated to Kita Osaka Health and Medical Care City (“KENTO”) in Osaka
Prefecture, and both institutes will deepen collaboration with medical institutions
and patients to develop a project to extend healthy life expectancy.
In 2024, the post-war baby boomer generation has reached the advanced age group,
raising the importance of living a long life with the healthy condition. Amid this,our second 7-years med- to long-term plan started in 2022. The plan addresses
various issues with an “era of 100-year lifespans”. One of the keywords is"individual optimization." In the future, it will be necessary to provide optimal
guidance and medical care tailored to each individual, whether it is to maintain andimprove health through diet and exercise or to select treatment methods in the
disease condition. We would like to further advance drug discovery and nutrition
research using cutting-edge AI technology, and contribute to our society.
Based on extensive collaboration with two Osaka Prefectural Hospitals, the Osaka
International Cancer Institute and the Osaka Women’s and Children’s Hospital,
NIBIOHN has begun working with patients, medical institutions, and research
institutes to make incurable disease to be curable. It is difficult for privatecompanies to develop drugs for intractable diseases and rare diseases. Fulfilling its
purpose as a national research facility under the three key words of medical
infrastructure, health and nutrition, NIBIOHN has made research and development
targeting these diseases as one of our priorities.
Additionally, in order to take full advantage of the benefits of integrating the two
research institutes, from health maintenance to drug development, we will further
focus on areas that integrate the pharmaceutical and health/nutrition fields. We
are exploring new possibilities, such as in our research on nutrition, intestinalbacteria, and immunity.
We will continue to make further efforts to contribute to extending healthy
longevity through the fundamental technologies for the development ofinnovative medicines, research on food, nutrition, and exercise, and basic research.
We would like to ask for your continued support as we move forward.

Living long with healthy conditions has always been a long-standing desire ofhumankind. For people suffering from illness and their families, living in darkness
without hope of a cure or living with even the slightest hope of a cure makes
a huge difference on their life.

In order to be a beacon of hope for such people, we are taking on the challenge ofinterdisciplinary research in both the medical and health sciences for drug discovery
that leads to new treatment possibilities and researches on nutrition and physical activity
that leads to prevent illness. Always with a spirit of challenges, we are deeplycommitted to revolutionize Japan and the world from Osaka.

As a research institute committed to peopleʼs health, we will not conduct research simply
for the sake of research, but rather always aim for new technological innovations,promoting collaborations with medical institutions,private companies, and local and central governments,
and conduct research that truly beneﬁts people and society.

C o n t e n t s
Greetings・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・ 2
History・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・ 3
Organizational Chart
An Introduction to Typical Research・・・・・・・・・・・・・・・・・・・・・・・ 4●Ⅰ.Intractable Diseases and ImmunoGenomics・・・・・・ 5●Ⅱ.Pharmaceutical and Health Sciences・・・・・・・・・・・・・ 7

Promoting local open innovation and interdisciplinary activities
leveraging a network of research infrastructures

In 2022, the National Institute of Health and Nutrition (NIHN) is moving to the Northern Osaka
Health and Biomedical Innovation Town (NohBIT or “Kento” in Japanese), which extends overparts of Suita and Settsu, Osaka Prefecture. The relocated institute aims to promote open
innovation in partnership with the National Cerebral and Cardiovascular Center, Suita
Municipal Hospital, private enterprises, and other organizations in the area. In collaboration
with local communities, the NIHN will find ways to apply research findings to local settings.
Moreover, the relocation of the NIHN will strengthen its ties with the National Institute of
Biomedical Innovation (NIBIO) located in the International Cultural Park (“Saito” in Japanese),
thereby expanding interdisciplinary research collaboration.

● Ⅲ.Research on Resources for

Drug Discovery・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・ 9● Ⅳ.Medicinal Plant Resources・・・・・・・・・・・・・・・・・・・・・・・・・・・・11● Ⅴ.Biological Resources Research・・・・・・・・・・・・・・・・・・・・・13● Ⅵ.Nutrition Science・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・15● Ⅶ.Physical Activity・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・ 17● Introduction of researchers passionately

engaging in research from new perspectives・・19

Overview of Research Themes・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・ 23

1

National Institute of Biomedical
Innovation (NIBIO),
International Cultural Park (Saito, Ibaraki City, Osaka)

National Institute of Health andNutrition (NIHN),

Northern Osaka Health and Biomedical Innovation Town
(Kento, Suita and Settsu, Osaka)

2History

Organizational Chart

The National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN) was founded on April 1, 2015, by integrating the
National Institute of Biomedical Innovation (NIBIO) with the National Institute of Health and Nutrition (NIHN).
The establishment of NIBIOHN was a part of the effort to review independent administrative institutions under the Basic Policy
regarding the Reform of Independent Administrative Institutions, approved by the Japanese Cabinet in 2013, for the purpose ofpromoting comprehensive research by integrating expertise in drugs, food, and other related fields.

National Institute of
Health and Nutrition

Laboratory of Drug Discovery Resources ResearchCenter for Drug
Discovery
Resources
Research

Laboratory of Cell Model for Drug Discovery
Laboratory of Functional Organoid for Drug Discovery
Laboratory of Drug Discovery Resources Research Collaboration Promotion Oﬃce
Laboratory Animal Resource Bank (LARB)
Medicinal plant screening project
Tsukuba Division
Hokkaido Division
Tanegashima Division

Tsukuba Primate
Research Center
Section of Laboratory Equipments (SLE)
Section of Laboratory Animals

Artiﬁcial Intelligence
Center for Healthand Biomedical
Research

Department of
Nutritional
Epidemiology and
Shokuiku
Department of ClinicalNutrition
Department of Food
Function andLabeling
Department of
Physical
Activity Research
Department of Nutrition
and Metabolism
International Center
for Nutrition
and Information

Laboratory of Bioinformatics
Laboratory of In Silico Design
Laboratory of Toxigenomics Informatics
AI Nutrition Project

Section of National Health and Nutrition Survey
Section of Nutritional Epidemiology
Section of Dietary Guidelines
Section of Nutritional Therapy
Section of Food Component Analysis
Section of Food Safety and Function
Section of Information Network of Health Food
Section of Exercise Guideline
Section of Behavioral Physiology
Section of Healthy Longevity Researches
Section of Chrononutrition
Section of Energy Metabolism
Section of International Nutrition Strategy
Section of Population Health Metrics
Section of Global Disaster Nutrition
Section of Research Collaboration and Partnership

3International
Research
Collaboration andPartnership

National Institute of
Biomedical Innovation

AuditorNational Institutes of Biomedical Innovation,
Health and Nutrition

Laboratory of Biofunctional Melecular Medicine

Physical Activity
and Metabolism

MergedExecutive Director

2015

Laboratory of Antibody Design

Food and Nutrition

Tsukuba Primate
Research Center

Laboratory of Drug Discovery Imaging

Laboratory of Advanced Biopharmaceuticals

ResearchCenter for
Medicinal
Plant Resources

National Institute of
Health and Nutrition

Research Center for
Medicinal Plant Resources

Center for Drug
DesignResearch

Interdisciplinary
Collaboration

National Institute of
Biomedical Innovation

Laboratory of XNA Screening and Design

Department of Research Support

Part of each organization merged

Laboratory of Proteomics for Drug Discovery

Biological Materials

National Institute of
Health and Nutrition

Pharmaceuticals andMedical Devices Agency

Laboratory of Gut Environmental System

Drug Discovery
Platforms

Transformed into an independentadministrative institution

Department of Strategic Planning

National Institute of
Infectious Diseases

National institute of
Health Sciences

Laboratory of Cell Vaccine

Laboratory of Gut Microbiome for HealthNational Institute of
Biomedical Innovation

Digital Transformation Oﬃce

National Institute of Health

2001

2005

Coordination Oﬃce of Research Ethics

Jurisdiction transferred to the
Ministry of Health andWelfare following its establishment

President
National Institutes of Biomedical Innovation,
Health and Nutrition

Institute of Nutrition(established within the Home Ministry)

1947

2004

Microbial ResearchCenter for
Health and Medicine

Tokyo Drug Control Laboratory

1938

1997

Department of General Aﬀairs

NIHN can be traced back to the Institute of Nutrition established in the Home
Ministry in 1920. After the Ministry of Health and Welfare was founded in
1938, oversight of NIHN was transferred from the Home Ministry to the
Ministry of Health and Welfare, and the NIHN was transformed into anindependent administrative institution in 2001.
NIHN’s mission is to conduct surveys and studies regarding the maintenanceand promotion of health of the people of Japan, as well as surveys andstudies regarding nutrition and diet for the purpose of improving and advancing public health.

1920

Laboratory of Rare Disease Information and Resource Library

Laboratory of Vaccine Materials

President Appointed Assistant

1874

Laboratory of Therapeutics for Intractable Diseases

Reverse Translational Research Project

Quick History of the National Institute of
Health and Nutrition (NIHN)

NIBIO was established in 2005, with the Osaka branch of the National
Institute of Health Sciences as the nucleus, and by integrating parts of the
National Institute of Infectious Diseases and the Pharmaceuticals andMedical Devices Agency.
NIBIO’s mission is to build the foundation for improvement of pharmaceutical and other related technologies by conducting universal research that
contributes to the development of drugs and other products, as well as
biological resources, and by promoting research and development in theprivate sector or other settings for the overall purpose of improving thehealth of the people of Japan.

Laboratory of Precision Immunology

Priority disease research areasin the med- to long-term plan

Quick History of the National Institute of
Biomedical Innovation (NIBIO)

Laboratory of ImmunoGenomics

Center for Intractable
Diseases and
ImmunoGenomics(CiDIG)

4

An Introduction to Major
代表 的 研 究 紹 介
Research ProjectⅠ

Intractable Diseases and ImmunoGenomics

Utilizing platforms for high-dimensional
immunological analysis seamlessly connecting
clinical and non-clinical data

Center for Intractable Diseases and ImmunoGenomics (CiDIG)
Center Director, Takuya Yamamoto

A professionalʼs commitment to research
I have always focused on human immunology research ever since I was a student. Before my posting at NIBIOHN, I had the opportunity to study at theforefront of translational research at major infectious disease research institutes in Japan, France, and the United States. However, I felt that someday I
would like to take part in drug discovery and vaccine development research originating in Japan. After being approached by NIBIOHN, which is one of
the most active translational research centers in Japan, I decided to return to Japan.

Informing patients in a timely manner and contributing broadly topeople’s health and longevity through interdisciplinary research involving
experts in the fields of intractable disease, genome and immunology
Exploring approaches to intractable diseases,
cancer and infectious diseases by elucidating
the hidden connections between genomic
and immune information

With the development of computer science, aparadigm shift to research and development
utilizing big data has long occurred in the ﬁeldof life sciences. With that being said, social
implementation schemes that aim to returnthe beneﬁts to patients are still underway. To
achieve this, it is important to comprehensively
prepare and analyze all human phenotypes as
general-purpose data, and to conduct omics
analysis that attempts to elucidate genomics,
transcriptomics, proteomics, and metabolomics.
The phenotype of the human genome, known as
the blueprint of the human body, varies depending on age, gender, health condition, and disease.
Therefore, it is necessary to examine biologicalsamples as temporally and spatially linked datain high resolution, and a high level of expertiseis required for such analysis.
In order to make the most of valuable biologicalsamples to beneﬁt patients, it is necessary tocollect and structure high-quality biologicalsamples that serve as the source of data andclinical data linked to each sample and to
appropriately implement the series of process-5

es based on established expertise, from thedigitization of samples through experiments
to advanced data analysis. Against thisbackdrop, the Center was established in April
2023 to promote research and development fromthe perspective of collecting clinical information as
well as combining genomic and immune information, to develop and implement diagnostic, preventative, and therapeutic methods for intractable diseases, cancers, and infectious diseases.

Figure.1

Center for Intractable Diseases and
ImmunoGenomics (CiDIG)
A platform of higher-dimensional
immunological analysis

Scheme for patient-oriented R&D aiming
for a society of health and longevity
Collection and structurizationof patient samples/data

Laboratory ofPrecision Immunology
Immunotherapy development
by ImmunoGenomics

Grasping the overall pictureof the target intractable diseases

Laboratory of
ImmunoGenomics(Database for designated intractable disease patients)

Extraction of problems by
Immunogenomic

Laboratory of Therapeutics for
Intractable Diseases

Patient stratification based on
immunogenomic data

Maintenance of specimens andinformation on intractable diseases

Creation of new diagnostic andtherapeutic methods

Laboratory of Rare Disease
Information and Resource Library(Incurable Disease Research
Resource Bank) / Ddrare)

Verification in non-clinical settings

Benefit topatients
Clinicaltesting

Collaboration with universities,
research institutes, and companies

Collaboration withintractable disease registrydisease1

disease2 …disease n

Verification in clinical settings

Tackle the challenge of a society ofhealth and longevity from theviewpoint of immunoGenomics

The Laboratory of Precision Immunology promotes
patient-centered, -oriented, -focused drug discovery research for intractable diseases, cancer,
and infectious diseases, based on realizing
precision medicine that delivers optimized
medical care to each patient through an
immunological approach. This requires anunderstanding of the complexities of the humanimmune system, which diﬀers from individual toindividual, and to deepen our understanding of
diseases by identifying problems in individuals
or speciﬁc disease groups. For this reason, ourlaboratory has equipped an analysis platform(advanced immunological analysis platform) that
can analyze the diﬀerences in the immune
system and response to immunogens in eachindividual from multiple perspectives and withhigh resolution (Figure.1).
By making full use of this platform, we aim toelucidate immune responses that exhibit various
phenotypes for each disease and patient, search
for new biomarkers and surrogate markers, anddevelop new diagnostic methods, immunotherapy, and preventive and therapeutic vaccines.
This analysis platform is used for research on
immunotherapy for chronic persistent infectious
diseases such as pancreatic cancer, HTLV-1
infection, AIDS, and hepatitis B, as well as for
non-clinical and clinical trials in vaccine development for acute infectious diseases such as inﬂuenza and novel coronavirus infections.

Developing cancer immunotherapies
based on genomic information
The Laboratory of Immunogenomics conducts
genomic analysis of various diseases, and in thecase of cancer, we are working on the development of personalized treatments, especiallyimmunotherapy, based on genomic information.
Over the last decade, the importance of immunity in cancer has been reported, and it has beenfound that cancer-speciﬁc antigens, neoantigens,small fragments of mutant proteins coded bysomatic genomic mutations in cancer cells areimportant targets for the immune system,
mainly by T cells. In other words, if we canidentify a neoantigen(s) that is recognized by T
cells, we can attack the cancer by activating
patient's immune responses. However, neoantigens vary among individual cancer patients, so it
is necessary to identify the right targetableneoantigens for each cancer patient. We havedeveloped a system to eﬃciently predict neoantigens based on information on genomic mutations
identiﬁed through the comprehensive genome
sequencing and bioinformatic technology.
Using this system t, we showed that T cells
speciﬁc to the predicted neoantigens weresuccessfully induced using blood samples frompatients and healthy donors. We are currently
conducting clinical research on cancer vaccines
targeting personalized neoantigens, which is
expected to provide new treatment options forpatients who have no treatment option. We
are developing new cancer immunotherapies
targeting cancer cells expressing neoantigens,such as T cell therapies using geneticallyFigure.2

Metaphorical illustration of higher-dimensional immunological analysis
Conventional method High-resolution and advanced immunological analysis

Observation from outside the earth:shapes of blue, green, and yellow areas.

Conventional blood tests:
limited information.

Observation on the ground:details of diverse organisms, artifacts

Individual characteristics.

higher-dimensional immunological analysis:
Millions of cells withvarious morphologies and properties

Individual proteins/molecules on
the cell surface and inside the cell.

Utilization of higher-dimensional immunological analysis platform fora healthy and long-lived society

Problem extraction

Solutions and Verification

modiﬁed T cells expressing with T cell receptors
or antibodies speciﬁc to neoantigens.

What are intractable diseases?
Why should we find a cure?
Generally, intractable diseases are diseases thatare diﬃcult to cure or for which no cure has beenfound. In 2015, the Ministry of Health, Labourand Welfare (MHLW) deﬁned 110 designatedintractable diseases that are eligible for medical
expense subsidies under the Intractable Diseases
Act. Since all of these diseases are rare andresearch and development is diﬃcult, Japan has
put in place a system to support research as anational policy. The Laboratory of Therapeutics
for Intractable Diseases and the Laboratory ofRare Disease Information and Resource Library
are working to develop research resourcesthat will serve as the foundation for researchon intractable diseases.
＊The National Database of DesignatedIntractable Diseases of Japan
Since 2015, the number of targeted diseases
has expanded, and currently 338 diseases aredeﬁned as designated intractable diseases. The
total number of recipients is about one million,
and the clinical research forms prepared andsubmitted when applying for medical expensesubsidies are used to promote research on
intractable diseases with the consent of thepatients. For this purpose, we have been entrusted by MHLW to operate the National Databaseof Designated Intractable Diseases of Japan(registration and provision of data) as a disease
registration center operator.
＊Resource and database for intractabledisease research
Patient samples (plasma, DNA, etc.) and information (clinical information, etc.) are importantresearch resources in the development ofClinical trial

diagnosis and treatment methods for intractable diseases. In order to bridge the use of thesevaluable resources for research, we have been
operating the Rare Disease Bank since ﬁscal 2009,
and we are collaborating with a total of 50
medical institutions, including the Rare Disease
Research Group, which operates patient registries,
to serve as a hub for the collection and distribution of resources. In addition, we analyze clinical
trial data on intractable diseases in Japan andoverseas, and provide what drugs have beendeveloped for which diseases, from a databasecalled DDrare. We also analyze the gene products
and biomolecular interactions that drugs interact
with in a cross-functional manner across diseases
and post them in DDrare. Based on these ﬁndings,
we are conducting exploratory research on drug
repositioning (applying one drug to anotherdisease) candidates.

Collaborating with experts fromresearch on intractable diseases,
cancer and infectious diseases to social
implementation
It is believed that the use of big data will lead toinnovation in all ﬁelds. The barriers to achieving
this, however, are high. In order to solve various
health problems based on actual clinical practice, it ispossible to implement solutions in society only after
a process that requires a high level of expertise,symbolized by 1) appropriate collection, management, and structuring of target biological samples
and clinical information, 2) appropriate non-clinicaland clinical trials, and 3) ensuring the quantity andquality of omics data analysis obtained from suchresearch. At the Center, a team with a high level ofexpertise organically collaborates to tackle diseases
such as intractable diseases, cancer, and infectious
diseases, and conducts research on a daily basis sothat we can contribute to the health and longevityof the people of Japan through the timely returnof research results in forms that beneﬁt patients.

6

An Introduction to Major
代表 的 研 究 紹 介
Research ProjectⅡ

Pharmaceutical and Health Sciences

shown that consuming barley containing a large
amount of dietary ﬁber increases the variety ofgut bacteria.

Microbial Research Center for Health and Medicine
Center Director, Jun Kunisawa

Why I became a researcher and my future goals
Originally, I had wanted to work for a trading company, but became a researcher after I found myself fascinated by new discovery through scientiﬁc
research. Currently, I am working diligently to expand my research to create a new and healthier society.

A Near-Future Vision for a Healthy Society from the
Perspective of Gut Environment:
Individualized and Stratified Dietary Guidance, Developmentof New Drugs and Functional Foods
Integrating the medical andhealth sciences
When you hear the term gut bacteria, you may
imagine that it has something to do with bowel
movements, but do you know that gut bacteria
may also be involved in various aspects of healthsuch as immunity, allergies, and obesity?
With the merger of NIBIO and NIHN in 2015,
NIBIOHN was able to integrate both medical(after illness) and health (before illness) sciences.
As one way to take this advantage, we establisheda group with some laboratories to focus on therelationship between intestinal environmentand health and medicine.
The primary function of intestine is absorptionof dietary components, which become part ofour body. Therefore, the contents and quantityof our diet greatly aﬀect our physical conditionin various ways, including obesity and brain
function. Intestine also contains numerous numbersof immune cells and aﬀect immune-related diseases
such as allergies and inﬂammation. Thus, thecrosstalk in the intestine among diet, bacteria andimmunity plays a key role in the control of ourhealth and diseases.
Results obtained from research focusing on theintestinal environment will expand the possibilitiesof the healthcare industry, including precision7

nutrition that dietary methods tailored toindividual needs, personalized and stratiﬁed
nutritional guidance, drug discovery, andthe creation of functional foods.

Informatics analysis of human big data
set and elucidation of mechanisms byanimal models
Looking at an overview of our research, we
ﬁrst collect sets of human data in collaboration
with various regional partners in Japan.
Possible correlations among the collected data
are determined using the latest informatics
methodologies, and the resultant ﬁndings arethen validated using animal models. The
obtained implications are used to guide future
human studies. As we repeat this cycle, we
advance our research intended to improvehealth and prevent and alleviate disease interms of the intestinal environment (Figure.).
＊Research on humans and practicalapplications in society
In this project, we collect various data related tolifestyle (e.g. diet, exercise [physical activity],
sleep, etc.) and health (medications, healthcheckup data, disease history, etc.) from residents

of diﬀerent regions in Japan. We also collectblood, stool, and saliva samples to determine the
proﬁles of gut and oral bacteria, food metabolites,
immune parameters and so on. As of the end of
FY2023, we have created a microbiome database
containing data on more than 10,000 individuals,
making it one of the largest databases in theworld.
By analyzing this data, we are examining
regional characteristics of gut bacteria. For
example, we investigated the gut bacteria of theresidents in Shunan City, Yamaguchi Prefecture.
Compared with the national average, Shunan
City residents had higher percentages of
Bacteroides, bacteria preferentially like protein
and lipids. A food survey showed that theseresidents had a lower intake of dietary ﬁber than
the national average. To apply our researchﬁndings in practical settings, we provided
personalized guidance that took into accountthe other identiﬁed dietary characteristics.
Research has also suggested that increasing thevariety of gut bacteria may lower the risk ofvarious diseases. Since the ingredients in thefood we consume serve as the source ofnutrition for gut bacteria, a well-balanced dietis important for establishing a beneﬁcial gut
bacteria community. Our recent studies have＊Exploring the relationship between food andbiological functions
Dietary ﬁber is metabolized by multiple speciesof gut bacteria into short-chain fatty acids, which
serve as the source of energy for the cells lining
the colon. Furthermore, short-chain fatty acids
help regulate immune function, rendering the
body less obesity prone.
Prompted by these ﬁndings, we are conducting
cohort studies together with the University of
Yamanashi and private sector companies toinvestigate the health beneﬁts of barley, whichcontains a large amount of dietary ﬁber. It is
known that there are individual diﬀerences in theeﬀects of diet, such as the production ofshort-chain fatty acids. To reveal the underlying
mechanisms creating this individual diﬀerence,
we have created a machine learning model topredict the health eﬀects of barley and ﬂaxseed
together with the NIBIOHN s AI Center for
Health and Biomedical Research. By further
building on our ﬁndings, we hope to create asociety where we can propose a diet tailored toindividual intestinal environment. We have also
developed the Microbiota and Phenotype
Correlation Analysis (MANTA) platform, whichfacilitates the search for factors related to
speciﬁc health conditions. This platform enables
us to identify useful bacteria and metabolites

that help prevent or improve pathologic
conditions. Moreover, to explore the biologicalprocesses of gut bacteria, we conduct animalmodel experiments and test the hypotheses
made using the MANTA platform.
＊Discovery of useful gut bacteria that may
alleviate obesity and diabetes, and elucidationof their mechanism of action
Through veriﬁcation of prediction proposedby MANTA platform, we discovered Blautia
wexlerae, a useful gut bacterium with the potential
to prevent or improve obesity and diabetes. Blautia
wexlerae produce L-ornithine, acetylcholine,
and S-adenosylmethionine, which act to inhibit
fat accumulation and inﬂammation. In addition,by producing short-chain fatty acids (i.e., aceticacid), and amylopectin, which is an indigestible
starch, they work with other gut bacteria toimprove the intestinal environment to preventor improve obesity and diabetes. Based on thisﬁnding, drug discovery involving Blautia
wexlerae and their use in healthy foods could
help lead to a healthy society.
＊Relationship between cooking oil
consumption and allergy or inﬂammation
Based on our research focusing on the dietaryoils, we are searching for substances that may
inhibit allergies and inﬂammation. Our researchusing animal models have indicated that
1 7 , 1 8 - epoxyeicosatetraenoic acid (EpETE),
1 2 - hydroxyeicosapentaenoic acid (HEPE),

15-HEPE, and 1 4 - hydroxydocosapentaenoic
acid (HDPA) are produced by the action of
speciﬁc enzymes in various tissues after theingestion of ﬂaxseed oil, which potentiallysuppress allergies and inﬂammation in theintestines, respiratory organs, and skin via
their own speciﬁc mechanisms.
We have also discovered that gut bacteria andmicroorganisms in fermented foods use oil toproduce metabolites that suppress allergies andinﬂammation. One of them is called αKetoA. It
is a metabolite that only microorganisms can
produce and humans cannot. In collaboration
with Kyoto University and companies, we foundin animal models that αKetoA suppresses
allergic dermatitis and diabetes by preventing
macrophage-mediated inﬂammatory response.
Based on these ﬁndings, new drugs andfunctional foods could be developed in the future.

Figure. An Overall Framework of Intestinal Environment Research and Practical Application of Results

Collaboration with academic institutions
and hospitals to collect data fromhealthy individuals and patients

Realization of ahealthy societyComprehensive
community care system

Collection of humanbiological samples anddata in collaboration withpartners in different regionsof Japan

Advanced bio-informatics
to analyze various factors
Database creation(≥10,000 healthy persons)
Food, nutrition, exercise,
physical activity, sleep

Stool, blood, and saliva samples
Health-related data

Advanced analyticalchemistry of humansamples
Genomic analysis
Microbes, host genome, microRNA
Metabolome
Food components, drugs,
metabolites
Immunome
Immune cells, cytokines,
antibodies, etc.

Nursing care, health-supporting
pharmacies, primary-care
physicians

Individualized/
Stratified nutrition
guidance system

informatics
Artificial intelligence

Dissemination of newscientific information
Creation of new
industries
Revitalization of local
industries

Collaboration with othercohort studies (including
those overseas)8

An Introduction to Major
代表 的 研 究 紹 介
Research Project

Ⅲ

Research on Resources for Drug Discovery

mycoplasmas and no misidentiﬁcation of cells
in cells of human origin are practiced by cellbanks around the world to provide a minimum
level of quality. However, the Center is alsocharacterizing biological resources andconducting quality control inspections to meetthe needs of the times in order to provide
researchers with reliable and safe resources.
Amid this, we have recently been focusing oureﬀorts on virus screening tests in particular. We
have independently developed a technology thatcan easily screen cells for 20 types of viruses,
including DNA and RNA viruses, which were oflittle concern to researchers in the past, andwe are implementing measures to provide cells
while ensuring the safety of researchers usingthem.
Two of the Center s unique resources are a cellcollection of bioluminescent cancer cells and acollection of cells from patients with cancer-prone
genetic diseases (e.g., xeroderma pigmentosum

Center for Drug Discovery Resources ResearchCenter Director, Arihiro Kohara

Why did I focus on cell biology?
While synthesizing compounds on my own under the Faculty of Pharmacy at university and analyzing the effects they have on cells and animals from achemical perspective, I became fascinated by the mystery of cells as a research tool.

Supporting drug discovery research by providing high-quality bioresources.
Development and distribution of drug
discovery resources that lead to an
immediate response to emergencies
In 1985, the Center began providing various typesof biological resources, including cultured celllines, to researchers. Since then, it has collected
and catalogued a number of biological resources
to support basic research, and especially drug
discovery research, in Japan. The Center has
created a system to distribute more than 1,900
types of cell lines, and is also adding more than
40 new types of biological resources every year
in an eﬀort to meet the needs of researchers.
Researchers who wish to use our biologicalresources can easily request them through the

JCRB Cell Bank website. We have built a system
in which the biological resources ordered can bedelivered to researchers within the next week
so that research can begin quickly. This systemthat helps to rapidly facilitate various types ofresearch has grown into an operation that now
distributes as many as 6,000 samples annually.
The response to the COVID-19 pandemic stands
an example of how we were able to respond
immediately to an emergency with our steadily
maintained system of distributing biologicalresources. In collaboration with the National
Institute of Infectious Diseases, we led theworld in providing a cell line (JCRB1819:
VeroE6/TMPRSS2) for use in isolating andChanges in the number of newly catalogued cultured cellresources
Number of celllines collected

Number of celllines catalogued

2015

79

70

2016

43

93

2017

73

56

2018

106

40

2019

47

42

2020

88

40

2021

66

44

2022

65

46

Total

567

431

6094
Number of ampoules

9

FY

The number of distributions to researchers.

4474 4515 4602

2015

2016

2017

6524
5789

4690 4885

2018

2019

2020

2021

2022

growing SARS-CoV-2 starting in February 2020,
right after the pandemic started. This enabled
us to contribute to the development of a numberof vaccines, therapeutics, and other products.

Commitment to high quality
resources to maintain reliability
Compared to when the Center started providing
biological resources, science and technology haveadvanced dramatically today, and technologies
for testing cell characteristics and quality thatwere not available at the time are being updated
and developed on a daily basis. Currently,
no infection with microorganisms such as

Developing novel resources for drug
discovery with new technologies
The needs of users of biological resources for
drug discovery have changed over time. Whenthe cell bank was ﬁrst established, users could
request human cancer cell lines by specifying
the type of organ from which the cancer cells
were derived, i.e., I would like cancer cells
from X organ. When bioresources are obtained
today, the needs have become much moresophisticated, such as the need for a proﬁle on
cancer gene mutations or for veriﬁcation thattarget molecules are expressed and their levelsof expression levels. The Center is also working
to develop new bioresources in response to theneeds of the times.
Catalogued cell bank resources, which mainly
consist of cancer cell lines cultured twodimentionaly in containers, cannot accurately
mimic three-dimensional cancers in the humanbody. This is mainly due to the fact that the celllines have been developed based on the easewith which the cells are handled since only
cancer cells with the proliferative potential
suitable for cell culturing conditions arepassaged and grown. Such easy-to-handle celllines are cryopreserved and used by many
researchers as a research tool because they canbe used repeatedly and reproducibly. However,the limitations on developing drugs using only
cells that are easy to handle has become evident
in drug discovery research today, and there isa growing need for research tools that are
more like living organisms and pathologies.
When cancer patients previously underwent
surgery, the tissue was removed and thendiscarded. However, the Center is creating a
Human Tissue Bank so that consenting surgicalpatients can provide researchers with cancer
tissue and tissue around the cancer. We are also
developing technologies to prepare cells fromremoved tissue and to fabricate and cultureorganoids three-dimensionally in vitro. This willallow some drug discovery research to be
conducted under conditions more like thosein living organisms and more like actualand Fanconi s anemia). The bioluminescentcancer cells incorporate a ﬁreﬂy gene (luciferase)
to signal the presence of cancer when the cells
have been transplanted into mice. We are
Visualization of bioluminescent cancer cells
transplanted into miceendeavoring to improve cells information by
analyzing the characteristics of these cells and by
informing users of those results so that they
feel comfortable using these cells.

Identification of abnormal chromosomes via a chromosomal analysis

Transplantation of bioluminescent gastriccancer cells into the stomach wall of a mouse

Neurite outgrowth of iPS cell differentiation-induced neurons after thawing

New freezing method

Conventional method 1

pathologies. So far, we have used these technologies to develop models needed for drug discovery
research, such as an experimental system tomodel drug absorption in the intestinal tract andan experimental system to model drug metabolism in the liver. We are also developing moreadvanced models for drug discovery researchthat combine methods of eﬃciently inducing theOrganoids prepared from the intestinal tract

Conventional method 2

diﬀerentiation of stem cells (such as human iPS
cells) into target cells and technologies such as
genetic modiﬁcation. This approach has been used
to prepare vascular endothelial cells to model the
blood-brain barrier. Such functional cells should be
able to serve as useful models of the central
nervous system for drug development.
In order to more eﬃciently utilize variousorganoids and modeling systems, including those
newly under development, for drug discovery, wemust prepare the right amount when needed
while maintaining each function. Utilizing our
experience in operating the cell bank and theknowledge gained from this experience, theCenter is conducting research and developmentof cryopreservation technologies that can store
and use these cell masses in a state that retains
their original functions. This will be achieved
through the development of cell cryoprotectants
and freezing device. In order to accelerate thisresearch, we are actively collaborating with
universities and companies to promote multiple
joint research projects.

Facilities for preparation/storage of biological resources

Safety cabinet

CO2 incubator

Ampoule sealing machine

Resource storage ampoules

Liquid nitrogencryo sample storage

External liquid nitrogen tank10

Ⅳ

An Introduction to Major
Research Project

Medicinal Plant Resources

Research on germination conditions of
medicinal plants(Cultivation Laboratory, Tsukuba
Division)
Recently, there has been a rapid decline in wild
plant genetic resources. The Cultivation Laboratory of the Tsukuba Division stores seeds at low
temperatures in order to preserve valuable plantresources. Seeds will not germinate if the storage
conditions are not suitable, and the optimal
storage conditions vary according to the plant
species and varieties. Seeds of wild and cultivatedspecies are sealed in cans or polystyrene jars andstored for long term at 10°
C, -1°C and -20°
C. Thisallows us to examine the optimal storage
conditions for diﬀerent plant species andvarieties. To conﬁrm the survival of seeds, weregularly conduct germination tests of preserved
seeds. For those whose germination rate has
decreased, we continuously conserve genetic
resources by reproduction of seeds. As partof international academic cooperation, we havebeen engaged in seed exchanges with overseas
botanical gardens for more than 70 years (Figure.3).

Research Center for Medicinal Plant Resources
Center Director, Kayo Yoshimatsu

Figure 3:Seed storage (top left, bottom left), germination
test (top right), Index Seminum (seed list) sent
to overseas botanical gardens (bottom right)

Prior to starting research on plants
After passing the national civil service examination, I was hired as a researcher in the Breeding and Physiology Laboratory of the Center, which was anational research institute at the time, and started biotechnology research on medicinal plants. I was and still am fascinated by the mysterious power ofplants.

Maximizing the potential of medicinal plants tobenefit people’s health in the future
Enabling the broad use of
medicinal plants in Japan
Medicinal plants have been used in pharmaceuticals since ancient times. They are also indispensable for the research and development of pharmaceuticals, including Western medicines. Japan,
however, must rely on imports of these medicinal
plants from China and other countries, as only
about 10% of the raw materials of crude drugs
produced from medicinal plants are sourced frominside the country. The Center cultivates andpreserves more than 4,000 strains of medicinal
plants according to vegetation at three locations

Figure 1:Locations (temperature in 2022)
Location：
44°22’ north latitude
142°28’ east longitude
Altitude 98m
Temperature：
Average temp. 6.7°C
Highest temp. 32.1°C
Lowest temp. -25.4°C
Site area:
83,253㎡
Location：
30°32’ north latitude
130°27’ east longitude
Altitude 26m
Temperature：
Average temp. 19.0°C
Highest temp. 34.1°C
Lowest temp 3.8°C
Site area:
108,693㎡

11● Cultivation Laboratory● Breeding andPhysiology Laboratory● Medicinal Plant
Screening Project
Location：
36°01’ north latitude
140°04’ east longitude
Altitude 26m
Temperature：
Average temp. 14.8°C
Highest temp. 37.4°C
Lowest temp -7.2°C
Site area:
45,814㎡

in Japan (subarctic, temperate, and near subtropics) (Figure.1). We regard medicinal plants asimportant assets and believe that it is our responsibility to make them available when needed andto pass them on to future generations. We areconducting various research to achieve this. In
addition, we supply seeds and seedlings to
research institutes in Japan and provide instructions on their cultivation techniques.

Preserving northern plants andbreeding ofsuperior medicinal plant varieties
using an expansive field(Hokkaido Division)
The Hokkaido Division has planted more than
1,000 strains of medicinal plants, mainly thosethat grow in cold regions, in herbarium garden,arboretum, useful plant garden for the Ainu
people, and research ﬁeld. These plants are used
for research on the cultivation of medicinal plants
and research and development of pharmaceuticals, functional foods, and others. We have also
been working on breeding medicinal plantvarieties suitable for the production of pharmaceuticals. So far, we have bred and registered a totalof seven medicinal plant varieties such as
coixseed, peony, glycyrrhiza, and perilla (Figure.2).

Figure 4:Plant tissue culture (top) (middle: Panax ginseng, right: Bupleurum falcatum) and planting work on
a clean bench (bottom)

Preserving tropical, subtropical andtemperate medicinal plants andLeading commercial production of
those difficult to obtain(Tanegashima Division)
Tanegashima has many plant species andvarieties including southern limit, northern limit
and rare plants and many of those are used as
medicines. The Tanegashima Division preserves
and propagates these medicinal plants. Some
crude drugs are diﬃcult to obtain from overseas
and should be produced domestically, such as
Rauvolfia serpentina, which is used in the tradition-

al Indian medicine of Ayurveda and whose roots
are also used in Japan for its hypotensive eﬀect.
Currently, this species is listed in CITES Annex
II due to declining stocks in India, a major production area. This makes it impossible to obtain theplant from overseas. Since 1950s, the Center haspreserved and cultivated the species in the ﬁeldsof the Tanegashima Division. Currently, we aretrying to establish a sustainable crude drug
production system for Rauvolfia serpentina by
reducing labor and enhancing eﬃciency in eachprocess, from seed to crude drug production. A
stable supply of Rauvolfia serpentina preparations
is helpful to reduce hypertension (Figure.5).

Figure 5:Examples of native medicinal plants in Tanegashima (top:Artemisia capillaris, Citrus tachibana, Prunus persica)
and an example of difficult-to-obtain medicinal plants (bottom:Rauvolfia serpentina)

A medicinal variety of coixseed known as
Kitanohato , which can be cultivated even incold regions, has been successfully producedin Hokkaido. It is widely used not only forpharmaceuticals, but also for quasi-drug lotions
and edibles. A medicinal variety of peony called
Benishizuka is actually produced in Okayama
Prefecture, and Yumesaika in Akita Prefecture. We are developing cultivation techniques,
such as optimization of fertilization and planting
conditions, mechanization of weeding and harvesting work, and testing expanded applications ofregistered pesticides. We are also attempting
to create cultivation manuals and disseminate them to production sites.
Figure 2:Medicinal plants bred and registered as
medicinal varieties at our Center

Kitanohato (coixseed)

Variety registered in 2007

Kitasaisho (peony)

Benishizuka (peony)

Variety registered in 1996 Variety registered in 2015

Glu-0010 (Glycyrrhiza) SUPACOR (Glycyrrhiza)
Variety registered in 2017

Yumesaika (peony)

Variety registered in 2021

per-001 (Perilla)

Variety registered in 2023 Variety registered in 2020

Plant biotechnology contributing to thestable supply of medicinal plantresources(Breeding and Physiology Laboratory,
Tsukuba Division)
In order to realize a safe, secure, and stablesupply of important medicinal plant resources,
the Breeding and Physiology Laboratory of the
Tsukuba Division conducts research on themaintenance, preservation, and quality improvement of medicinal plant resources using plantbiotechnology, and their application in pharmaceutical production. Plant tissue culture is a coretechnology of plant biotechnology that utilizes
the ability of plants called totipotency thatallows plants to regenerate into a complete plantfrom any part. The Breeding and Physiology
Laboratory uses this technology to cultivate andmaintain a wide variety of plants, each with thesame genetic background, as clones of 300
species and strains in an aseptic environment.
These plants are expected to play an importantrole as a source of healthy and high-quality
seedlings of important medicinal plants requiredfor domestic production (Figure. 4).

Artemisia capillaris
Medicinal part:capitulum
Indications:Choleretic, anti-inflammatory,
diuretic

Citrus tachibana
Medicinal part: pericarp of mature fruit
Indications: aromatic stomachic,antiemetic, antitussive, expectorantPrunus persica
Medicinal part: seeds and leaves
Indications: antibacterial, anti-inflammatory
and anti-blood-stasis, drainage,
emmenagogic, laxative

Rauvolfia serpentina
Medicinal part: roots
Indications: hypotensive, sedative

Medicinal plant screening project
Our planet is believed to contain some 270,000
plant species. However, the use of natural
resources overseas is becoming more diﬃcult
every year due to the Convention on Biological
Diversity and other factors. In this project, morethan 10,000 extracts (representing more than
3,000 plant species in terms of scientiﬁc name)prepared mainly from plants growing in Japanare stored and maintained as dimethyl sulfoxide(DMSO) solutions at -20°
C. They are provided toresearch institutions in various research anddevelopment ﬁelds such as pharmaceuticals,
cosmetics, health foods, and agrochemicals, andso on. Our eventual goal is to commercialize theactual products utilizing these extracts.

Figure 6:Collection of wild plants (top) (left, middle),
extraction equipment (top right), and DMSO
solution of plant extracts stored at -20°C(bottom left) and biological activity evaluation
using plant extract library (anti-cancer activity
evaluation: bottom middle, right)）

12

An Introduction to Major
Research Project

Ⅴ

Biological Resources Researchreared aseptically at our center are unparalleledin terms of quality and population.

Providing experimental animals andtechnological support
to help streamline drug discovery
We do more than just supply pharmaceuticalcompanies and academic institutions with NHP.
We provide contract research services andconduct outsourced experiments using monkeys
at our facilities. We accept only studies deemed
appropriate by our internal evaluation committee. Besides supplying primates, we can provide
researchers with a wide range of resources andservices, such as computed tomography scans,anatomy, experimental skills, and expertise.
Through these services, we support drug
manufacturers to accelerate and reduce thecost of drug discovery.

Combating intractable diseases, rarediseases and infectious diseases with noestablished therapy

Tsukuba Primate Research Center
Center Director, Yasuhiro Yasutomi

Day-to-day research activities
Research using Nonhuman Primates (NHP) covers many areas, from basic research to practical applications in medicine, with the ultimate goal being
disease control. In this way, medical science research using NHP aims to control diseases starting with basic research and shed light on the ﬁnal phaseof disease overcome. To reach this future goal, we are building drug discovery technology platforms, conducting research on the creation of animalmodels for human diseases using NHP, and furthermore, the development of vaccines with the best possible effects on global public health.

Supplying Quality Nonhuman Primates for Medical Research andUsing them to Conduct Independent Medical Research
NHP for medical experiments are
essential for drug discovery
A variety of evidence is needed, from drug
development and research to the provision of
those drugs to society. Among these, experiments for conﬁrming eﬃcacy in animals before
clarifying it in humans are an indispensable
part of that process. Testing in NHP, which
are closely related to humans, is particularly
crucial to drug discovery. As the export oflaboratory NHP from other countries has
ground to a halt since the pandemic, NHP for
medical experiments are becoming increasingly important to drug discovery in Japan.

Breeding SPF monkeys with an
unparalleled pedigree
to secure a population of elderly monkeys
The Center is the only facility in Japan providing cynomolgus macaques for medical science.
It has established a system for maintaining andsupplying quality cynomolgus monkeys as a
research resource, and is conducting medical
research using primates from the individual to
the genetic level.
After I took up my position as the center director
in 2007, we started breeding speciﬁc pathogen

13

free (SPF) monkeys that cannot compromise
research integrity. We have documented thebackground data, including rearing history,
pedigree, and laboratory test results, of allmonkeys bred at our center. The breedingbuilding holding SPF monkeys was at 14.0%
capacity in 2007, reaching 88.9% by the end of2022, a level close to the feasible upper limit(Graph 1).
Since my appointment as director, I have beenstressing the importance of planning several
decades ahead to ensure a stable supply of elderlymonkeys. Although this is an arduous task, elderlymonkeys are a valuable research asset which is
absolutely necessary in the rapidly aging world.
The colonies of elderly monkeys that have been

Our research targets diseases for which nostandard therapies have been established andthat should be addressed by public research
initiatives. Our monkeys have well-documented pedigree records. Therefore, when monkeys
spontaneously develop a certain incurable
disease, we can investigate the genetic likelihoodof the disease appearing in the oﬀspring born tospeciﬁc parents. For example, we have naturally
developed experimental NHP models of retinal

macular degeneration, dilated cardiomyopathy,
and other rare diseases. These models enable
us to track the disease course from theirpresymptomatic stages and to analyze pathological changes over time. We are also developing
animal models of experimentally induced
disease, focused mainly on infectious diseases.
Our recent achievements involving monkeys
include the establishment of an in vivo COVID-19
evaluation system. This simian model can be used
for the pharmacological evaluation of candidate
COVID-19 therapies. Based on these foundations,in 2023, we reported that the coronavirus is also
eﬀective in monkeys using the ACE2 protein,which is also an infection target, as a treatmentthat is eﬀective against the mutant virus(Omicron strain) for which antibodies havebecome ineﬀective.
We are also investigating a cynomolgus monkey
model of vertically transmitted human T-cellleukemia virus type 1(HTLV-1) infection because
this represents a disease that Japan must
address. Japanese individuals account for 10% of
patients infected with HTLV-1 worldwide. Japanis the only developed country with a highprevalence of this disease. The disease is vertically transmitted to infants through breast milk, andvirus carriers have a 5% lifetime risk of leukemia.
No cure is available, and no useful animal models
of disease have existed. We succeeded inestablishing the world's ﬁrst primate model of
HTLV-1 infection by artiﬁcially inseminating
female cynomolgus monkey infected with
HTLV-1. When the oﬀspring of the infectedmonkeys were being weaned, we replaced themwith newborns born to monkeys that were notinfected with HTLV-1. We examined whether an
infection was acquired via breast milk lacking
maternal antibodies. Our study using this modelis in its early stages. It will play a crucial rolein developing new vaccines and other drugs for
HTLV-1 infection.
In addition, we have created an attenuated AIDS
virus incorporating an adjuvant molecule, and weare developing and researching a vaccine technology that could lead to a cure for HIV. We are also
conducting research to evaluate this technology
using primates. We plan to embark on a humanclinical trial after the simian study is successfullycompleted. While patients with AIDS currently
need to take drugs for the rest of their lives, avaccine that could cure HIV is highly anticipatedby researchers and patients around the world.

Infectious Disease Experimental Facility to Support Advanced Basic Research:
Animal Biosafety Level (ABSL)-3

Graph1. Chronological Changes in the Numbers
and Percentages of High-Quality
SPF Cynomolgus Monkeys Produced％

Numbers of monkeys
1600

Numbers of monkeys

1400
1200
1109

1000

1205

1271

1335

1361

100

%

・90

1396

・70
・60

1013

・50

800

・40

600

・30

400

・20

200
0

・80

Biosafety level (BSL)-3 laboratory

BSL-3 animal housing room

Cynomolgus monkey
housing cages

Shower room

・10
2016

2017

2018

2019

2020

2021

2022

0

FiscalYear

Number of Cynomolgus Monkeys Produced and Supplied Each Year
Category
Number of monkeys
produced

2016

2017

2018

2019

2020

2021

2022

210

219

214

210

222

211

189

Normal monkeys

189

187

143

196

163

154

206

Number of monkeys
Special monkeys*
supplied

8

24

15

4

10

10

2

197

211

158

200

173

164

208

Total

*Special monkeys include: fetuses; pregnant, elderly, and newborn monkeys; and monkeys with macular degeneration, heart disease, diabetes, etc.

An autoclave

Biosafety suits

Wastewater processing equipment

14

An Introduction to Major
Research ProjectⅥ

Nutrition Science

A life-course based approach for the
100-year-life era

National Institutes of Biomedical Innovation, Health and Nutrition Executive Director,
National Institute of Health and Nutrition Director,
Department of Nutritional Epidemiology and Shokuiku Chief, Hidemi Takimoto

As described above, we are engaged in various
research activities from the viewpoint of
nutritional epidemiology. We are also conducting research to help people live long andhealthy lives in the coming 100-year-life era,
where health-related quality of life will be morevaluable than mere gains in longevity. Nutritional
requirements diﬀer by diﬀerent life stages andconditions. They diﬀer between newborns andelderly people, between ill and healthy persons,and between pregnant and nonpregnant women.
Children require nutrients that help them grow.
Many adults need to control the risks of lifestylediseases. Elderly people may need nutritional
support to maintain and improve their physicalperformance and cognitive functions. This
life-course based approach to physical wellbeing,
involving life stage-speciﬁc nutritional interventions, is becoming more important.
In human lives, conditions in a given life stage
aﬀect the conditions in the next generation. As
current children will eventually become parents,
and they may face greater challenges in raising ahealthy next generation if they are not healthy
enough. Similarly, the health conditions in middle
age will signiﬁcantly determine those in older
age. Focusing on the dietary patterns of

Nutrition Intake Recommendations Presented in the Dietary Balance Guide

想定エネルギー量2,200kcal±200kca（
l 基本形）

pregnant and nursing women, we worked with
the Ministry of Health, Labour, and Welfare todevelop the Dietary Guidelines for Prepregnant,Pregnant, and Nursing Women, this work wasdone as part of the Investigation for SupportingChild Development and Rearing Program and ispublicly available from NIBIOHN's website(Photo 3). We are also involved in an MHLW
Scientiﬁc Research Project to examine theplans for the National Nutrition Survey onpreschool children, which is conducted every
10 years to monitor the nutritional status of
infants and toddlers.

Why I started this research
I was previously an obstetrician and gynecologist. A pregnant woman who I saw for a routine health checkup asked me, “What should I eat during
pregnancy for my baby?” I was shocked because I couldn't answer. This is what led me to research nutritional science.

Promoting Lifelong Health Through Healthy Eating: Investigation andAnalysis of Food and Nutrition Intake Among Japanese People
Exploring the scientific basis ofnutrition for a healthier future
To clarify the health eﬀects of diet and nutrition,
our department conducts epidemiological studies
on nutrition. There are several foundations forour research, including the National Health andNutrition Survey (Photo 1) conducted annuallyby the Ministry of Health, Labour and Welfare.
Initiated in 1945, this national survey, which has
amassed more than seven decades of ﬁndings,
now covers not only dietary intakes, but also
daily physical activity, height, weight, blood
parameters, and lifestyle factors such as smoking
and alcohol consumption of the people of Japan.
These results provide important scientiﬁc

evidence that informs national guidelines, as well
as recommendations regarding the types andamounts of nutrients that should be taken daily
for healthy living. These results are also used tomonitor achievement of the goals proposed in thenational health promotion plan, Health Japan 21(the 2nd term).
The Laboratory of Nutritional Epidemiology
aims to establish scientiﬁc evidence to help
extend the healthy life expectancy of the
population, and it conducts research to ascertain
the relationship between diet and non-communicable diseases and health problems using
various large-scale datasets in collaboration with
universities and research institutes here in Japan

Related Publications

Photo 1. National Healthand Nutrition Survey

15

Photo 2. Dietary Reference
Intakes for Japaneseand overseas. We are focusing on researchon the relationship between protein intake
and frailty in the elderly (in collaboration
with entities such as the National Center for
Geriatrics and Gerontology) and on therelationship between polyphenol levels inthe blood and colorectal tumors (in collaboration with entities such as the National
Cancer Center Japan and Kyoto University).
In the future, we will also propose a diet thattakes both the environment and health into
account in order to achieve the Sustainable
Development Goals (SDGs).
Furthermore, our data on nutrition intake wereused to develop dietary guidelines presented in
the Dietary Reference Intakes for Japanese (Photo 2).
We aim to improve those guidelines by compilingresearch on the people of Japan with regard tocreating the scientiﬁc basis for nutritional
intake, so as to prevent healthy people fromsuﬀering from diseases caused by nutritionaldeﬁciencies or lifestyle-related diseases, and also
help people to prevent their current condition
from deteriorating. Where evidence is lacking,we will conduct further research. The Dietary
Reference Intakes for Japanese are used as
standards in various settings, such as meals in
facilities, cafeterias, and hospitals. Improving theguidelines will lead to better meals being servedin schools and other settings.

Guidelines on desirable eating habits for expectant mothers:
A practical application of research findings
The purpose of this publication was to addressa particular challenge identiﬁed by the National
Health and Nutrition Survey. This survey
reported a high prevalence of underweight(body mass index <18.5) among women in their
20s and 30s, who are in their reproductive age.
There have been little improvements in thisprevalence since the previous edition of the
dietary guidelines was published 15 years ago.
Pre-pregnancy underweight can have negativeeﬀects on pregnancy, postpartum recovery, andfetal and infant development. From the perspective of life-course management, underweight inyounger ages may cause women to be susceptible to physical frailty as they grow older.
A major diﬀerence between the ﬁrst and second
editions is that whereas the ﬁrst edition
addressed pregnant and postpartum women
only, the second edition also includes women
expecting pregnancy, and encourages them todevelop and maintain physical wellness in
preparation for pregnancy. Speciﬁcally, thecurrent guidelines have 10 key recommendations, including a well-balanced diet, suﬃcientenergy intake from staple foods, side dishes
to supplement the most commonly deﬁcientvitamins and minerals, tips for calcium
intake, and appropriate weight gain during
pregnancy.
Our guidelines and recommendations area practical help in community settings. For
example, they are used by public health nurses
and dieticians who support expecting mothers
and babies during pregnancy and by parentingclasses hosted by local health centers. They arealso included in the Maternal and Child Health
Handbook and education brochures provided by
local municipalities. In these ways, the results ofour research are being shared through various
means and media.

Academic Collaboration:

Photo 3. “Dietary Guidelines for Prepregnant, Pregnant,and Nursing Women”(https://www.nibiohn.go.jp/eiken/ninsanpu/)

registered and then interviewed by nutritionists to record their daily

A Joint Study with Tokyo Medical and Dental University

meals. Other members of the research team include dietitians,

Partly because I started my career as an obstetrician andUniversity's Medical Research Institute conduct genetic analysis.

gynecologist, my research interests include dietary intakes andAlthough clinicians understand the important role of nutrition andplacental development in pregnant women. With the assistance of

diet in health, they face challenges in making dietary advice in

the Tokyo Medical and Dental University Hospital, I conducted aclinical practice. We hope that the ﬁndings of this study will be usedcohort study in which approximately 200 pregnant women werein clinical practice to improve womenʼs health conditions.

obstetricians, gynecologists, and pediatricians. Researchers at the16

Ⅶ

Physical Activity

physical activity and exercise against frailty andto implement the results not only in research but
also in society at large.

Department of Physical Activity Research
Chief, Rei Ono

Why I decided to begin my research at NIBIOHN＊A study on healthy longevity in Kameoka City,
Kyoto Prefecture
Kameoka City has developed a program toprevent the need for nursing care in the community and is testing its eﬀectiveness. The methodof the program's implementation has been
veriﬁed in the short term. Elderly participants
who attended a weekly exercise class werecompared to a group who exercised at home todetermine if either had an increase in motor
function or muscle mass. The results indicatedthat both groups saw an increase in motor
function or muscle mass. In addition, a publiccourse was conducted to train assistants toprevent the need for nursing care in conjunction
with public education about the program. Someof those assistants later established an NPO, andthey have continued to provide support to theclass participants even after the study concluded. In addition, research results in this ﬁeld
recently revealed that elderly people who walk
more, who consume more protein, and who eat ahigher quality diet are less likely to be frail andthat elderly people with a higher or lower BMI(an indicator of one's physique) than normal are
more likely to be frail. Moreover, the results also
showed that people with a larger sphere ofThrough working at the hospital, I realized the importance of physical activity for patients returning home and improving their prognosis, and I became
interested in research on physical activity (exercise). NIBIOHN is the only institution in Japan that can conduct research on physical activity and reﬂect it inpolicies through guidelines, and I started working there because I thought it could greatly contribute to improving the physical activity of the people.

Improving the public’s physical activity and exercise habits through guidelines
on exercise and accurate assessment of physical activity
To improve people’s physical activity
and exercise habits through exercise
guidelines
In Japan, the National Health and Nutrition
Survey (known as the National Nutrition
Survey until 2002) has been conducted since
1989 to assess the level of physical activity among
the people of Japan. The survey uses pedometers
to measure the number of steps taken by people
in a day. The survey has been conducted continuously and on a large scale, and it provides
important data on trends in physical activity forreference around the world. The Department of
Physical Activity Research has been engaged in
two major eﬀorts to help increase the number ofsteps measured in the National Health andNutrition Survey.
The ﬁrst is to disseminate information to improve
the public's physical activity and exercise habits.
In order to share evidence-based information,
academic papers on physical activity, exercise,
physical ﬁtness, and health from aroundthe world have to be collected and analyzed(literature reviews and meta-analyses). We areresearching the relationship between physicalactivity; exercise, and physical ﬁtness and healthoutcomes. Based on the evidence obtained, we
have drafted exercise guidelines such as
Exercise and Physical Activity Reference
for Health Promotion (EPAR) and the Active

17

Guide (physical activity guidelines) to provide
information to the public to improve their
physical activity and exercise habits.
The second eﬀort is to develop and validate
methods of assessing the level of physicalactivity. Over the last few years, assessment of
the level of physical activity, as typiﬁed by the
number of steps taken, has been based on values
obtained by processing signals from an accelerometer built into each pedometer. However, apedometer can be located in various places on ornear the body, such as one worn on the waist, on
the arm, or built into a smartphone. In otherwords, even if the number of steps taken is thesame, one can never know whether or not it
accurately reﬂects the actual number of steps
taken depending on the method of measurement. The Department of Physical Activity
Research is verifying the validity and accuracy of the values from each model of pedometerin order to allow continuous assessment oftrends in the number of steps taken according
to the National Health and Nutrition Survey
and to facilitate physical activity research inother ﬁelds.
Following the spread of COVID-19 beginningin 2020, lockdowns and other restrictions on
activities were imposed around the world. A
survey we conducted found that the objectively observed level of physical activity wassigniﬁcantly lower in the Tokyo metropolitan
area than in rural areas due to the declaration ofa state of emergency in April and May 2020 inJapan. As evidence-based policymaking isincreasingly being emphasized, we hope thatmonitoring changes in the physical activity ofthe public in this manner will continue to play animportant role in policymaking at the national
and local levels.

＊A study on preventing frailty among theworking-age population in Osaka Prefecture
The Department of Physical Activity Research,
together with the Osaka Prefectural Government, is developing a lifestyle modiﬁcation
program to prevent frailty. As part of the
program, a survey on frailty featuring a basic
checklist was conducted. Results revealed acertain percentage of both the elderly as well asworking-age people in their 40s and 50s were
frail and that respondents who were familiar
with the term frailty were less likely to be frail
than those who were unfamiliar with the term.
In 2022, the program conducted frailty checks atcompanies during speciﬁed health exams. Thesechecks revealed that a certain percentage ofworkers were frail. We aim to prevent frailty inthe long term by increasing the awareness offrailty among the working-age population.
Assessment by the basic checklist

City of Settsu

40s

50s

60s

A new approach:The human water turnover

City of Hannan

70sOver 80 yearsof ageWater is constantly needed to sustain human life
and to facilitate blood circulation and physicalThe devised formula for calculating
the human water turnover in an adult

Identification of modifiable factors toprevent frailty, from research to
implementation in society at large
Japan has the world's highest rate of aging, andthe world is looking to see how Japan will copewith a super-aged society. As people age, their
physical and mental vitality (e.g., motor andcognitive functions) declines, and their vitality
can be aﬀected by the presence of multiple
chronic diseases. This can lead to impaired dailyfunctions and greater susceptibility to mental
and physical frailty. This condition is known as
frailty. Frailty is a decline in daily functions
common to old age, but daily functions might bemaintained and improved through early
detection of frailty and appropriate interventions
and support. The Department of Physical
Activity Research is working with local governments to ascertain the relationship between

activity in daily life had a lower risk of mortality
and that leaving the house to run errands in thecity at least one to three times per week did not
see any change in their risk of mortality. The
evidence generated by the local community is
helping to extend healthy life expectancy notjust in Kameoka City but in the rest of Japan.

Prevalence of individual with frailty

An Introduction to Major
Research Project

Factors due to lifestyle
Physical activity

SportsHumandevelopment
index

Age

Human water turnoverSex

Air temperature

Humidity

Lean body mass

WeightFactors due to physiqueactivity. Thanks to previous studies, the stockof water in the human body can be determined.
Perhaps surprisingly, determining the ﬂow ofwater in and out of the human body has beendiﬃcult. The Department of Physical Activity
Research has integrated data measured inJapan and in various countries and it has used
a technique known as the doubly-labeledwater method to devise the world's ﬁrst
formula for predicting water turnover in
adults. The resulting approach can be used toformulate guidelines for water intake toprevent dehydration during physical activity.
This research has been published in aninternational journal and it has attracted
worldwide attention. The United Nations
estimates that about one-third of the world's
population lacks safe drinking water at home
and water shortages are becoming a more
pronounced problem, especially in developing
countries. Thus, this predictive formula could
be used to formulate strategies to allocate
drinking water and food in the event of adisaster or emergency in diﬀerent countries
and it could be used to create models to predictwater shortages due to population growth andclimate change around the world.
In addition, this research will open up new
avenues in this ﬁeld, such as examining therelationship between dementia and frailty andthe metabolic turnover of water

Elevation

Factors due tothe environment
18

Introduction of researchers passionately engaging in research from new perspectives

I started my research activities at NIBIOHN soon after
obtaining my degree from the Graduate School of Engineering. I have been developing nucleic acid drugs with the hopeof making a diﬀerence in the lives of patients suﬀering fromincurable diseases without any known eﬀective treatment
option.
There are two types of nucleic acid drugs: antisense
oligonucleotides and siRNAs that act on nucleic acidmolecules, and aptamers and decoy nucleic acids that act onproteins. By taking advantage of the characteristics of each,
all molecules in the body can be targeted for drug
discovery. Therefore, in theory, there are no restrictions on
the target disease. This is the greatest appeal of nucleic
acid drugs.
So far, we have succeeded in improving the functionality of
aptamers by introducing artiﬁcial nucleic acids (xeno nucleic
acids; XNAs) and developing new methods to create them.
We have also designed and developed highly active andlow-toxicity antisense oligonucleotides from an engineering
perspective, and created therapeutic drug candidates for
intractable diseases. Antisense oligonucleotides for peritoneal
dissemination of gastric cancer are in the ﬁnal stage ofpre-clinical testing. We are conducting research so that they
can be delivered to patients as soon as possible.

Gapmer-type antisense oligonucleotides

Enhances binding afﬁnity to target RNA
using artiﬁcial nucleic acids
Forms a double strand with target RNA andinduces degradation by RNaseH
artiﬁcial nucleic
acids

Phosphorothioate
linkageDNA

Developing an antisense oligonucleotide targeting
peritoneal dissemination of gastric cancer

Antisense oligonucleotide
candidate

0.8
0.6

Aptamer

Target molecule(proteins, etc.)

Complex formation

Structure-speciﬁc binding to target moleculesand control of their functions by forming
intramolecular structures
Developing a drug delivery systemusing aptamers
Select sequence that
migrates into the cell

Only antisense
oligonucleotide

Conjugate withthe aptamer

Migrate

0.4

Nucleus0.2
0.0

Utilizing diﬀering macro- and micro-level information to conduct data-driven
drug target discovery

Aptamers

Survival analysis (each group n=8)
1.0Survival rate

Capitalizing on an engineering perspective to develop nucleic acid drugs withlimitless potential!

Cytoplasm

Control group0

10 20 30 40 50 60 70 80 90 100

Survival days (after seeding)

Top photo: control group
Bottom photo: antisense oligonucleotide candidate
K. Tanaka et al. Mol Ther Nucleic Acids, 2020

Blue: nucleus
Green: antisense oligonucleotide

Application as a delivery tool to improve
cellular uptake of antisense oligonucleotides

The inability to conﬁrm the eﬃcacy of drugs in human isthe culprit behind the high rate of failure in many clinical
trials. In response, we have started the development oftechnologies and data analysis methods for drug discovery targeted searches utilizing human derived medical
information and omics data.
While the acquisition of medical information (macro-level
information at the individual level) and omics data
(micro-level information at the molecular level) is signiﬁcant,the content and format of the two are diﬀerent, and it isdiﬃcult to determine a connection between them throughanalysis. Therefore, we developed an analysis technology
with RIKEN that can ﬁnd related item groups. In joint
research with Osaka University, we succeeded in ﬁnding
drug discovery target candidates and their inhibitors for
idiopathic pulmonary ﬁbrosis.
We believe that this approach can be applied to all diseases.
Especially in the case of intractable diseases, we can search
for important factors without relying on previous knowledge.
This is why I feel a deep sense of calling in fulﬁlling thehopes of patients who are suﬀering.

Data-driven drug target discovery
This process can be applied to any disease

Indication of drug
targets
Analysis by AI(subset binding)Creation of a database
Medical information
Omics data

Further expansion of target diseases and availability ofpre-emptive and personalized medicine

K. Tanaka et al. Mol Ther Nucleic Acids, 2020

Working on unique and importantresearch using primates only possible
at NIBIOHN

Focusing on exosomes in the blood, weare developing technologies for less-invasive approaches to diagnosis andpathology monitoring

Laboratory of XNA Screening and Design
Center for Drug Design Research
Project Leader Yuuya Kasahara

Disease discovery using proteome analysis

Laboratory of Bioinformatcs
Artiﬁcial Intelligence Center for Healthand Biomedical Research
Project Leader Yayoi Natsume

Infectious disease research using cynomolgus monkeys
HTLV-1 infected
cynomolgus monkey model

Catalog of blood EV proteins

HTLV-1 infected cynomolgus monkey
model using ATL-040 cells with hightransformation ability in vitro

Experimental primate
cynomolgus monkey

SARS-CoV-2 infected
cynomolgus monkey model
Comparative study using both young and elderly
individuals conﬁrmed changes in viral pathology
are similar to those seen in humans

Syncytia formation
using ATL-040 With Jurkat cells
cells

Establishing puriﬁcation methods for eachtissue-speciﬁc extracellular vesicle (EV)

Brain

Lungs

Optic nerve Pancreas

Muscle

Liver

Heart

✓ Most genetically related to humans✓ Have characteristics similar to humans✓ Similarity in physiological functions andanatomical structures

HTLV-1 infection by intravenous
inoculation
ATL-040 cells: 1x108 cells

Elderly individual D5

Elderly individual D5

Elderly individual D12

infections

Throat swab viral load
Viral load in young individual
Viral load in elderly individual
Viral titer value in young individual
Viral titer value in elderly individual

Elucidation of viral dynamics
and pathology

LiverdiseaseEnabling early disease detection
and monitoring of disease state

19✓ Similarity in susceptibility to various

Provirus amount inperipheral blood
lymphocytes

Visualizing changes in each tissue
Neurological disease

Young individual D5
Chest infection

Alone

When I arrived in 2016, I became involved in primate
research. I was fascinated by the clever survival strategiesof viruses, and although I have been mainly researching
HIV since my university days, I had no experience in
conducting experiments with animals, so I started oﬀ
somewhat perplexed.
I was ﬁrst involved in a study to establish a primate
model for HTLV-1. HTLV-1 is a retrovirus, as is HIV,but because of its distinctive characteristics, we set up
an analysis method and launched primate experimentsin parallel. As a result, we established the world's ﬁrst
HTLV-1-infected nonhuman primate model.
As for COVID-19, an elevated risk of severe illness has beenreported in the elderly. By adding elderly primates, which
are a valuable research resource worldwide, we haveshown that the cynomolgus monkey model reﬂects thehuman COVID-19 pathology well.
Both models are also useful as evaluation systems for
drug development. We are now evaluating the eﬃcacy
of multiple vaccines and therapeutics. In the future, wewill continue to pursue research responsibly that is thecornerstone of preclinical studies and can only be
performed by us at NIBIOHN.

Chronic example

When I was studying abroad, I came across neurologicaldisease research, and I was intrigued by the diﬃculty andinteresting nature of the ﬁeld. Neurodegenerative diseases
are important diseases in Japan, where the population
is aging. Many therapeutic drugs are expected to be
developed in the future, but the key is being able to stratify
patients who respond to treatment.
In recent years, exosomes circulating in the blood stream
have been in the spotlight in the development of biomarkers. Diagnosis by blood is minimally invasive, and there isa strong likelihood that changes in the pathology can bedetected instantaneously.
Through proteomic analysis of blood exosomes, we
identiﬁed candidate tissue-speciﬁc exosome markers. We
believe that the establishment of brain-derived exosome
puriﬁcation technology will lead to the diagnosis andsuppression of the onset of neurodegenerative diseases.
Although challenges are emerging one after another, I am
conducting research with the excitement of discovering
unknown phenomena with the priority of rolling out myﬁndings for patients as soon as possible.

Previous efforts have indicatedthat drug targets can be discovered
using medical informationand omics data.

Heart
diseaseLaboratory of Proteomics for Drug Discovery
Center for Drug Design Research
Senior Researcher Satoshi Muraoka

Establishment of evaluation
system/drug development

Tsukuba Primate Research Center

Senior Researcher Emiko Urano
20

Introduction of researchers passionately engaging in research from new perspectives
Introduction of researchers playing anactive role in each NIBIOHN laboratory
Research on Related factors inﬂuencing appropriate dietarybehaviour for healthy eating habits
With the enactment of Japan s Basic Act on Shokuiku (Foodand Nutrition Education), I have asked myself the question,"What is eﬀective dietary education?" and have been examining factors related to the diets and eating behavior among
Japanese. In particular, my starting point was the desire to
elucidate the inﬂuence of nutrition knowledge on diet.
First, I started developing a questionnaire to evaluate thenutrition knowledge for Japanese adults . I initially struggled
somewhat because I had to review materials from Japan andother countries. However, the completed questionnaire is
now widely used and I am pleased that I developed it.
Currently, I have also been examining factors related to dietby life stage and course and the appropriateness of nutrient
intake for the working population. In addition, I have been
evaluating the appropriateness of nutrition and food information spread on social media.
Additionally, I am engaged in research to realize healthyeating habits by examining food issues through verifying theaccuracy of the National Health and Nutrition Survey andsupporting the formulation of health promotion plans.

Examination of factors related to Japanese diet and eating behavior
Do the sources of salt intake differ among Japanese adults by age?
Participants : 95,581 Japanese adults over 20 years old who participated in
the National Nutrition and Health Survey from 2007 to 2019
(43,129 males, 52,452 females)

20-39 years old

Males

12.1 g/day

12.4 g/day

10.5 g/day

10.7 g/day

11.4 g/day

Females 9.5 g/day
8.6 g/day

Top row：2007
Bottom row：2019

Components of human water turnover
Feces

Water / drinks

Stored in
the body

9.1 g/dayGrains

9.8 g/day
Vegetables

Seafoods

Meat

Seasonings

Overview of Research (Aim of Research on Digestion/Absorption Rates)
What affects differences in thedigestion/absorption rates as
determined from feces and urine?

What is the adjusted response of digestion/absorption
rates when different energy amounts are in balance(overeating, etc.)

Reviewed determining factors of digestion/
absorption rates and accurately veriﬁed results
Differences in energy excretion rate in feces and urine
among individuals (contrasting eating conditions)
Urine

Average: 3.4%
Minimum/Maximum: 3.0 to 4.1%
When consuming 2,500 kcal:75to103kcal difference

Feces

Average: 8.4%
Minimum/Maximum: 7.1 to 10.7%

When consuming 2,500 kcal:178to268kcal difference
Urine
and
feces

Average: 12.5 %Minimum/Maximum: 10.2 to 14.8%

When consuming 2,500 kcal:255to370kcal difference

Development of estimation method(questionnaire)(visualization of digestion/absorption rates)
Future concepts
Nutritional and exercise support based on digestion/
absorption rates (implementation in society)Set estimatedenergyrequirements

Improve accuracyof health support
systems using AI,
etc.

Nutritional
guidance
School lunch

AI toil

Nutrition caremanagement

Develop estimation method for energy requirements
based on differences in digestion/absorption rates
between individuals
Able to objectively explain people who are susceptible
to being overweight (or people who donʼt gain weight)
Propose health measures based on digestion/
absorption rates, in addition to intake and expenditure

Excretion rate (%)

Conducting the world s ﬁrst research onwater turnover in humans to tap into newﬁelds of researchReﬁning my specialization in disasternutrition to create evidence that can beutilized in future disasters

There is an especially important technology called the
doubly labeled water (DLW) method that calculates thetotal daily energy expenditure, which also leads to themeasurement of physical activity levels. As one of theworld's leading laboratories for the DLW method, we haveaccumulated data from more than 10,000 people in 40
countries in collaboration with research institutes aroundthe world with the support of the International Atomic
Energy Agency (IAEA). We also published the world's ﬁrst
formula to predict human water metabolism.
In addition, I have been studying the relationship between
skeletal muscle and water since I was a university student
through my own experience in sports. Skeletal muscle is
75% water and is an important reservoir of water forhumans. Previously, we have shown that intracellular ﬂuid
in skeletal muscle decreases with aging and that it isrelated to skeletal muscle quality, muscle and physicalfunction. While learning more about the principles of the
DLW method, we have clariﬁed for the ﬁrst time thedeterminants of the amount of water turnover in humans
using the IAEA database. Currently, I am researching therelationship between water, health, and aging. I hope tocreate and pioneer a research ﬁeld that is unparalleled in theworld.

When I was in university, I met a world-leading female
researcher at NIBIOHN, who taught me that expertisethat is second to none is important for social independence.
I was also keenly aware of the need for food and nutrition
research in the event of a disaster, and thought about what
I could do for people living in disaster-prone countries. Withdisaster nutrition as my specialization, I decided to work at
NIBIOHN, because I admired its high-level research.
I have shown in my previous research that the quantity andquality of meals improved after the Great East Japan
Earthquake by increasing the frequency of mass feeding forevacuees and having menus prepared by registereddietitians. Currently, I am researching the relationshipbetween malnutrition and health problems after disasters.
When a disaster occurs, I immediately collect information on
the aﬀected areas and provide food and nutrition support.
I felt worthwhile when the evidence generated by myresearch was used in the training of dietitians for disastersupport. There are some birth pangs, but I will do my best
to create a future where there are no health hazards causedby food and nutrition in the event of a disaster.

Section of Energy Metabolism
Department of Nutrition and Metabolism
Head Eiichi Yoshimura

Results of fact-ﬁnding survey on the Great East Japan Earthquake
Percentage of emergency shelters that met nutrition reference values* (n=114)

CO2≥ Nutrition Reference Values< Nutrition Reference Values

EnergyUrine

Water Efﬂux

Water iningestedfoodProteinDiagram of the
doubly-labeledwater method

VitaminB1
VitaminB2

Transdermal or
Insensible
water loss

Body water content(intracellular ﬂuid + extracellular ﬂuid)

21

10.8 g/day

The energy we see in our daily lives originates in our food,minus the energy excreted from the body. The digestion
and absorption rates are set uniformly regardless ofgender, physique, or other factors. Although, there areindividual diﬀerences in the ability to digest and absorb.
For highly accurate health management, it is necessary
to precisely estimate the energy requirements by anindividual based on their ability to digest and absorb.
With the motivation of wanting to know the digestive
and absorption capacity of people who are skinny but bigeaters, I launched my current research with the support ofmany people. During this research, We evaluated absorption energy and excretion energy by the method of evaluating physical energy from the changes in water temperaturein an aquarium by completely combusting samples (food,feces, urine, etc.) in an oxygen-ﬁlled cylinder, we found that
there were non-negligible individual diﬀerences in thelatter that could not be ignored. While there are still
obstacles to overcome, we continue my research with theaim of contributing to a society where it is possible toconduct highly accurate health management according toindividual characteristics.

Respiration

Water Inﬂux

Total amount of water turnover（ℓ/day）

Sweat
Transdermal

10.4 g/day

Salt intake from seasonings accounts for 70% of salt intake for all ages

Head Mai Matsumoto

Metabolic water

60 years and older

11.4 g/day

Section of the National Health and Nutrition
SurveyDepartment of Nutritional Epidemiology and
Shokuiku

Respiration

40-59 years old

Conducting research focused on digestion
and absorption linked to more accurate
health management

l

stil
were
uality
and q
ake
u
y
q
it
h
t
t
n
r
qua
e ea
ional
ter thnutritnth af
Both
ne mo
o
r
o
po

VitaminC

Section of Exercise Guideline
Department of Physical Activity Research
Head Yosuke Yamada（%）*Nutrition Reference Values for Dietary Assessments and Planningfor the Provision of Food to Emergency Shelter
Reference: Harada, Tsuboyama et al. J. J. Disast. Med. (2017)

Section of Global Disaster Nutrition
International Center for Nutrition and Information
Researcher Moeka Harada

22

Overview of Research Themes

Priority Diseases
Laboratory of Therapeutics for Intractable Diseases
We operate the National Database of Designated Intractable
Diseases of Japan, based on clinical research forms for about
one million patients per year. By registering and providing theextensive patient clinical data, we support research and development in the area of intractable diseases.

Laboratory of Rare Disease Information and Resource
Library
Seeking to promote drug discovery for rare and intractablediseases through utilization of information and resources, weare analyzing drug target genes/pathways based on clinical
trial data and constructing their database, as well as operating abiobank collaborating with patient registries and analyzing theresources.

Reverse Translational Research ProjectThis Project is implementing a reverse translational approach inwhich various questions that arise in clinical practice aretranslated into basic research subjects and answered. Researchers are working to elucidate the pathogenesis of intractablediseases and to analyze data on intractable diseases using
machine learning, and they will use the results of that research
to solve clinical problems.

Laboratory of Vaccine Materials
Focusing on the immune system of mucosal tissues, the Laboratory is conducting research to develop vaccines, immunotherapies, and healthcare products to prevent and alleviate
infectious diseases, allergies, inflammatory diseases, andlifestyle-related diseases. As examples, researchers are developing vaccines and diagnostic systems to combat bacterial foodpoisoning and adjuvants created using components of intestinal bacteria.

Laboratory of Precision Immunology
We aim to achieve personalized and stratified medicine using
immunological approaches to overcome intractable diseases,
including cancers, chronic infections and neurodegenerative
diseases. We will advance the understanding of accurate
immune status changes for each donor through multilayered
immune omics analysis, and develop disease-specific surrogate
marker exploration, as well as vaccines and immunotherapies.

Laboratory of Immunogenomics
In order to provide precision medicine with the optimaltreatment for individual patients, our Laboratory is identifying
the pathogenesis and biomarkers of diseases based on
multi-omics data, mainly using genomic and immunogenomic
analyses. We also seek to develop novel immunotherapies
based on patients’ genomic information.
23

Laboratory of Cell Vaccine
Several cell vaccine therapies that use dendritic cells and chimeric antigen receptor T cells have reached clinical stages. Given
that functional cell vaccines are a promising future modality,
research pursues the methods for creating and using them fortherapy.

Laboratory of Gut Environmental System
Focusing on the intestinal environment created by symbiotic
microorganisms (such as intestinal bacteria) and food components, the Laboratory is performing human and animal studies
to ascertain the relationship between the intestinal environmentand health and disease. The results will be used to develop new
drugs and health care products.

Laboratory of Drug Discovery Imaging
Focusing on the dynamic immune network, research explores
the fundamental principles that regulate and maintain thefunctional integrity of organs and tissues. Knowledge about
these principles will help create innovative drugs.

Laboratory of Biofunctional Melecular Medicine
The project is investigating the biofunction of ‘cancer-related
genes’ identified via comprehensive omics analyses in cancer
elucidating the molecular mechanisms of cancer development
and resistance to treatment and developing therapeutic
approaches through the biofunctional regulation.

Laboratory of Nuclear Transport Dynamics
Laboratory of Gut Microbiome for HealthResearch focuses on the role of gut microbiome in the relationship between lifestyle factors and healthy conditions including
frailty, and aims to build evidence for extending healthy life
expectancy, taking note of metabolic and chrono-nutritional
perspectives.

Drug Discovery Platforms
Laboratory of Proteomics for Drug Discovery
We are developing state-of the-art proteomics technology forlarge-scale clinical proteomic analysis in order to develop new
biomarkers and treatment methods. Furthermore, large-scaledata sets are used to elucidate pathological mechanisms and to
discover new biomarkers and therapies.

Laboratory of Antibody Design
The overall goal of the project is to create next-generation
antibody therapies with maximum efficacy. We are conducting
research on establishing new classification concepts and designing methods of antibody-binding site (epitopes) structures underin vivo environments that determine the function of antibodies
as therapeutic agents.

Laboratory of XNA Screening and Design
The Laboratory is working to create new nucleic acid-based
drugs by synthesizing artificial nucleic acids (xeno nucleic
acids: XNA), designing sequences containing XNAs, isolatingtarget-specific nucleic acid molecules via screening, evaluating
their functions, and optimizing them for their intended use.

To develop new drugs with novel mechanisms of action,
researchers investigate the pathogenetic mechanisms underlying various disorders from the perspective of nucleocytoplasmic transport of macromolecules.

Laboratory of Advanced Biopharmaceuticals
Basic technologies are being developed to create novel biopharmaceutical modalities using techniques such as protein engineering, antibody engineering and synthetic organic chemistry. We
are developing new technologies to create biopharmaceuticals
with greater functionality than existing antibody drugs, mainly
modified antibodies.

Biological Materials
Laboratory of Drug Discovery Resources Research
The Laboratory operates the JCRB cell bank, which has thelargest number of cell samples in Japan, and a human tissuebank, which provides tissue leftover from surgery to researchers in Japan. The laboratory facilitates drug discovery researchin Japan and abroad by providing quality biological resources.
We are also working to develop tools required for drug discovery research.

Laboratory of Cell Model for Drug Discovery
Activities seek to develop efficient methods that differentiate
stem cells into functional cells using the knowledges of embryology and molecular biology, and to create novel drug discovery platform technologies (e.g., screening systems) using
engineered functional cells.

Laboratory of Functional Organoid for Drug Discovery
To accelerate drug discovery, new in vitro systems are developed
using cells (e.g., hepatocytes and intestinal epithelial cells) thatare differentiated from human induced pluripotent stem cells.
These systems are used to predict drug efficacy and toxicity.

Laboratory of Drug Discovery Resources Research
Collaboration Promotion Office
To accelerate drug discovery research, we are developing
efficiently resources of evaluation system models by using cellswith some function or with a disease phenotype throughinternal and external collaborations.

Laboratory Animal Resource Bank
The Laboratory develops small animal models of diseases
essential for the study of diseases, including intractable diseases. We also operate an animal research resource bank for testing
and the development of treatments. The laboratory facilitates
disease research and drug discovery by developing and analyzing models, collecting, storing, and supplying animals withspontaneous diseases and genetic modifications, and developing related technologies.

Research Center for Medicinal Plant Resources
As the sole comprehensive research institution for medicinal
plant resources in Japan, this center conducts research on
cultivation techniques, new plant breeding approaches, andmethods for the evaluation and application of medicinal plants.
This center cultivates and maintains more than 4,000 strains of
medicinal plants at three sites in Japan (Hokkaido, Tsukuba,
and Tanegashima), it provides many research organizations
with seeds, seedlings, and plant extracts, and it provides technical guidance.

Tsukuba Primate Research Center
We have the only facility in Japan where everything from breeding of cynomolgus monkeys to research and development canbe done consistently. In addition to promoting research anddevelopment related to drug discovery and treatment using
high-quality cynomolgus monkeys, we develop, manage, andsupply new cynomolgus monkey research resources.

Unit for promotion of shared equipment experiments
We are promoting the operation and sharing of research equipment that supports cutting-edge research, with the aim of
responding to diverse research needs both inside and outside
the organization.

Management of Laboratory Animals
Proper management of the animal facility in the Osaka Saito
area, support for animal experimentation, and assistance foranimal experimentation committees are provided.
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Overview of Research Themes

Interdisciplinary Collaboration
Laboratory of Bioinformatics
To promote data-driven drug target discovery, machine learningand other recent technologies are being used to develop new
analysis methods and to analyze disease-related data (clinicalinformation and omics data).

Food and Nutrition
Section of National Health and Nutrition Survey
The Section is working to tabulate and analyze the National
Health and Nutrition Survey data conducted annually by the
MHLW. In order to help promote national policies such as HealthJapan 21 (the 2nd term), the Section conducts research using thedata from the National Health and Nutrition Survey and it
disseminates information via NIBIOHN’s website.

Laboratory of In Silico Design
Informatics and molecular simulation techniques are employed
to elucidate molecular recognition mechanisms in biologicalsystems. Research topics also include efficiently designingcandidate drugs, screening for drug targets, and predicting
drug efficacy, pharmacokinetics, and toxicity.

Laboratory of Toxicogenomics-Informatics
The Laboratory is conducting basic research on drug discovery
related to the identification of pharmacological/toxicologicalbiomarkers, the development of systems to predict toxicity, andthe elucidation of the mechanisms of adverse drug reactions byusing next-generation sequencing-based transcriptome analysis and AI technology.

AI Nutrition Project
In collaboration with institutions inside and outside, cohort
data, measurement data, and other evidences are accumulated
to develop AI/machine learning technologies and knowledge
base for health, nutrition, and metabolic data.

Laboratory of Clinical and Analytical Chemistry
We are developing unique separation columns and functional
probes using nano- and micro-material synthesis technologies
to improve our fundamental measurement capabilities anddevelop new enrichment and analysis technologies for clinicalapplication.

Section of Nutritional Epidemiology
In order to establish evidence to help extend the healthy life
expectancy of the population, the Section is conducting epidemiological studies on the association between diet and non-communicable diseases and other public health problems, using datafrom large-scale cohort studies and the National Health andNutrition Survey. We collaborate with colleagues from otherresearch institutions in Japan and abroad.

Section of Dietary Guidelines
The Section is conducting epidemiological studies, reviews,
and other research in collaboration with domestic and international partners to establish the evidence needed to improve
nutrition-related guidelines such as the Dietary Reference
Intakes for Japanese, which are standards for nutrient intake
necessary to maintain and improve health.

Section of Nutritional Therapy
In order to elucidate the optimal nutrition of mothers andchildren from pregnancy to infancy, we conduct detailed
research to better understand the nutritional intake, physicalcondition, and health of pregnant women and babies.

Section of Food Component Analysis
This section is responsible for the food labeling regulated under
the Food Labeling Act and the Health Promotion Act. It inspects
food products by chemical analysis to verify whether they
contain the nutrients and functional components coincident
with the labeled values. In addition, this section conducts
research to ensure that nutritional labeling is accurate andsuitable.

Section of Food Safety and Function
The Section conducts research to assess the health effects offunctional food ingredients and materials that are widely usedas health foods. We also conduct research studies on people
focusing on the effects of meals and health foods, in order toprovide scientific evidence on safety and function of healthfoods.
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Section of Information Network of Health Food
The Section continuously collects health information based on
scientific evidence and provides information to experts and the
public. The Section also conducts research to ensure effective
communication of the benefits and potential risks of food products.

Physical Activity and Metabolism
Section of Exercise Guideline
The Section is conducting research to provide the scientificbasis required to formulate and revise the Exercise and Physical
Activity Reference for Health Promotion and the Active Guide(physical activity guidelines), which indicate the level of physical activity and amount of exercise necessary to prevent
lifestyle-related diseases and cancer and to prevent the impairment of daily functions by conditions such as dementia andmusculoskeletal disease.

Section of Behavioral Physiology
The Section is conducting research to verify the validity ofmethods to assess lifestyle (diet and physical activity) and toascertain the relationship between lifestyle and health. Genetic,
physical, psychological, and other factors determine humanbehavior in a complicated manner. Their impacts and interrelationships are investigated using genetics, physiology, epidemiology, and other disciplines.

Section of Healthy Longevity Researches
In collaboration with local municipalities, community residents,
academic institutions, national research organizations, industry,and other stakeholders, research are ongoing to identify thecauses of frailty and sarcopenia, and their potential interventions. These scientific evidence for extending healthy life expectancy will be applied to real world.

Section of Energy Metabolism
This section measures average daily energy expenditure using
the doubly labeled water method, human calorimetry, and othertechniques, and contributes to the determination of the estimatedenergy requirements in the Dietary Reference Intakes for Japanese.

International Research
Collaboration and Partnership
Section of International Nutrition Strategy
This section promotes collaboration with the WHO and otherinternational organizations. It also coordinates joint research
projects with health or nutrition research institutions in
Asian-Pacific countries. The Section also oversees a program forinternational cooperation that invites foreign researchers toJapan every year and it holds an international symposium
every other year.

Section of Population Health Metrics
To support the development and assessment of public health policies
aimed at preventing lifestyle-related diseases, our efforts encompass:(1) conducting research on health metrics by analyzing survey data
sourced from official statistics, (2) performing economic evaluations
on sustainable and healthy diets, and (3) fostering international
cooperation to compile comprehensive global health statistics.

Section of Global Disaster Nutrition
This section collects the knowledge and experience of people
living in this disaster-prone country, and disseminates them tonational and international stakeholders. To prevent post-disaster health damage, it works to solve the food- and nutrition-related problems experienced by disaster-affected people and to
fill gaps in their nutrition. It also provides evidence-based
logistical support.

Section of Research Collaboration and Partnership
In order to realize a healthy and delicious diet that can be continued naturally, we are implementing the Industry-Academia-Government Joint Research Project to Promote the Improvement of theFood Environment together with food companies. We aim to build
a food environment model in which all people, not just those whoare highly health conscious, can naturally achieve good health.

Promotion of Pharmaceutical Development
 Promoting the Development of New Medicines andMedical Devices

In order to effectively promote the development of pharmaceuticals, medical devices and cellular and tissue-based products, we
collaborate with universities, companies, and research institutes inaccordance with the stage of development, and we draw on our
expertise to provide guidance and advice so that pharmaceuticals
and other products can be commercially viable.

 Promoting the Development of Orphan and“Specific-Use” Medical Products

The NIBIOHN provides financial support, guidance, and advice
to accelerate the development of products that have been
granted the orphan or “specific use” medical products
designation by the Minister of Health, Labour and Welfare.

 Development Support: Specialized Program

The NIBIOHN provides guidance and advice to support startups,
small businesses, and other enterprises involved in the final
stages of clinical development. Specifically, current activities
center around the “projects suited for practical application” ofmedicine and medical devices that received national funding
between FY 2004 and FY 2010.

 Administration of the Fund Supporting Domestic
Production of Antibiotic APIs

In order to ensure a stable supply of antimicrobial substance
preparations, we provide subsidies and carry out related
operations to fund the efforts of certified supply providers tosecure antimicrobial substances in accordance with the Certified
Supply Assurance Plan for Antimicrobial Substance Preparations
stipulated in the Enforcement Order of the Economic Security
Promotion Act.
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