World Premier International Research Center Initiative (WPI)
Summary of Research Center Project* Compile in English withinA4 2 pages.

Center name:Institute for the Advanced Study of Human Biology

Host institution:

Kyoto University

Head of host institution:

Juichi Yamagiwa, President

Prospective Center Director:

Mitinori Saitou, Professor, Graduate School of Medicine

Prospective Administrative Director:

Tadashi Ogawa, Specially appointed Professor/Program

Manager, Center for Enhancing Next-generation Research1) Overall Framework of the Center Project
The Institute for the Advanced Study of Human Biology will elucidate the design principles ofhuman traits, including disease states, using multidisciplinary integrative strategies, and create a basis fordeveloping innovative therapeutic opportunities.

The Institute will inaugurate with 13 principal

investigators (PIs): 9 PIs investigating key individual themes in human biology with an intense focus on
genome regulation/evolution and disease modeling, 2 PIs that will respectively direct essential
interdisciplinary science between life sciences and mathematics, and between life sciences and humanities,
and 2 PIs organizing research development cores for cutting-edge single-cell genome information analysis
and primate genome editing, respectively.

The Institute will recruit 3 young PIs to accelerate its mission.

The Institute will establish a link with international institutions such as the EMBL, University of Cambridge,
and Karolinska Institute, creating a stratified organization for research promotion and strengthening its
international profile.

Thus, the Institute will realize the advanced study of human biology as a forefront

life science in the coming decades and provide a foundation for medical innovation.
2) Content of Research
The Institute will target humans and non-human primates as major research subjects in an effort touncover the design principles of human beings and disease states, through a multi-disciplinary science
approach. The key goals are: 1) to achieve outstanding research in key individual themes in humanbiology in the area of reproduction, development, growth and aging as well as heredity and evolution; 2)
to elucidate the principles for the emergence of species differences among humans, non-human primates,
and rodents for proper extrapolation of the findings in model organisms to humans; 3) to generate primate
models for key gene functions and intractable diseases, particularly those affecting the central nervous
system and kidney; 4) to reconstitute key human cell lineages and tissues in vitro and validate theirproperties based on integrative information; and 5) to formalize an ethics for the use ofhuman/non-human primate materials and create a philosophy to direct the values of the Institute’s
research outcomes.
3) Interdisciplinary Research
The Institute will establish two lines of interdisciplinary science that are highly integral to its mission andgoals.

First, the Institute will promote fusion between the life sciences and mathematics, such as

topological data analysis and machine learning. Based on multi-species/multi-cell type/multi-hierarchicalomics information, the Institute will define the principles of the emergence of species differences inphenotypes of homologous cells among humans, non-human primates, and rodents, allowing better

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extrapolation of the knowledge from model organisms to humans as well as providing insights into theprinciples for the creation of organismal diversity through evolution.

This analysis will be extended into

the identification of the principles for the species differences on the scales of time and physical dimensions
in development and growth.

Second, by integrating life sciences with the humanities, the Institute willcontribute to the creation of a world-standard bioethics for the proper use of human/non-human primate
materials and create a natural philosophy regarding the values of its key research outcomes (e.g., artificial
gametes/cerebral cortexes, genome-edited monkeys).
4) International Research Environment
To realize an international research effort, the Institute will provide the PIs from overseas with adequate
budget support for building teams of professional research staff: one associate professor as co-PI, 2
postdoctoral fellows, 200 m2 research space, and 30 million JPY of start-up funding. The co-PIs willcommunicate closely with their PIs and work full-time at the Institute to run the PI group efficiently,
particularly when the PIs are absent from the Institute.

All the staff and postdoc positions will be calledby open international recruitments through the Institute’s web site, advertisements in major journals, andother opportunities. All the PIs will recruit at least one non-Japanese staff/postdoc to their group.

The

Institute will appoint Professor Edith Heard, who is the incoming Director General of EMBL, as seniorconsultant to advise the Institute’s research direction and management, enhancing the ability of theInstitute to attain international standards both in science and management.

The Institute will alsoestablish links with other prominent international institutions for collaborative efforts.

Finally, theInstitute will hold international symposia, workshops, and seminars, by inviting world-leading researchers,
and will provide full administrative support for researchers and their families joining from overseas.
5) Center Management and System Reform
The Director will have the authority to make the final decision on key issues, such as choice of research
direction, personnel affairs, and budgetary concerns, in consultation with an Executive Board consisting ofa director, 2 vice directors, 2 PIs, and an administrative director. A PI board comprising 16 PIs and 4
co-PIs, according to the direction of the executive board, will make concrete decisions and action plansconcerning the Institute. The Administrative Office will consist of the administrative director, 13 staffs(bilingual), and 2 URAs (PhDs).

The URAs of the Institute, assigned to the strategical research support

section, will play a key role in planning and implementing international meetings, younger-researcher
fostering programs, and academic–industry cooperation, receiving strong support from the Kyoto
University URA organization (KURA) and the University’s next-generation researcher fostering projects(HAKUBI). Kyoto University will conduct 2 major system reforms. First, to enhance its competitiveness,
the Institute will strategically establish world-leading research core facilities, which will play unique andhighly specialized roles in Japanese research.

The specialty of the core facilities (ultra-performance

instruments and robust analysis technologies) and the employment of technical specialists will enable
them to grow as a global research hub. Based on the experiences of the Institute, Kyoto University will
construct a generalized core-facility model for utilization throughout the university and Japan.

Second, toensure the independence of the Institute after the end of the WPI grant period, it will be essential tosecure appropriate funds to cover indirect costs (e.g., management personnel expenses, depreciation in
facilities). To this end, Kyoto University will newly create an indirect-cost estimation model to secureindirect costs of an appropriate scale and will verify this model at the Institute as a test bed.
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Research Center Project* Compile in English within 20 A4 pages.

Center name: Institute for the Advanced Study of Human Biology
Host institution: Kyoto University
Head of host institution: Juichi Yamagiwa, President
Prospective center director: Mitinori Saitou, Professor, Graduate School of Medicine
Appendix 1: “Biographical Sketch of Prospective Center Director” (to be attached)
Appendix 2: “Reference (recommendation) for prospective center director by world’s distinguished researcher(s) in the center’s target field”(to be attached)

Prospective administrative director: Tadashi Ogawa, Professor, Center for Enhancing
Next-Generation Research
Appendix 3: “Biographical Sketch of Prospective Administrative Director” (to be attached)

1) Overall Framework of the Center Project* Cleary and concisely describe your center’s mission statement as a WPI center, its identity, and its goals toward achieving the objectivesof the WPI program.

The mission of the Institute for the Advanced Study of Human Biology is to elucidate the designprinciples of human traits, including disease states, using multidisciplinary integrative strategies, andcreate a foundation of knowledge for developing innovative therapies (Figure: page 1).
The goals of the Institute are:1) to achieve outstanding research in key themes in human biology with an intense focus on genome
regulation and disease modeling in the areas of reproduction, development, growth and aging aswell as heredity and evolution.
2) to elucidate, with multi-disciplinary approaches, the principles for the emergence of species
differences for appropriate extrapolation of the findings in model organisms to humans.
3) to generate primate models for intractable diseases and key gene functions.
4) to reconstitute and validate key human cell lineages and tissues based on integrative information.
5) to formalize an ethics for the appropriate use of human and non-human primate materials andcreate a philosophy to direct the values of the Institute’s research outcomes.
In the realization of these goals, the Institute will
create and promote advanced study of humanbiology” as a forefront life science in the coming
decades. Although recent advances in genome
science have allowed successive identifications ofgene mutations responsible for many diseases, abenchmark strategy for exploring human genefunctions has been lacking.

The advanced study ofhuman biology will create such a strategy, providing
a foundation for the development of innovative
medical interventions.
Despite the obvious importance and urgent need,
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due to technical/ethical difficulties, there is as yet no institute among the world’s leading countries thatis primarily focused on human biology. Therefore, the Institute for the Advanced Study of Human
Biology will assume a distinguished identity and play a leading role in fundamental research in humanbiology and its applications worldwide.
2) Content of Research2) -1 Research fields* Write in your target research field(s)* Describe the importance of the target research field(s), including the domestic and international R&D trends in that research domain
and neighboring field(s), and describe the scientific and/or social significance of the field(s).
* Describe the value of carrying out research in the field(s) as a WPI center (e.g., Japan’s advantages in the subject fields, the project’s
international appeal as an initiative that challenges world-level science issues, and the future prospects of the research)* List up to 5 centers either in Japan or overseas that are advancing research in fields similar to the center’s field(s), and evaluate
research levels between your center and those centers.
* Appendix 4: “Up to 10 English-written papers (review papers are also acceptable) closely related to the center’s project and their list”(to be attached)

Target Research Fields
The target research field of the Institute is Human Biology. The Institute will investigate criticalthemes in human biology in the area of reproduction, development, growth and aging, as well asheredity and evolution, with an intense focus on genome regulation and disease modeling.
Specifically, using humans and non-human primates as major research subjects, the Institute will
explore germ-cell development, early embryonic development, brain development/growth/pathogenesis,
kidney development/growth/pathogenesis, stem cell aging and tumorigenesis, and lymphocyte
development/aging, as well as epigenetic inheritance and primate-specific transposable elements.
The Institute will perform interdisciplinary research in the fused domains between life sciences
and mathematics involving machine learning and topological data analysis (TDA) andbetween life sciences and humanities/social sciences (bioethics and philosophy on life),
respectively, and will implement two research development cores for multi-hierarchical genome
information analysis at the single-cell level and cutting-edge genome editing in primates,
respectively.

The interdisciplinary research program and the research development cores will be

integral to the research programs of all principal investigators (PIs), thereby creating a system for theInstitute to deliver a highly coherent research program.
The Importance of the Target Research Fields
The elucidation of the design principles of human traits, including diseased states, is fundamental in life
science and has direct relevance not only to our primitive quest on human evolution, but also toapplications in medicine and the well being of our society. Using a diverse array of model organisms,
including the mouse, tremendous research efforts have been made and substantial amounts ofknowledge have been accumulated on the mechanism that supports an organismal life cycle. On theother hand, such knowledge has often been difficult or unsuccessful to translate to human biology due
to species differences in the regulations of key biological pathways.

We consider that the time hascome for us to directly address what it is to be human.

This is also because many

outcomes of drug discovery research in model organisms such as mice have not been
replicated in human clinical trials. We would here like to point out two prominent examples:
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First, during human evolution, remarkable changes have been accomplished in the organizationand size of the central nervous system (CNS), with expansion of the cerebral cortex being the mostprominent. For example, primates, but not rodents, have developed an outer subventricular zone
(OSVZ), which is a critical zone for the expansion of the cerebral cortex in primates.

The cerebral

cortex regulates context-dependent behaviors in a flexible manner, whereas the subcortical systems
regulate innate and reflex-like behaviors.

Primates depend more on the cortical functions, whilerodents depend more on the subcortical systems.
Consequently, after damage to the motor cortex, rodents still can walk, while primates cannot.
Rodent models for basal ganglia disorders, such as Parkinson’s disease or dystonia, exhibit quite
different phenotypes from those of human patients. Furthermore, there is a marked difference in the
cognitive functions, especially those involving the dorsolateral prefrontal cortex, which exhibits
executive functions and is absent in rodents.

Such differences in the CNS limit the value of rodent

models of neurodegenerative or psychiatric disorders. As a result, during the past decades, drug
development for these disorders has faced serious problems, with many of the candidate drugs
developed using rodent models proving ineffective in pre-clinical trials and many mega-pharmas
withdrawing from drug development for such disorders.
Second, the kidney is a critical organ that maintains homeostasis of the body fluid.

It is becoming

clear that rodent models are insufficient for understanding the pathology of human kidney diseases.
For example, diabetic nephropathy is a main cause of the end-stage renal failure.

However, none of therodent models recapitulate all key features of human diabetic nephropathy. Accordingly, drugs that are
effective in treating rodent models are often invalid in treating human diseases.
(AKI) refers to a condition in which kidney function declines rapidly.

Acute kidney injury

Various drugs have shown

effectiveness in the pre-clinical trials using AKI mouse models, but no treatment for human AKI has beendeveloped so far. Thus, mouse models may not replicate human diseases and may not be suitable forestablishing drug efficacy in human diseases.
Therefore, the current rodent models show clear limitations as human models due to species differences,most likely in most tissues/organs.

Accordingly, human biology necessitates the use of humanmaterials. However, such materials, particularly those for human development, are technically andethically difficult to obtain.

We therefore need to create systematic and ethically appropriate

opportunities for access to human materials, as well as for the use of non-human primates as humanmodels.

However, it is important to note that even the macaques (e.g., rhesus and cynomolgus

monkeys), who are the closest to humans among the models amenable for experimentation, have
evolved independently from humans over ~25 million years.

Hence, in order to significantly

promote human biology beyond current practices, it is imperative to perform parallelinvestigations into humans and non-human primates, and simultaneously, to clarify theprinciples of the emergence of species differences, allowing better extrapolation of theknowledge from model organisms to humans.
challenge for

21st

Indeed, in a broader context, a major

century life science will be to understand the mechanistic basis of

species differences—namely, the diversity of life forms driven by evolution.
Direct investigation of human traits requires human or non-human primate materials. To carry out
research using such materials with the public’s trust, appropriate regulations and understanding of
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public values are indispensable. In recognition of this imperative, on May 2, 2018, Nature announced
that it would include ethicists among the peer reviewers for articles that use materials such as humanembryos and germ cells. The emphasis placed on the role of bioethics in human biology will continue
to grow in the future.

There are several elements of the research findings anticipated at this Institute(artificial human gametes, cerebral cortices, genome-edited monkeys, etc.) about which society’s
existing values are ill-equipped to make judgments regarding their moral statuses.

For example,

whether human gastruloids and fertilized human embryos created for experiments from artificial
gametes demand the same ethical considerations as surplus embryos resulting from fertility treatment isa philosophical question on the brink of becoming a real-world problem. Moreover, while the researchuse of human and non-human primate materials is indispensable for elucidating human life, it must becomplemented by strict ethical considerations. Thus, it will be essential and highly timely to implementa Group for Bioethics and Philosophy and create a fused domain between life sciences andhumanities/social sciences in the Institute.
In light of all the above, we consider that the target research fields of the Institute will beof fundamental importance in life science in the coming decades.
The Value of Carrying out Research in the Field(s) as a WPI Center
To realize the salient and ambitious goal of establishing advanced study of human biology as a forefront
life science in the coming decades, it will be essential for a critical mass of scientific experts to cometogether and to perform their research and exchange ideas in a coherent fashion.

The establishment ofa WPI center by drawing scientists with outstanding potential from Kyoto University and relevant
institutions in Japan and overseas is an ideal means to achieve such goals, by creating an intellectuallyinteractive, highly interdisciplinary, collaborative and productive setting.
Currently, the access to human materials is more limited in Japan than other countries. On the other
hand, Japan has a clear advantage over Europe and the USA in terms of the access to non-humanprimates.

While creating systematic opportunities for the access to human materials, the Institute will

simultaneously implement the Core for Primate Genome Editing as a domestic satellite at the
Research Center for Animal Life Science, Shiga University of Medical Science, which
maintains one of the largest primate colonies and most advanced reproductive
technologies both in Japan and worldwide (~700 cages, isolation of ~40 oocytes perweek).

In collaboration with Mitinori Saitou, the Research Center for Animal Life Science has

already established expertise in the developmental engineering of cynomolgus monkeys and published
key papers (Nature, 537, 57-62, 2016; Dev. Cell, 39, 169-185, 2016; Cell Stem Cell, 17, 178-194, 2015;

Cell Stem Cell, 21, 517-532, 2017; Sci. Rep, 6:24868, 2016); such activity is unique to this Center, bothin Japan and around the world.

Thus, it is highly timely and advantageous for the Institute toimplement the Core for Primate Genome Editing and expand on research using non-humanprimates. Moreover, the Core for Primate Genome Editing will be tightly linked and will
perform collaborative efforts with the Division of Marmoset Research at the Central
Institute for Experimental Animals, creating an opportunity to promote primate
genome-editing research in Japan to world-class status.

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Five Centers in Fields Similar to the Center’s Field(s)The Institute for the Advanced Study of Human Biology will be very timely and assume a unique positionat the forefront of the field of human biology worldwide. There is rapidly increasing interest in studying
human biology, including human developmental biology.

For instance, one of the top journals indevelopmental biology, Development, has recently generated a new subsection dedicated to Human
Development and established a regular meeting on Human Development since 2014 (From stem cells tohuman development: to which Mitinori Saitou is invited in 2018).

The Wellcome Trust is

currently preparing a new initiative, the Human Developmental Biology Initiative (HDBI)(in which Takashi Hiiragi is involved), at a cost of £10m. These activities are primarily driven by
the recognition that the current lack of success in regenerative medicine stems from the lack offundamental knowledge in human developmental biology.

An improved understanding of humandevelopmental biology should thus form a strong basis for the success of stem-cell based regenerative
Further, although recent advances in genome science have allowed for

medicine.

successive identifications of gene mutations causative for many diseases, there is still nobenchmark strategy for exploring the functions of human genes.

However, there is as yet

no institute among the world’s leading countries that is primarily focused on humanbiology.

We consider that advanced study of human biology will create such a strategy,

providing a foundation for the development of innovative medical interventions.
In terms of developmental biology, one of the world-leading institutes would be the Gurdon Instituteat the University of Cambridge, UK (to which Takashi Hiiragi belongs as of October 2018).

However,the primary focus of that institute is developmental biology and cancer, and research on human biology
is dependent on each lab and overall very limited. EMBL has recently established a new outstation in
Barcelona dedicated to tissue biology and disease modeling.

However, their studies are so far limited

to stem cell culture or organoids without reference to basic human biology.

The Francis Crick

Institute in London has a prominent interest in human health and disease. However, their primary
aim is to understand fundamental biology with a particular emphasis on interdisciplinary collaboration;
as such, they are not necessarily focused on human biology. Moreover, their large size and highdiversity would make it difficult to coordinate their efforts along a focused research line such as humanbiology. The Curie Institute in Paris is a leading scientific institution in France, and collaborates
actively with hospitals in Paris.
institute.

However, there is no coordinated effort for human biology in this large

In the US, while there are many “stem cell institutes” (e.g., the Harvard Stem Cell

Institute), their research activity is not necessarily coordinated with research in basic human biology,
and such research is carried out on an individual lab basis.
Taken together, these facts indicate that the Institute for the Advanced Study of Human Biology could
play a unique and world-leading role in the fundamental research of human biology.
Ten papers closely related to the center’s project and their list
Appendix 42)-2 Research Objectives and Plans* Describe in a clear and easy-to-understand manner by the general public the research objectives that your project seeks to achieve by
the end of its grant period (in 10 years). In that process, what world-level scientific and/or technological issues are you seeking to

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solve? What will be the expected impact of the scientific advances you aim to achieve on society in the future?
* Describe concretely your research plan to achieve these objectives and any past achievements related to your application.

Research Objectives
The Institute’s objective is to create a scientific basis for elucidating what it is to be human,
including our diseased states.

Accordingly, the Institute will explore humans and non-humanprimates as major research subjects and clarify the mechanisms underlying the acquisition of humantraits and disease states. Over the next ten year, the key research goals of the Institute will be thefollowing:1) to achieve outstanding research in human biology with an intense focus on genome regulation anddisease modeling in the areas of reproduction, development, growth and aging as well as heredity
and evolution.
2) to clarify the principles for the emergence of species differences in organismal traits among humans,
non-human primates, and rodents, creating a strategy for better extrapolation of the knowledge
from model organisms to humans.
3) to uncover the primate-specific functions of key genes and to create critical disease models by
genome editing in cynomolgus monkeys.
4) to re-create in vitro the development and physiology of key cell lineages and tissues (e.g., early
embryos, germ cells, neural tissues, lymphocytes, etc.).
5) to formalize an ethics for the appropriate use of human and non-human primate materials andcreate a philosophy to direct the values of the Institute’s research outcomes.
Thus, the Institute’s research will not only uncover how human beings have evolved, butalso create a foundation for delineating the etiologies of many intractable diseases and thedevelopment of innovative therapies, and thereby a basis for a healthy start to life and ahealthy aging society.
Research Plans
The Institute will inaugurate with 13 PIs. These will include 9 PIs investigating key individual themes inhuman biology in the areas of reproduction, development, growth and aging, as well as heredity andevolution (Life Science Groups), 2 PIs leading the interdisciplinary sciences and 2 researchdevelopment cores (2 PIs).

Together, these units will allow the Institute to achieve a coherent research

program focused on its goal of advanced synthesis of human biology (Figure: page 7). The Institutewill recruit 3 young PIs (Associate Professors) to accelerate its mission.
The two lines of interdisciplinary research and two research development cores are as follows:
Yasuaki Hiraoka (Prospective Vice Director), a world-leading mathematician in topological
data analysis (TDA) and applied mathematics, will lead the Group for Mathematical Science. This
group will develop novel methodologies for analyzing multi-hierarchical, large-scale omics data based onmathematics such as TDA and machine learning to clarify the principles for the emergence of species
differences of “homologous” cell types or on the scales of time and physical dimensions in development
among humans, non-human primates and rodents, allowing appropriate extrapolation of the knowledge
from model organisms to humans.
Misao Fujita, an expert in bioethics using an empirical approach, will lead the Group for
Bioethics and Philosophy. This group will formalize an ethics for the appropriate use of human andKyoto University-6
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non-human primate materials and create a philosophy to direct the values of the Institute’s researchoutcomes (e.g., artificial gametes, artificial cerebral cortexes, genome-edited monkeys). For details on
their activities, see section 3) Interdisciplinary Research.
Takuya Yamamoto, an expert of genome information analysis, will lead the core forsingle-cell genome information analysis.

The core will develop cutting-edge technologies foracquiring multi-hierarchical large-scale datasets for gene expression, genome sequence and structure,and epigenetic profiles at the single-cell level, supporting the research of all groups. In addition,
Yamamoto will develop methodologies for measuring global post-transcriptional modifications andtranslational regulations to capture entire gene expression processes, contributing to exploration of theprinciples for the emergence of the species differences based on such comprehensive datasets.
Masatsugu Ema, who is an expert of developmental engineering based at the Research Center
for Animal Life Science, Shiga University of Medical Science (the domestic satellite of theInstitute), will lead the core for primate genome editing.

The core will ensure a stable supply ofembryos/adult tissues of cynomolgus monkeys, and by developing cutting-edge genome-editing
technologies, will generate genome-edited cynomolgus monkeys for exploring primate-specificgene functions and establishing relevant disease models, serving an integral function for the research
performed by all the PIs.

The target genes include those responsible for brain functions inprimates and for kidney development and growth, which are significantly divergent
between primates and rodents, and for which rodent models have been largely
unsuccessful in drug screening (see “The Importance of the Target Research Fields”). Specifically,
these include the core knockouts genes, such as CHX10 (Isa: a candidate for instructing thedevelopment of primate-specific hand dexterity), DYT1 (Isa: a gene responsible for dystonia), DISC1(Isa: a gene responsible for schizophrenia), PKD1 (Ema: a gene responsible for polycystic kidney),

NPHS1 (Yanagita: a gene responsible for congenital nephrotic syndrome), and NPHP1 (Yanagita: agene causative for nephronophthisis type 1).

With the progression of the Institute’s research, the core

will target new candidates in primate-specific traits and disease development.

The Institute will

establish a close link with the Division of Marmoset Research at the Central Institute forExperimental Animals, which is a key center for generating gene-edited marmosets, promoting the
research for primate genome editingin Japan to the world top level.

The

Institute will also establish a link with
the

Kyoto

University

PrimateResearch Institute, promoting suchresearch goals as the sampling ofmaterials from aged macaques andthe derivation of iPSCs from a variety
of primates.
The

life

sciencegroupswill

promote intensive investigations on
key targets in human biology in theareas of reproduction, development,
growth and aging as well as heredity
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and evolution.
Mitinori Saitou (Prospective Director) is a world leader of germ cell biology and in vitro
reconstitution of germ cell development in mice, monkeys and humans. Saitou’s group will develop
ex vivo culture systems for differentiating human (h) and cynomolgus monkey (cy) primordial germ cells(PGCs) into oocytes and spermatogonia.

Based on such systems, the group will develop in vitro

systems to generate oocytes and spermatogonia from PGC-like cells (PGCLCs) derived from h/cy
induced pluripotent stem cells (iPSCs)/embryonic stem cells (ESCs), realizing in vitro analyses of themechanism for h/cy germ-cell development. Saitou’s group will focus on the mechanism for thegeneration of genetic and epigenetic diversities through meiotic recombination and epigenetic
reprogramming, respectively, and uncover species differences of such key processes among mice,monkeys and humans. In addition, Saitou’s group will clarify the mechanism of the species difference
in relation to the developmental time for germ cell development among these species.
Takashi Hiiragi is an expert in the developmental biology of mouse early embryos and of their
live-imaging analysis.

By using the cutting-edge technique of in toto live-imaging as well as bydeveloping an in vitro culture system from zygotes to the blastocyst and gastrulation stages, Hiiragi’s
group will establish a primate early development atlas at single-cell resolution. Hiiragi’s group will
combine imaging data with cutting-edge lineage mapping and single-cell RNA-seq data tocomprehensively elucidate the mechanism for early development of primates, uncovering the principles
conserved across mammalian species and those newly evolved in primates.
Mototsugu Eiraku is a pioneer of the induction of neural tissues, such as optic cup structureswith well-stratified retina, from mouse and human PSCs, and has demonstrated that the in vitro
development of neural tissues recapitulates the differences in developmental time between mice andhumans, e.g., the induction of optic neurons from mouse PSCs requires ~20 days of culture, whereasthat from human PSCs requires more than 150 days. Using cutting-edge imaging technologies andmulti-hierarchical omics analysis, Eiraku’s group will investigate cellular, molecular and genomic
dynamics during the induction of neural tissues from mouse, monkey and human PSCs, clarifying theprinciples that create the species differences of neurons and their developmental time.
Anne Ferguson-Smith is a world leader of the investigation into the mechanism of epigenetic
inheritance.

Ferguson-Smith’s group will test the hypothesis that certain repetitive elements inprimates have the potential to influence the behaviour of endogenous genes via their epigenetic
properties, that these elements are more sensitive to the environment and that these elements caneither propagate or reconstruct an epigenetic memory of the previous generation with an influence on
phenotype.

The group will also utilise an in utero compromise model in Cynomolgus to decipher theextent and mechanisms of non-genetic inheritance of such compromise with implications for humanhealth and well-being.
Guillaume Bourque is an expert of comparative genome information analyses and has been
studying the impacts of repetitive elements on the acquisition of species-specific regulatory circuitry
during evolution.

The specific objectives of the Bourque’s group will be to: 1) Build detailed

epigenomics maps in different human individuals and non-human primate species; 2) Develop
computational methods to predict the impact of non-coding variants; 3) Apply these new predictive tools
to study various disease cohorts; 4) Facilitate the distribution of software to study genomics andepigenomics datasets. These works will be a better characterization of non-coding DNA and its impact
on health and disease.
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Tadashi Isa (Prospective Vice Director) is a world leader of studies of neural networks inprimates. Isa’s group will explore three key aspects of brain functions specific to higher primates: 1)
highly skilled hand movements; 2) motor systems highly dependent on the cortico-subcortical loop
circuits; and 3) highly developed cognitive functions.

For 1), using single-cell RNA-seq analysis, thegroup will explore genes and their networks specific to cortico-spinal neurons in macaques.

The group

will first analyze knockout monkeys for CHX10 or SPP1, which are specifically expressed in spinal
interneurons mediating the cortical command or cortico-spinal neurons in primates, respectively. For2), the group will generate knockouts for DYT1, a gene responsible for dystonia, a basal ganglia disorder,
and analyze the neural basis of their behavioral phenotypes, which are expected to be specific toprimates. For 3), the group will generate knockouts for DISC1, one of the candidate genes responsible
for schizophrenia, which is considered to be caused by dysfunction of the neural network involving thedorsolateral prefrontal cortex highly developed in primates, and analyze their phenotypes.

Thus, Isa’sgroup will create a foundation for the study of gene functions in primate brain functions and generatecritical disease models.
Motoko Yanagita is an expert of kidney biology and has made key contributions tounderstanding of the pathogenesis of many kidney diseases. Yanagita’s group will perform threelines of research using cynomolgus monkeys: 1) verification of kidney disease models; 2) generation ofgene-knockout monkeys; and 3) verification of “fetal programming” in the kidney.

For 1) the group will

generate an ischemia reperfusion model as an acute kidney injury model, and compare its pathologies
with those of mice and humans.

For 2), the group will generate knockouts for NPHS1, a gene

responsible for congenital nephrotic syndrome and encoding NEPHRIN, a slit-membrane protein of
podocytes. The group will also generate knockouts for NPHP1, a gene causative for nephronophthisis
type 1 and encoding nephrocystin-1. Nephronophthisis type 1 is characterized by cyst formation andinflammation in the kidney, and leads to end-stage renal disease at around age 13-14 in humans. For3), using the maternal nutrition restriction model, the group will verify whether the decrease in thenumber of nephrons can be reproduced in monkeys, and analyze the gene expression over time to
explore the mechanism of nephron number determination by maternal nutrition.
Seishi Ogawa is an expert of genome biology of cancer and has been identifying key mutations
responsible for many types of cancers. Ogawa’s group will clarify pathways through which successive
aging-associated mutations lead to tumorigenesis.

Targeting tissues including the mammary

epithelium, esophagus, large intestine and hematopoietic system, Ogawa’s group will analyze~100,000 single cells in incipient tumor lesions or in normal stem cells for their genome sequence andgene expression, and delineate a comprehensive picture of clonal selection and evolution as a nascent
step of tumorigenesis.

To this end, Ogawa’s group, together with the Core for Single-Cell Genome

Information Analysis, will develop a methodology to detect mutations and measure global gene
expression simultaneously from single cells and to determine the pathways for clonal selection andevolution based on informatics for population genetics.
Hideki Ueno is an expert of human immunology and a world leader of the investigation into
human T follicular helper cells (Tfh).

Ueno’s group will define the genetic and epigenetic basis

regulating the differentiation of naïve CD4+ T cells of different origins. Specifically, the group will define
the commonalities and differences among species, i.e., mice, macaques, and humans; among
anatomical sites in human organs, i.e., peripheral blood, tonsils, spleen, and gut; and among peripheral
blood naïve CD4+ T cells obtained from subjects of different ages.

In this way, the group will establish

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the principles for the emergence of species/environmental/age differences of the immune responses.
All the PIs are committed to creating a new chapter in the study of human biology, on the basis of theirresearch focusing on key targets in human biology.
Moreover, under the leadership of the director, all the life science groups will acquire
multi-hierarchical omics data for gene expression, genome sequences and structures, and epigenetic
profiles of relevant “homologous” cell types and their differentiation processes among mice, monkeys
and humans, which they will then use to actively contribute to the clarification of the principles
explaining the emergence of species differences.
Thus, with the assistance of Yamamoto in the single-cell genome information core, Saitou andFerguson-Smith will acquire such data for germ cells, Hiiragi for early embryonic cells, Isa andEiraku for neurons, Yanagita for kidney cells, and Ogawa and Ueno for hematopoietic lineages, andall such data will be subject to meticulous analyses by novel mathematical methodologies being
developed by Hiraoka in close collaboration with Bourque.

The principles for the emergence ofspecies differences uncovered as a synthesis of these endeavors will serve as a strong basis to overcome
the gaps between humans and model organisms (Figure: page 10).
All the PIs will therefore be tightly linked with the theme of how the human genome is regulated andhow it has diverged from that of model organisms, creating ample opportunities for mutual discussion
and synergistic research development toward the single theme of addressing “how it is to be
human as a biological entity”. We envision that this initiative will lead to the elucidation of thedesign principle of human beings, a key goal and breakthrough of the Institute with direct relevance tomedical innovation.
To date there have been
no studies making careful
comparison

of

human

disease phenotypes with
those

of

non-human

primate models.

As amajor and unique initiative oftheInstitute,

with

the

assistance of Ema in the
primate genome editing core,
we will conduct such studies
using cynomolgus monkeys
one-by-one with a major
focus on brain and kidneydiseases.

Combined withthe theoretical strategy as
described above (see also 3)
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World Premier International Research Center Initiative (WPI)
Interdisciplinary research for details), which will realize a better extrapolation of the knowledge frommodel animals to humans, defining a strategy to create an original benchmark for exploring
human gene functions (Figure: page 10).
Thus, the Institute will delve into key areas of human biology and will be highly integrativewith the activities of interdisciplinary science and research development cores, realizing a
coherent progression of the field of advanced study of human biology.
2)-3 System for advancing the research* Describe the center’s research organization (including its research, support and administrative components) and your concept forbuilding and staffing the organization.
* Describe your concrete plan for achieving the center’s final staffing goal, including steps and timetables.
* If the center will form linkage with other institutions, domestic and/or foreign, by establishing satellite functions, provide the name(s)of the partner institution(s), and describe their roles, personnel composition and structure, and the collaborative framework with thecenter project (e.g., contracts to be concluded, schemes for resource transfer).
* If the center will form linkage with other institutions, domestic and/or foreign, without establishing satellite functions, provide thenames of the partner institutions and describe their roles and linkages within the center project.
* Appendix 5: “List of Principal Investigators” (If there are changes from the PI list in the first screening application documents, describe
the points changed and reasons.) (to be attached)* Appendix 6: “Biographical sketch of principal investigator” (to be attached)* Appendix 7: “Composition of personnel in center” (to be attached)* Appendix 8: “Letters from researchers invited from abroad or other Japanese institutions expressing their intent to participate in thecenter project” (to be attached)

The Center’s Research Organization
The Institute will inaugurate with 13 PIs.

These will include 9 PIs investigating key themes in humanbiology, 2 PIs working on leading interdisciplinary sciences and 2 PIs for the research development cores.
The Institute will also recruit 3 young PIs (Associate Professors), who will join the Institute in FY2019, toaccelerate the Institute’s mission.
Postdocs).

Each PI will recruit 3 research staff (Assistant Professors or

The PIs from overseas will recruit 1 co-PI (Associate Professor) and 2 research staff(Assistant Professors or Postdocs).

Each PI will recruit at least 1 non-Japanese staff/postdoc. Young

PIs will recruit 1 research staff (Assistant Professor or Postdoc). All PIs can recruit research support
staff and research associates (RA) at their discretion. In addition, the Core for Single-Cell Genome
Information Analysis will recruit 2 technical experts and the Core for Primate Genome Editing
will recruit 5 support staff to efficiently run the cores.

The Institute will reach a fully staffed state by

the end of FY2019.
The Institute will begin with an Administrative Director and 2 university research administrators (URA)
allocated from Kyoto University, and by the end of FY2018 will run its administration with 14
administrative staff in total.

See a) Principal Investigators and b) Total Members below.

The Center’s Satellite
The Institute will create a key satellite at the Research Center for Animal Life Science, Shiga
University of Medical Science, where Masatsugu Ema (Professor, Shiga University of Medical
Science) will lead the Core for Primate Genome Editing, which bears one of the largest
cynomolgus monkey colonies and the most advanced capacities in reproductive
technologies in Japan and in the world (~700 cages and isolation of ~40 oocytes per week).
The core is located within an easy commute (~1 hr) from the Institute.
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The core will ensure the Institute’s research by establishing two units: the Reproduction Unit willconsist of 4 personnel and will supply embryos/adult tissues of wild-type and genome-edited
cynomolgus monkeys through reproductive technologies: ovarian stimulation, oocyte collection, sperm
injection, egg transfer to recipients and recovery of embryos.

This unit will develop a novel strategy to

improve the efficiency of the egg recovery, leading to the promotion of animal welfare. The Genome
Editing Unit will consist of 5 personnel, and will develop cutting-edge strategies to create transgenic
and knock-out/knock-in monkeys for disease models.
The core will support the analysis and characterization of the animals by utilizing CT, MRI and otherequipment. The isolated samples (embryos or adult tissues) can be directly analyzed in the core ortransferred to the Institute for various analyses. Under appropriate regulations, some of the adultanimals, including genome-edited monkeys, can be transferred to the Institute of Laboratory
Animals, Graduate School of Medicine, Kyoto University for various analyses.
Linkage with Other Institutions (Figure: page 12)
The Institute will appoint Prof. Edith Heard, who is incoming Director of the European
Molecular Biology Laboratory (EMBL), as senior consultant, seeking her advice on the Institute’s
research direction and management, and establishing an intimate link with EMBL, e.g., having periodical
joint meetings and exchanging ideas and expertise. The linkage with EMBL, the leading institute for life
science in Europe, will help the Institute attain international standards both in science and management.
Mitinori Saitou will collaborate with Edith Heard on the regulatory mechanisms of X chromosome
activities during primate embryogenesis and stem-cell differentiation, corroborating the linkage.
Takashi Hiiragi (current PI in EMBL) will play a key role in establishing the linkage.
The Institute will also form a linkage with RIKEN, particularly with the RIKEN Preventive Medicine &Diagnosis Innovation Program (Program Director, Yoshihide Hayashizaki), and will perform
high-resolution enhancer mapping, thereby promoting exploration of the principles for species
difference emergence among humans, non-human primates and rodents.

The Institute will also form alink with the Karolinska
Institute,

whereSeishi

Ogawa is Visiting Professor,
and will collaborate with the
Karolinska

Institute’s

core facility for Eukaryotic
SingleCell(Facility

Director, Rickard

Sandberg)

Genomics
todevelop

cutting-edge methodologies
for single-cell genomics.
The Institute will form close
linkages with the Division
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of Marmoset Research at the Central Institute for Experimental Animals (Principal
Investigator, Erika Sasaki) and the Bioresource Engineering Division at RIKEN Bioresource
Center (Principal Investigator, Atsuo Ogura), developing cutting-edge genome editing technologies inprimates.

The Institute will form a link with Kyoto University Primate Research Institute,promoting such research as the sampling of materials from aged macaques and the derivation of iPSCs
from a variety of primates.
The Institute will form a link with the Oxford Uehiro Centre for Practical Ethics/Wellcome
Centre for Ethics and Humanities (Director, Julian Savulescu), and make a cooperative effort tocreate a novel system of bioethical values for human research.
The Institute will form linkages with the Cincinnati Children’s Hospital Medical Center (Yutaka
Yoshida), Kyoto University Primate Research Center (Masahiko Takada) and National
Institute for Physiological Sciences (Atsushi Nambu), with which Tadashi Isa will perform
intense collaboration.

The Institute will also form links with the University of Cambridge [AnneFerguson-Smith and Takashi Hiiragi (as of October 2018)], Icahn School of Medicine at Mount
Sinai (Hideki Ueno), and McGill University (Guillaume Bourque) to promote the Institute’s
research activity.
a) Principal investigators (full professors, associate professors, or other researchers of comparable
standing)* Paste onto table a) in Appendix 7.

(persons)
Final goal
(Date: 4, 2020)

At the start of the
project

At the end of FY 2018

8

8

11

4

4

4

1

1

1

13

13

16

At the start of the projectAt the end of FY2018

Researchers from within
the host institution
Foreign researchers invitedfrom abroad
Researchers invited fromother Japanese institutions
Total principal
investigatorsb) Total number of members* Paste onto table b) in Appendix 7.

Researchers

Number of
persons
13％

Number of
persons
26％

Final goal
(Date: 4, 2020)
Number of％
persons
58

Overseas researchers

4

31%

8

31%

18

31%

Female researchers

3

23%

6

23%

17

29%

Principal investigators

13

Overseas PIs

4

31%

4

31%

5

31%

Female PIs

3

23%

3

23%

4

25%

13

16

Other researchers

0

Overseas researchers

0

-

13
4

31%

13

42
31%

Female researchers

0

-

3

23%

13

31%

Research support staffs

2

15

20

Administrative staffs

3

14

14

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Total number of people

18

55

92

2)-4 Securing research funding
Past record* Give the total amount of research funding (e.g., competitive funding) secured by the principal investigators who will join the center
project. Itemize by fiscal year (FY2013-2017).

Amount of External Funding
Fiscal Year
Domestic PIs
Overseas PIs

2013
487
201

2014
540
229

2015
528
240

2016
616
292

(million yen)

2017
547
507

Total
2,718
1,469

Funding prospects after the establishment of the center* Based on the past record, describe your concrete prospects for securing resources that match or exceed the WPI grant(FY2018-2022).
* Calculate the total amount of research funding (e.g., competitive funding) based on the amount of funding that the researchers will
allocate to the center project. Be sure that the funding prospects are realistically based on the past record.

Amount of External Funding
Fiscal Year
Total

2018
600

2019
630

2020
662

2021
695

(million yen)

2022
730

Total
3,317

The funding prospects are calculated as the sum of expected competitive funding of each PI (bothdomestic and overseas), which is the multiplication of the expected funding of each PI (the average ofthe past record) with the effort of each PI to the Institute’s research, with an expectation that the
secured funding will increase by 5% each year until YF2022. Note that Kyoto University will allocate all
the indirect cost (30% of the competitive funding) to the Institute.
3) Interdisciplinary Research* Describe the fused research domains, why interdisciplinary research is necessary and important in the target field(s), and what new
field(s) can be expected to be created by way of this project. Describe your concrete strategy for fusing different research domains andcreating new field(s) by the fusion.

The Institute aims to uncover the design principles of human traits. To achieve this goal, the Institutewill clarify the principles for the emergence of species differences, allowing appropriate extrapolation of
the knowledge from model animals to humans.

Indeed, understanding the mechanistic basis for

species differences—i.e., the diversity of life created through evolution—will be one of the mostfundamental challenges in 21st century life science. Although it has been extremely difficult toaddress such themes, along with the recent advances in genome science, it has become
highly timely to explore this key theme using multi-disciplinary approaches.
Accordingly, the Institute will clarify the principles underlying the emergence of species differences in
the properties of “homologous” cell types and in their responses to key biological stimuli in humans,
non-human primates, and rodents using an interdisciplinary approach of life science and mathematics.
Specifically, using these species, the life science groups and the Core for Single-Cell Genome
Information Analysis will acquire multi-hierarchical large-scale omics data for gene expression,
genome sequence and structure, and epigenetic profiles of: 1) “homologous” cell types that appear withhomologous timing during development, growth and aging (e.g., epiblast, primordial germ cells, naïve T
cells, and hematopoietic cells types); 2) cell differentiation processes of specific lineages (e.g.,differentiation of the epiblast from the inner cell mass) or of specific cell types by cytokines in vitro (e.g.,differentiation of naïve T cells); and 3) induction processes of specific lineages from pluripotent stem
cells (e.g., the germ cell lineage, neural tissues).
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World Premier International Research Center Initiative (WPI)
As discussed in 2)-2 Research Objectives and Plans, under the leadership of the director, all the life
science groups will acquire necessary data and actively contribute to the clarification of theprinciples

explaining

theemergenceof

species

differences.

Thus,

SaitouandFerguson-Smith will acquire such data for germ cells, Hiiragi for early embryonic cells, Isa andEiraku for neurons, Yanagita for kidney cells, and Ogawa and Ueno for hematopoietic/lymphopoietic
lineages.
Yasuaki Hiraoka, a world-leading mathematician in topological data analysis (TDA), leads the Groupfor Mathematical Science.

By combining mathematical theories such as those related to topology,

representation, and probability, Hiraoka has succeeded in making TDA highly powerful and general for
resolving practical problems such as structural clarification in materials science.

Based on theseexperiences, Hiraoka and the Group for Mathematical Science will develop novel methodologies
for analyzing large-scale, multi-species/multi-cell type/multi-hierarchical data using methodologies suchas TDA (analyses based on theories such as persistent homology and quiver representation theory) andmachine learning (analyses based on theories such as neural network or sparse model), identifying theprinciples for the emergence of species differences generated by divergent genome sequences in theproperties of “homologous” cell types and in their responses to biological stimuli in humans, non-humanprimates and rodents (Figure: page 15).
Furthermore, Takashi Hiiragi will develop novel experimental and image-processing pipelines for the
integration of multi-hierarchical single-cell omics data into a 4D morphogenetic map of primate andhuman embryonic development.

The same strategy will be potentially widely applicable to the dataset

obtained by all other PI groups.

Accordingly, the Institute will ultimately combine theseinterdisciplinary strategies to identify principles for the species differences in the scales of time andphysical dimensions of development and growth. A systematic interdisciplinary science basedon multi-species/multi-cell type/multi-hierarchical large-scale data can only be achieved
through the establishment of this Institute.
The Institute will realize this interdisciplinary research through tight cooperation among the Group forMathematical Science, life science groups, and the Core for Single-Cell Genome Information
Analysis.
scientists

Specifically, 1)
in

life

sciencegroups will provide scientists
in

Group

the

Mathematicalfor

Sciencewith intensive lectures forgenome science and species
differences, and establish asystemformathematicalscientists to truly understandthe cutting-edge knowledge
and issues in life science; andKyoto University-15
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World Premier International Research Center Initiative (WPI)
2) scientists in mathematical science will train scientists in life science for mathematical analyses andestablish a system for life scientists to gain the capacity to develop new analytical methods and perform
in depth analysis of the data.

This system is critical to foster life scientists with capability forcutting-edge mathematical analysis.

The Institute will also create ample opportunities for specificproblem-oriented discussions among postdocs and students, and for small-scale joint lab meetings tofacilitate interdisciplinary science.

With these systems, the Institute will create a truly fused domain

between mathematics and life science.
At the outset, in order to robustly acquire biological data as well as to realize a real fusion between
mathematics and life science, the Institute will implement one Group for Mathematical Science(three staff scientists: Yasuaki Hiraoka, and an associate and assistance professor), and Guillaume
Bourque and Takuya Yamamoto, who are proficient in statistics-based informatics, will support theGroup for Mathematical Science.

The Institute will expand the Group for Mathematical

Science along with the progression of the Institute’s research activities.
See “The Importance of the Target Research Fields” for the importance of the fuseddomain between life science and humanities. Misao Fujita, an expert of bioethics using anempirical approach, will lead the Group for Bioethics and Philosophy. In close collaboration withall life science groups, the Group for Bioethics and Philosophy will consider the appropriate use ofexperimental subjects (human and non-human primate materials) and the values of research outcomes(e.g., artificial gametes, artificial cerebral cortexes, genome-edited monkeys) by performing four lines ofresearch: 1) theory-driven study, 2) empirical study, 3) outreach activities, and 4) policy proposals.
Based on their findings, the group will formalize an ethics for the advanced study of human biology.
More specifically, the Institute will, 1) have regular meetings with key international centers for ethics
such as the Oxford Uehiro Centre for Practical Ethics/Wellcome Centre for Ethics andHumanities (Director, Julian Savulescu) and the Institute for Practical Ethics at UCSD
(Co-Directors, Craig Callender and John Evans) to investigate and discuss key bioethics andphilosophy issues including the creation of artificial human embryos, human embryo cultures beyond 14
days, etc (theory-driven study), 2) create questionnaires and surveys to investigate perceptions ofscientists in relevant fields and of the general public regarding such key issues (empirical study), 3) holdpublic symposia to disseminate the outcomes of these empirical studies and thereby

createopportunities for more open and public discussion (outreach activities), and 4) publish papers asserting
the Institute’s position and lead active discussions in relevant areas such as at the Cabinet Office, theInternational Society for Stem Cell Research (ISSCR) and UNESCO, in all three of which Fujita has been
serving as a member of the committee on bioethics, in order to spur the generation of new regulations(policy proposals).
Furthermore, we will create regular opportunities for mutual discussion among scientists in the life
science and the bioethics and philosophy groups. We will also make it a rule to have a bioethics sessionin all regular international scientific symposia of the Institute, to promote timely discussions in aninternational context.

Through these efforts, we will contribute to the creation of aworld-standard for bioethics, leading the forefront of the life sciences for the coming
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World Premier International Research Center Initiative (WPI)
decades.
Additionally, during the course of the Institute’s research, the director will play a leading role infacilitating continuous discussion among the PIs and the Institute’s members on how tocreate truly interdisciplinary scientific domains and attain the goals of such new
disciplines.
4) International Research Environment4)-1 System for advancing international research* Describe your concrete plan for building an international research center including the makeup of its foreign researchers, establishmentof oversea satellites, or similar functions. Include a time schedule for the plan.
* Describe concretely your strategy for staffing foreign researchers (e.g., postdoc positions) through open international solicitations.
Describe the procedures you will use to do so.

To realize an international research effort, the Institute will provide the PIs from overseas with adequate
budget support to build teams of professional research staff and postdoctoral researchers (one associate
professor as co-PI, two postdoctoral fellows, 200 m2 research space, 30 million JPY of start-up funding).
The PIs from overseas will first recruit a co-PI/associate professor, who will establish close
communications with the overseas PIs and work full time at the Institute to efficiently run the overseas
PI group, particularly when the overseas PIs are absent from the Institute.

The overseas PIs and theirco-PIs will then recruit two postdoctoral fellows and research support staff to fully initiate their research.
We fully understand that the actual presence of overseas PIs on site is crucial for the ongoing activitiesof their groups, and therefore, during the course of the development of the Institute’s research, thedirector will discuss with each overseas PI the ways in which to increase opportunities tobe present on site, so that these PIs’ work on site will have a strong presence in theInstitute.
Furthermore, among the three young PIs to be recruited, at least one will be non-Japanese and will stayin Kyoto at an effort level approaching 100%. Active international recruitment will take place forpostdoc and other positions, with an aim to have well over one-third of the research staff be
non-Japanese, according to WPI program standards. And the hiring of administrators with English
language ability and overseas experience will be given a top priority, to provide a world-class working
and living environment for all the Institute’s personnel (see also 4)-2 Establishment of international
research environment).
And finally, regular meetings, events, and retreats, both for core members as well as for all staff, will beheld to increase inter-group communication and mutual understanding, all of which we expect willcontribute solidly to the internationalization of the Institute (see also 4)-2 Establishment of international
research environment).
The Institute will appoint Professor Edith Heard, who is the incoming Director General of
European Molecular Biology Laboratory (EMBL), as senior consultant to advise theInstitute’s research direction and management, establishing a tight link with EMBL.
Further, the Institute will establish a link with international institutions such as the University of
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Cambridge and Karolinska Institute (see 2)-3 Linkage with Other Institutions for details), creating astratified organization for research promotion and strengthening the Institute’s
international profile and competitiveness.
４) -2 Establishment of international research environment* Describe your concrete strategy for establishing an international research environment, administration system, and support system (e.g.,
appointment of staff and provision of startup funding) to accommodate researchers from overseas.
* Concretely describe how the center will provide an environment in which researchers can work comfortably on their research by being
exempted from duties other than research and related educational activities, and how they will be provided adequate staff support tohandle paperwork and other administrative functions. Include your procedure and time schedule.
* Describe your strategy, procedure and timing for periodically holding international research conferences or symposiums (at least once ayear).

Internationalization of Administrative Supports in the InstituteIn the Institute, the administrative staffing will comprise bilingual employees. Paperwork, e-mailexchanges, and other internal communications will be performed in both English and Japanese.
Additionally, the Institute will provide a wide range of support to foreign researchers and their families
for the duration of research activity and their daily lives in Japan, in cooperation with the International
Service Office of Kyoto University. If necessary, the Institute administrative staff will accompany theforeign researchers to municipal government offices to complete registration procedures.
Support for
Research Activity

Support in Daily Life

Laboratory start-up support
Management of research funds
Seminars on research ethics, information security, and other topics
Introduction to the foreign researcher community
Provision of visa and certificate of eligibility before arrival
Residential registration at municipal government offices
Housing information (orientation concerning deposits/key money)
Application for university accommodation
Medical care and national health insurance
Japanese language education

International Research Meetings at the Institute
The Institute plans to hold international symposia, workshops, and seminars, by inviting world-leading
researchers. Such gatherings would greatly stimulate the intellectual curiosity and motivation of theinstitute researchers, particularly the younger researchers and graduate students.
International Symposium

PI Seminars
Meetings Based on
Younger Researchers’ Initiative

The institute will hold an annual international symposium, to whichworld-class investigators in the Institute’s specialty research fields
and related fields are invited.
Individual PIs at the Institute will each hold a seminar at least once
every two years (or six times a year for the Institute as a whole),
inviting researchers whose recent work has been highly
distinguished.
Younger researchers are highly encouraged to hold interdisciplinary
meetings together with investigators in other fields.

Supports for Overseas PIs and Independent Young Researchers
Overseas PIs and younger, independent researchers will be provided with a start-up fund, research
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space, and employment expenses.
Overseas PIs (four professors)
Independent Young Researchers(three associate professors)
Domestic PIs (nine professors)

One associate professor (as co-PI)
Two postdoctoral fellows
200 m2 research space
Start-up fund (JPY 30 million)
One assistant professor
200 m2 research space
Start-up fund (JPY 10 million)
Three postdoctoral fellows

5) Center Management and System Reform5) -1 Project management* Describe the role of the center director and the administrative director.
* Concretely describe your concept for establishing an administrative organization, the center’s decision-making system and how authority
is allocated between the center director and the host institution.
* Concretely describe how the center will adopt a rigorous system for evaluating research and will introduce a system for merit-based
compensation (e.g., annual salary scheme). Describe your procedures and timing for operationalizing these systems.

The Institute’s Independence within its Host Institution
The WINDOW concept was formulated in August 2015 by Kyoto University as a vision for its future. WPI
is an important aspect of this concept (Strategic Priority 2-2).

To realize this conceptual plan, in April

2016, Kyoto University created a new organizational structure called Kyoto University Institute forAdvanced Study (KUIAS) to house WPI as a permanent entity. The KUIAS is designated a special
district having a high degree of autonomy. Under the KUIAS umbrella, the Institute’s director can
exercise strong leadership, implementing top-down management.

Decision-Making System within the Institute
The director of the Institute will have the authority to make the final decision on important matters, suchas the choice of research direction, personnel affairs, and budgetary concerns. The executive board,consisting of the director, two vice directors, two PIs, and the administrative director, will convene oncea month to discuss important matters under the leadership of the director. A PI board comprising 13
PIs, 4 co-PIs#1, and 3 independent associate professors will discuss the matters decided by the
executive board and make concrete decisions and action plans concerning the Institute.

The external

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World Premier International Research Center Initiative (WPI)
advisory committee comprising five internationally recognized researchers including Professor Edith
Heard will evaluate the activities of the Institute periodically (e.g., once a year) and provide advice on
the implementation of programs.
Administrative Office Supporting the Institute research#1Co-PI System

A co-PI system will allow overseas researchers to participate in the Institute’s research activities. Four overseas PIs
will respectively employ younger researchers (associate professors) as co-PIs. These co-PIs will study full-time at theInstitute, maintaining close contact with overseas PIs.

The administrative office will consist of the administrative director, the strategical research support
section, and the management section (general affairs, finance, overseas/public relations). Tadashi
Ogawa, the prospective administrative director, is currently the program manager at both the HAKUBI
and K-CONNXE researcher development programs#2 (where he has served for more than 3 years).
Under the leadership of the director, the administrative director will lead and manage these two sections.
The strategic research support section will employ two URAs (PhD holders in biology or life science).
#2Kyoto University HAKUBI and K-CONNEX projects

Both the HAKUBI and K-CONNEX projects aim at fostering young researchers and currently employ ~60
associate and assistant professors. Their research activities are highly evaluated and have major influence worldwide(an article from HAKUBI published in Nature was selected as one of the 2017 top-10 papers in physics). The HAKUBI
project is managed by the university’s own fund, and K-CONNEX is managed by the fund from MEXT.
#3Kyoto University Research Administration Office: KURA

KURA is the largest URA organization in Japan, and its work is highly respected. KURA received the highest
possible score of an S-rank in the MEXT’s interim (mid-term) evaluation. KURA currently consists of more than 40
URAs whose role is to strategically support university functions, intra-university synergies, and international
commitment, and enhance the research environment, by promoting university reform, research enhancement, andglobal engagement.

The URAs will play a key role in planning and implementing programs to foster younger researchers,international training courses, academic–industry cooperation, and other programs. To effectively fulfill
such missions, the administrative director and the two URAs of the Institute will operate as a hub,maintaining close cooperation with KURA#3 and the HAKUBI/K-CONNEX projects.
Evaluation System and Incentives
The Institute will introduce an additional-compensation program as an incentive founded on theperformance of the director, vice directors, PIs, and administrative director. The performance of these
individuals (except that of the director) will be evaluated in a formal manner, with the amount ofcompensation being determined by the director.

The director’s incentive will be determined by acommittee including some executive directors (vice-presidents) of Kyoto University, with consideration
for the achievements of the Institute.
Fostering Young Researchers and Supporting Research Activities of Female Researchers
To foster young researchers, the strategical research support section will hold various seminars andworkshops. For example, younger researchers will learn the art of scientific writing directly from theeditors of Nature (Nature masterclasses) and will learn how to find and obtain overseas research

positions (the Nature job interview). In order to promote gender equality, the Institute will provide theessential support for female researchers to balance work with personal responsibilities such as childbirthand childcare, in cooperation with the Kyoto University Gender Equality Promotion Center.
Kyoto University-20
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World Premier International Research Center Initiative (WPI)
5) -2 Research environment* Concretely describe how equipment and facilities, including laboratory space, will be provided in a manner appropriate for a “world
premier international center.” Include your procedure and timing.
* Concretely describe how the center will consider to arrange for its researchers to participate in the education of graduate students.
* Describe your measures other than the above to ensure that world’s top researchers from around the world can comfortably devote
themselves to their research within an international and competitive environment at the center.

Research Spaces and Facilities
Kyoto University provides 4,600 m2 of space for research activity at its Faculty of Medicine Campus:
1,700 m2 of new space, in addition to the existing 2,900 m2 of space designated for the 9 PIs of Kyoto
University. Most research spaces related to the Institute will be located closely. The new space will be
used for the four overseas PIs, the three young PIs, the core for single-cell genome analyses, meetingrooms, the director’s office, and the administrative division office. Moreover, another space (the total
floor space: 19,000 m2) in the same area will be secured for a new building, providing the opportunity
for all researchers in the Institute to be gathered within the same building.
The Specialization and Uniqueness of the Institute Cores Will Enhance Visibility andCompetitiveness
The Institute will implement two cores to facilitate its capacity for research development.

First, theInstitute will establish the core for single-cell genome information analysis within the Institutebuilding at Kyoto University.

To greatly strengthen its international competitiveness, the Institute will

strategically introduce a set of ultra-fast, high-performance, and/or large-scale analysis instruments andimprove their performance by assigning two technical staffs, in addition to several highly-skilled staff
scientist, to the core.

Second, the core for primate genome editing will be established at the

Research Center for Animal Life Science of the Shiga University of Medical Science, which has one of thelargest colonies of cynomolgus monkeys in Japan.

The Institute will also set up

high-performance instruments in this core. The specialization and uniqueness of the two cores will
enhance the visibility and competitiveness of the Institute.
Opportunities for Teaching Graduate and Undergraduate Students
The Institute is a core institution of KUIAS, whose faculty members are able to participate in the
education of graduate students, within the confines of the agreement between KUIAS and the graduate
school. Additionally, Kyoto University hosts teaching courses called ILAS seminars, in which faculty
members educate small numbers of undergraduates face-to-face.

This will provide the chance toperform outreach to young students and to draw their attention to the basic sciences in order to secure
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World Premier International Research Center Initiative (WPI)
the next generation of researchers.
5) -3 Establishing an independent research center in sync with reorganizing the hostinstitution* Concretely describe how your proposal seeks to establish a new center that will achieve independence within 10 years and how the
project will advance synchronization between WPI center support and reform of the host institution’s existing organization?
* With prior consent from the host institution, describe concretely the host institution's mid-to-long-term plan and schedule for achieving
the center's independent operation within the host institution, including adjustments to the existing organization and/or acquisition of
external funding.

The Institute as a Permanent Research Institution in KUIASAs previously noted, Kyoto University has created a new organizational structure called KUIAS to house
WPI on a permanent basis.

Because KUIAS is designed as a special district, having a high degree of

autonomy, the Institute’s director will have the freedom to implement strong leadership, making
decisions on the most important matters concerning the Institute.
Exceptional and Unique Core Facilities Will Contribute to the Independence of the InstituteAs described above, the Institute will strategically establish two cores to provide specialized functions inJapan. The specialization and uniqueness of these core facilities (including the technical know-how
to use them) will enable them to grow as central research hubs, effectively realizing core facilities for thewhole of Japan (FY2018, FY2019).

The Institute plans to hold open-use programs and international

training courses, in which other university researchers and company investigators will be able to utilize
the core facilities, further increasing the visibility of the Institute (beginning FY2021). In addition, theimprovements of the facility performance and the accumulation of technical know-how will enhance thecompetitiveness of the Institute.

Based on this strong visibility and competitiveness, the Institutefaculty members will attempt to acquire major external funding, in cooperation with those researches
who are not the Institute members but heavy/power users of the core facilities, in order to maintain andrenew the core facilities after the end of the WPI support period (after FY2023).
Systematic Support by KURA for the Acquisition of Large-scale External Funding
Although the PIs of the Institute will have significant ability to obtain external funding, this may not be
sufficient to sustain the Institute following the grant period.

So that the Institute can achieve

independence, KURA will support it to increase the amount of its overall budget.

KURA will be able toprovide crucial support for the acquisition of overseas, large-scale external funds. Additionally, KURA
will provide crucial support for foreign researchers seeking KAKEN grants, revealing any barriers to entry
for foreign researchers and assisting them to overcome those barriers.
Securing Indirect Costs of Appropriate Scale for the Institute's Independence
To ensure the Institute's independence after the end of the WPI support, the Institute must fund its
indirect costs, such as management personnel expenses, facility depreciation, cost of lighting, andheating. However, it is difficult to directly calculate indispensable indirect costs.

The University will

make a prototype model that can appropriately evaluate the amount of the indirect costs required forthe Institute’s management (FY2019, FY2020).

This model will be actually applied at the Institute as atest bed (from FY2021).

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Prospective Center Director’s Vision
We propose to establish the Institute for the Advanced Study of Human Biology, with the mission of elucidating
the design principles of human traits, including disease states. The Institute will investigate key targets in humanbiology using multi-disciplinary integrative strategies and clarify the grand design of human attributes. The
knowledge gained should provide insights into human evolution, while also creating a basis for delineating
disease etiologies and developing innovative therapies, thereby promoting health from birth to senescence(Figure).
Understanding the basic biology of human beings is a fundamental challenge in the field of life sciences. In the 20th
century, the life sciences have elucidated the physical/chemical basis of life, demonstrating that basic processes forlife have largely been conserved during evolution. On the other hand, the knowledge gleaned from model organisms
has often been difficult or impossible to translate to human biology due to species differences in the regulations of
key basic pathways. Accordingly, many outcomes of drug discovery research in model organisms such as mice
have not been replicated in human clinical trials. This is not entirely surprising, considering that humans andmice have evolved independently over ~80 million years. The two species have diverged in crucial ways, withhumans securing a much longer time span for individual development and growth, acquiring unique metabolic
regulations, and achieving a remarkable development of their brain functions. Although the genome andtranscriptome in many organisms have now been sequenced, the exploration of species-specific genefunctions, particularly in humans and other primates, is only in its incipient stage, and the methodologies for
integrative analysis of multi-omics information across species remain to be developed.
The exploration of human biology thus necessitates the use of human materials. However, such materials, inparticular those for human development, are technically and ethically difficult to obtain, and consequently, themechanism for the origin of human life, i.e., human development, has been elusive. Note that the access to humanmaterials is more restricted in Japan than other countries. To circumvent this difficulty, it is critical to create asystematic opportunity for access to human materials, as well as for the use of non-human primates as a humanmodel. In this context, however, it should be noted that even the macaque monkeys (e.g., rhesus and cynomolgus
monkeys), who are the closest to humans among the models amenable for experimentation, have evolved
independently from humans over ~25 million years. Hence, to promote human biology significantly beyond thecurrent practice, it is imperative to perform parallel investigations into humans and non-human primates,and simultaneously, to clarify the principles for the emergence of species differences, allowing an
extrapolation of the knowledge from model organisms to humans. Indeed, in a broader context, a major
challenge for the 21st century life sciences is to understand the mechanistic basis of species differences—i.e.,the diversity of life forms driven by evolution.
Accordingly, the Institute will target humans and non-human primates as major research subjects in an effort touncover the design principles of human beings and disease states, through a multi-disciplinary science approach.
This approach consists of meticulous analysis of target processes, systems-level understanding of the collated
information, reconstitution of key lineages, tissues and disease states based on such information, and further
analysis of the reconstituted systems, leading to“synthesis” of a comprehensive understandingof target processes.
Towards this goal, the Institute will perform
intensive investigations on key targets inreproduction, development, growth and aging
as well as heredity and evolution. Moreover, theInstitute will establish two lines ofinterdisciplinary science and two core facilities for
cutting-edge technologies to deliver a highly
coherent research program.
First, by creating a fusion between the life
sciences and mathematics, such as machinelearning and topological data analysis to
extract the geometry of large-scale data, wewill define the principles of the emergence of species differences in phenotypes of homologous cells based on
multi-species/multi-cell type/multi-hierarchical omics information, allowing better extrapolation of theknowledge from model organisms to humans. We will extend this analysis to identify principles for the species
differences on the scales of time and physical dimensions in development and growth. Second, by integrating thehumanities and social sciences, we will formalize an ethics for an appropriate use of human and non-human primate
materials and create a philosophy regarding the values of research outcomes of the Institute.
With respect to the two core facilities, we will first establish a core for single-cell genome information analysis
to facilitate the acquisition of high-quality, multi-hierarchical, large-scale omics data for gene expression, genome
sequence and structure, and epigenetic profiles at the single-cell resolution. Second, we will implement a core forprimate genome editing, which will provide a stable supply of embryos/adult tissues of macaques and create
macaques lacking key genes for primate-specific traits for disease modeling and biological analysis. In particular,
this core will generate disease models for the nervous system and the kidney, two key examples for whichrodent models have been largely unsuccessful in drug screening. Note that Kyoto University will expand onthese core-facilities for utilization throughout Japan.
Thus, on the basis of individual research focusing on key targets in human biology, the Institute will elucidate theprinciples underlying the emergence of species differences, reconstitute key lineages and tissues, and generate
primate models for specific gene functions and intractable diseases. Together, these efforts will realize advanced
study of human biology as a forefront life science in the coming decades and as a foundation fortransformative therapeutic interventions.
The prospective center director, Professor Mitinori Saitou, has been a world leader in germ cell biology and in vitro
reconstitution of germ cell development (for review, see Cell Stem Cell, 2016). To extend the findings in mice tohumans, Professor Saitou has promoted research using cynomolgus monkeys and created a basis for defining thespecies differences among humans, monkeys and mice. This includes elucidation of a developmental coordinate of
the spectrum of pluripotency among mice, monkeys and humans (Nature, 2016); the finding that the germ celllineage in primates originates in the nascent amnion (Dev. Cell, 2016); and a robust induction of germ cell fate fromhuman iPSCs and the identification of an underlying transcriptional architecture unique to primates (Cell Stem Cell,
2015; 2017). In addition, Professor Saitou established a procedure for single-cell transcriptome analysis more than adecade ago (NAR, 2006; Genes Dev., 2008). Professor Saitou’s research thus represents a benchmark of thesynthesis approach, which will be further broadened in his vision of the advanced study of human biology.
The Institute for the Advanced Study of Human Biology will build a critical mass of scientific expertise by drawing
scientists with outstanding potential from Kyoto University and relevant institutions in Japan and overseas, creating
an intellectually interactive and highly collaborative setting.
To realize an international research effort, the Institute will provide principal investigators (PIs) from overseas withadequate budget support for building teams of professional research staff and postdoctoral researchers. It will call all
the staff and postdoc positions by open international recruitments. In addition, the budget from the Institute supports
the recruitment to each PI team of at least one non-Japanese staff/postdoc. The Institute will appoint Professor
Edith Heard, who is the incoming Director General of European Molecular Biology Laboratory (EMBL), as
senior consultant for advising the Institute’s research direction and management, establishing a tight linkwith EMBL. Further, the Institute will establish a link with international institutions such as the University ofCambridge and Karolinska Institute, creating a stratified organization for research promotion andstrengthening the Institute’s international profile and competitiveness.
Finally, we should note that the missions of this Institute will be clearly distinct from those of the Institute forIntegrated Cell-Material Science (iCeMS). iCeMS has accomplished outstanding research on the regulation of
biological processes using materials such as porous coordination polymers, and has become a member of the WPI
academy. Kyoto University founded the Institute for Advanced Study (KUIAS), to which it assigned iCeMS as aconstituent institute, thereby realizing a system for the continued development of iCeMS. As a new WPI at KUIAS,
the Institute shares an administrative department with iCeMS, and adopts and further advanceswell-established and successful administrative systems for its effective management, playing a leading role in
the revitalization of the University.

World Premier International Research Center Initiative (WPI)
Host Institution’s Commitment
29/05/2018
To MEXT
Kyoto University
Juichi Yamagiwa, President
Signature

I confirm that the measures listed below will be carried out faithfully and concretely as follows regarding“Institute for the Advanced Study of Human Biology” if it is adopted under the World Premier International
Research Center Initiative.

Concrete Measures

・Describe the concrete measures that the host institution will take to satisfy the following requirements.

1)

For the center to become a truly “world premier international research center” andindependent by the time WPI support ends, the host institution must clearly define thecenter’s role within its own mid-to-long-term strategy and provide its comprehensive
support from the time that the funded project starts.
※Describe the center’s role within host institution’s own mid-to-long-term strategy.

Kyoto University clearly defines the role of the Institute for the Advanced Study of Human Biology
in its mid-to-long term strategy and provides its comprehensive support to the Institute.
<Positioning of the Institute in the University’s mid-to-long-term strategy>
The roles of the WPI center are clearly specified in the University’s mid-to-long-term
concepts/plans, namely, “Kyoto University’s Vision for the Future (the WINDOW concept),” “MediumTerm Goals and Plans,” and “Designated National University Proposal.”

The “Kyoto University Institute for Advanced Study (KUIAS)” was set up as a foundationalorganization for the purpose of gathering superior researchers from Japan and around the world,
creating an international research center with flexible organization, achieving an organizational
structure able to respond to globalization, and providing research support functions.
By positioning the WPI center within KUIAS, we have laid down the organizational structure tocreate a world-leading research center.
<Comprehensive support from the host institution>･ Balancing intra-university interests by the Kyoto University provost
The “Kyoto University Provost” and the “University Strategy Council” will balance the interests ofother departments to provide quick and flexible support for the Institute.
･ Organizational support by Kyoto University Research Administration Office (KURA)
The Institute could receive organizational and comprehensive support from KURA, which is thelargest URA organization in Japan (over 40 URAs) and received the highest possible score “S-rank”
on MEXT’s interim evaluation. Further, Kyoto University employs two URAs at the Institute, and they
operate as a hub maintaining close cooperation with KURA.
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World Premier International Research Center Initiative (WPI)･ Collaborative support by the Kyoto University HAKUBI project
The HAKUBI project aims to foster and support young researchers who will pioneer new paths intheir fields. This project currently employs more than 40 associate and assistant professors. Kyoto
University proactively offers opportunities for the Institute’s younger researchers to collaborate with
HAKUBI researchers, promoting the creation of new interdisciplinary research.
2)

Providing a mid-to-long-term policy for amending the plan on the direction of the hostinstitution’s organization and operation, one that includes the reform of the institution’s
existing organization in ways that will achieve the center’s independence and create apermanent place for it within the organization. A concrete plan and schedule must be set
and carried out for restructuring the host institution’s organization.
※Describe both a mid-to-long-term policy for amending the plan on the direction of the host institution’s organization andoperation and provide a concrete plan and schedule.

<Establishing and maintaining a globally competitive core research facility>

To become a truly world-leading research center, it is essential for the center to possess globallycompetitive research facilities shared by researchers across Japan (core facility). Actually, the Instituteplans to establish two globally competitive core facilities. One is the Core for Single-cell Genome
Information Analysis, which has ultra-performance instruments and robust analysis technologies forgenome analyses at the single-cell level. The other is the Core for Primate Genome Editing, which has
one of the largest colonies of cynomolgus monkeys for genetic manipulation in the world. In addition
to several highly-skilled staff scientists, two or more technical staffs will be exclusively assigned tothese facilities to maintain and improve the performance of their instruments and analysis
technologies.

The Institute’s efforts to establish and maintain these two core facilities will serve as a basis tomake a generalized model, which are applicable to other departments, to set up a globally competitive
core facility. The University will take the initiative to spread this model to other departments.
<Basic plan/schedule>･ Set up the instruments and technologies of the core facilities (FY2018/FY2019).
･ Develop the core facilities so as to become a university-level research center (FY 2021).
･ To provide open-use programs and training courses that other university researchers/students andcompany investigators can use as core facilities(FY 2021).
･ Improve and renew the instruments of the core facilities to maintain their competitiveness (FY2023).
<Securing indirect costs of appropriate scale for the center’s independence>

To ensure the independence of the center after the end of the WPI grant, the center must fundits indirect costs, such as management personnel expenses, facility depreciation, cost of lighting, andKyoto University-2
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World Premier International Research Center Initiative (WPI)
heating. As it is difficult to directly calculate indispensable indirect costs, they are conventionallydetermined by the ratio to direct costs in Japan. However, this ratio is often inappropriate and could
result in insufficient funds after the grant ends. To determine indirect costs of appropriate scale, Kyoto
University has created a new basic estimation model, like in Europe and the United States. Throughits experiences at the Institute, the University has also created a generalized estimation model
applicable to the other departments within the university. The University has taken the initiative tospread this estimation model across Japan.

<Basic plan/schedule>･ The University analyzes the indirect cost data in the Institute to formulate a new estimation modelthat can appropriately evaluate the indirect costs required for the Institute’s management, and thenverifies this model (FY2019, FY2020).
･ The new estimation model is applied in the Institute as a testbed (from FY2021).
･ The indirect cost model is generalized so that it can be applied to other departments within the
University (from FY2023)
3)

Provide sufficient support for carrying out the center’s operation and research activities,
including necessary personnel, financial, and system support.

In order to carry out the Institute’s operation and research activities, Kyoto University provides
various supports as described below.
<Personnel support>
Kyoto University takes responsibility for the personnel expenses for the director, the vice director,
six PIs designated to Kyoto University, the administrative director, two URAs at the Strategic Research
Support Office of the Institute, and two technical specialists at the Institute’s Core facility.
The university also takes responsibility for the personnel expenses for three independent associate
professors (from FY2023)
Of the 13 administrative staff, three are employed as permanent employees of Kyoto University.
<Financial support>
The Institute is allowed to take all indirect funds associated with competitive grants acquired by
the Institute’s researchers.
<System support>
The age limit retirement system is abolished and a flexible allowance payment system is applied.
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World Premier International Research Center Initiative (WPI)

4)

Provide necessary support to achieve the independence of the center and sustain its
research at a top world level after the WPI grant period ends.

Kyoto University will continue to supply the Institute with the support stated in (1)–(3) and (5)–(9) after the end of the WPI grant.
5)

Provide a system that will in practice allow the center director to make decisions in
implementing the center project, including personnel and budgets, and that will secure theautonomy of its operation.

Under the umbrella of KUIAS, which is a special research district at Kyoto University, the Institute’s
director has the authority to make the final decision on important matters, such as choice of research
direction, personnel affairs, and budgetary concerns.
6)

Provide support to the center director by coordinating with other departments regarding theassigning of researchers to the center and the creating of an effective environment for thecenter within the host institution. Needed adjustments to do so should be made proactively
while giving consideration to their effect on the educational and research activities of thosedepartments.

In the WINDOW concept (Strategic Priority 5-3), Kyoto University declares the following:

In order to break new ground in uncharted domains of academic endeavor, Kyoto University
implements flexible and effective reorganization that removes the boundaries of existing academic
departments through the Faculty Consort/ Platform System #1 of academic staff organization.
Based on this conceptual direction, Kyoto University provides all-out support for the Institute’s
director by proactively adjusting the interests of other academic departments whose researchers aredispatched to the Institute.
#1

7)

京都大学 学域・学系制

Offer cooperation in flexibly applying, revising, or supplementing the host institution’s
internal systems as needed for the center to effectively implement new management
methods unfettered by conventional modes of operation (e.g. English-language
environment, merit-based pay, top-down decision making, linkage to graduate school
education).

Under the umbrella of KUIAS, which is a special research district at Kyoto University, it is possible
to flexibly revise and improve the institution’s systems, such as abolishing mandatory retirement,
establishing an incentive system based on performance, assigning bilingual administrative staff, anddetermining personnel affairs based on top-down management by the Institute’s director.
8)

Secure, provide and deliver the necessary infrastructure for the center to carry out its
activities (e.g. research space, facilities, land).

<Research space>
Kyoto University is providing 4,600 m2 of space for research activity in its Faculty of Medicine
Campus, specifically 1,700 m2 of new space in addition to the existing 2,900 m2 of space designatedfor the director, one vice director, and the six PIs of the University. The new space will be used forthe research activities of new four overseas PIs (including one vice director), three independentassociate professors, and one core facility (the core for the single-cell genome information analysis).
Moreover, space for a new building (the total floor space: 19,000 m2) has been secured in thesame area (1 or 2 minutes’ walk from the main building) for the future expansion of the center.
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World Premier International Research Center Initiative (WPI)

Space for center executives and the administrative division
A director’s room, conference rooms, administrative division offices, and open space for researcher
interactions will be provided in the same area as the research space, facilitating regular interactions
between the Institute’s executives, researchers, and administrative staff. Another director’s room will
be secured in the KUIAS building, enabling regular exchanges with KUIAS’s executives and theutilization of KUIAS’s expertise and knowledge.
Use of animal research facilities
Participating researchers will be given approval to use the Institute of Laboratory Animals, which
is one minute’s walk from the main research building, in the Graduate School of Medicine Kyoto
University.
9)

Provide other types of assistance to give the center maximum support in achieving its
concepts and objectives and in becoming a world premier international research center inboth name and deed.

Kyoto University provides maximum support for the establishment of the Institute as a leadinginternational research center under the University’s mid-to-long-term vision.
10) The host institution is to self-evaluate the results of the system reforms achieved by thecenter and distribute the results that it evaluates highly to all of its departments.

The two URAs assigned to the Institute qualitatively and quantitatively examine the Institute’s
system reform efforts and their outcomes. The Institute’s URAs summarize the results and propose
generalized reform models for the University, in cooperation with KURA.
The University Strategy Council members and the University executives evaluate the Institute’s
system reform outcomes and the proposed reform models. If positively evaluated, the Kyoto
University Provost will take the initiative to spread the good system reforms to other departments
throughout the University.
11) (For host institutions that already have an existing WPI center) Fully support and sustain
the existing center and advance its development as a top world-level research institutewhile being concurrently capable of fully supporting the new center.

The existing WPI center, iCeMS, is now located as a core and the research institute of KUIAS as apermanent entity. Separate to the support for the new WPI center, Kyoto University will provide
personnel support for iCeMS (11 tenure posts) as well as financial support (full allocation of indirect
expenses to iCeMS from competitive grants acquired by the institutions’ researchers). Kyoto University
will support both research institutions continuously in the future.
12) (For host institutions that already have an existing WPI center) Take the initiative to spreadthe existing center’s good system reform results to other departments throughout theinstitution and thus applied them to its own reform.

Kyoto University has extended the good system reform results from iCeMS throughout theuniversity. Three representative examples are shown below.
1) System reforms newly provided by iCeMS such as the cross-appointment system, annual salarysystem, and exceptions to mandatory retirement have been introduced in other departments(Graduate School of Advanced Integrated Studies in Human Survivability, the Institutefor Liberal Arts and Sciences, and KUIAS).

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World Premier International Research Center Initiative (WPI)
2) Various forms of support for foreign researchers from the Overseas Researchers Support
Office in iCeMS have led to the establishment of the International Service Office in the University.
This has been expanded to many other departments in the University.
3) Based on knowledge gained at iCeMS concerning international public relations, a new Officeof Global Communications was established in the University in October 2015.

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World Premier International Research Center Initiative (WPI)
List of Principal Investigators
・If the number of principal investigators exceeds 10, add columns as appropriate.
・Place an asterisk(*) by the name of the investigators who are considered to be ranked among the world’s top researchers.
・Give age as of 1 April 2018.
・For investigators who cannot participate in the center project from its beginning, indicate the time that their participation will start in the “Notes” column.
・If there are changes from the PI list in the first screening application documents, describe the points changed and reasons in the “Notes” column.
・Include principal investigators affiliated with satellite institutions. Give the name of their satellite institutions in the “Notes” column.
・Fill in the achievements of each PI in the “Biographical Sketch of Principal Investigator."

Name

1

Mitinori Saitou＊

Age

Current affiliation(Department/
School/Institution) ・Title

Specialization

Effort *(%)

47

Professor, Department of
Anatomy and Cell Biology,
Graduate School of Medicine,
Kyoto University

Cell Biology,
Developmental
Biology90%

Neuroscience80%2Tadashi Isa＊

57

Professor, Department of
Physiology and Neurobiology,
Graduate School of Medicine,
Kyoto University

3

Yasuaki Hiraoka＊

40

Professor, Kyoto University
Institute for Advanced Study

Mathematics,
Topological Data
Analysis

80%

4Anne C FergusonSmith＊56

Arthur Balfour Professor of
Genetics and Head of the
Department of Genetics,
University of Cambridge

Epigenetic
Inheritance,
Mammalian
Developmental
Genetics

15%

5Guillaume Bourque＊

41

Associate Professor, Human
Genetics, McGill University

Bioinformatics,
Genomics,
Epigenomics

30%

55

Professor, Department of
Pathology and Tumor Biology, Hematology, Cancer
Graduate School of Medicine, Genetics
Kyoto University

90%

Human
Immunology

95%

6

Seishi Ogawa＊

7

Hideki Ueno＊

50

Professor, Department ofMicrobiology
Global Health and Emerging
Pathogens InstituteIcahn School of Medicine atMount Sinai

8

Takashi Hiiragi＊

50

EMBL Group Leader

Cell Biology

20%

43

Professor, Laboratory ofDevelopmental Systems,
Institute for Frontier Life andMedical Sciences, Kyoto
University

Developmental
Biology, Stem Cell
Biology70%

9Mototsugu Eiraku＊

Notes

10

11

12

13

Motoko Yanagita＊

Takuya Yamamoto

Masatsugu Ema

Misao Fujita

48

Professor, Department ofNephrology, Graduate Schoolof Medicine, Kyoto University

Nephrology

70%

40

Associate Professor,
Department of Life Science
Frontiers, Center for iPS Cell
Research and Application,
Kyoto University

Molecular Biology,
Bioinformatics

70%

49

Professor, Department of Stem
Developmental
Cells and Human Disease
Biology, Human
Models, Research Center for
Disease Modeling
Animal Life Science, Shiga
University of Medical Science

70%

48

Associate Professor, Uehiro
Research Division for iPS Cell
Ethics, Center for iPS Cell
Research and Application,
Kyoto University

70%

Bioethics,
Psychology

Satellite institution: Shiga
University of Medical
Science* Percentage of time that the principal investigator will devote to working for the center vis-à-vis his/her total working hours. (Activities carried out using
competitive funding can be included as effort as long as they correspond to the purpose of the WPI center and are conducted for the center.)

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