Summary of Research Center ProjectCenter name:
Human Biology-Microbiome-Quantum Research Center (Bio2Q)
Host institution: Keio University
Head of host institution: Kohei Itoh, President of Keio University
Prospective center director: Kenya Honda, Professor, Keio University School of Medicine
Prospective administrative directors: Oltea Sampetrean (Assistant Professor) and Haruhiko Siomi(Professor) Keio University School of Medicine(1) Overall Framework of the Center Project
1. Mission Statement: We will establish a new life science research institution (Human BiologyMicrobiome-Quantum, namely the “Bio2Q” research center) aimed at furthering our understanding of how
humans process external environmental information and maintain homeostasis by dispersing andintegrating signals among cells/organs, at resolutions higher than those achieved so far. We will address
the question of how human homeostasis is regulated by the epithelial, immune, nervous, and metabolic
systems, with an emphasis on microbiome analysis. We will conduct multimodal analyses of humanspecimens by leveraging microbiome, genomic, and metabolomic approaches. Further, we will develop anovel pipeline that implements quantum computing together with artificial intelligence (AI) to robustly
analyze the collected multiomics data and uncover novel multiorgan interaction pathways. The causalityof the associated pathways will be verified through state-of-the-art technologies in structural biology,
connectomics, organoids, and humanized animal models. Our mission is to forge a new interdisciplinary
research area that will lead to groundbreaking progress in elucidating the regulatory mechanisms of
biological homeostasis in humans. In the long term, we will develop new prophylactic/therapeutic
approaches to promote healthy longevity.
2. Identity: In humans, homeostasis is maintained through complex interactions between multiple organs.
This interaction includes the microbiome, which exists on every external surface of the body, and theresulting information is converted, regulated, and utilized in a coordinated manner. Under the direction ofa world leader in microbiome research, our center will draw from the experience of top experts in multiple
life science disciplines in the Bio-1 (Multidimensional data analysis) and Bio-2 (Homeodynamics
mechanistic analysis) core units. Furthermore, the center will implement a quantum computing (Q) core to
support these Bio cores, reducing the time it takes to discover biological pathways and bring scientificbreakthroughs from bench to bedside. The Q core is the only team in Japan that can perform bothannealing and gate-based quantum computing and will be the first to address complex biology andmultidimensional omics data. Thus, our center will function as a unique and highly competitive research
institution that will establish a new interdisciplinary research field by blending human biology, microbiome,and quantum computing research with the goal of decoding the human multiorgan homeostatic interactions.
3. Goals of the program: To accomplish our mission, the collaborative team will focus on six main goals:
1. Accumulate multiomics data from humans (including those from centenarians) and model organisms(animals/cells) and compile a multidimensional database. 2. Elucidate the structure and function of
microbiome-derived metabolites. 3. Refine imaging metabolomics and structural biology to promote in situ
functional analysis of metabolites in organs and cells. 4. Develop quantum computing-based algorithms
and pipelines to analyze the complex interactions between multiple organs and microorganisms. 5.
Establish research approaches that can model the interface between the environment and epithelial,
immune, and nervous systems by advancing organoid technology and animal models and elucidate themechanisms underlying the conversion of information from external environmental factors into internalsignals. 6. Invent new technologies in connectomics and structural biology to understand the organizedcomplexity and dynamic multiorgan interactions, including gut-brain communication.
By achieving these goals, we will generate a new entity of life science and decipher causal
relationships in multiorgan and microbiome interactions in humans during health and disease, with a

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particular emphasis on the understanding of microbiome-derived metabolites, microbiome-epithelialinteractions, gut-brain communication, and healthy longevity in a way that cannot be accomplished byconventional approaches.
(2) World-Leading Scientific Excellence and Recognition
1) Research content: We will establish three core units designed to accelerate the discovery andvalidation workflow to identify multiorgan and microbiome interactions: Bio-1, Multidimensional data
analysis core (Core Director: Makoto Arita); Bio-2, Homeodynamics mechanistic analysis core (Core
Director: Toshiro Sato); and Q, Quantum computing core (Core Director: Shu Tanaka). These threecores will share technologies, expertise, and pipelines to streamline data generation, mining, andevaluation. The Bio-1 core will analyze human multiorgan samples and model organisms by integrating
human microbiome, genomic, epigenomic, and metabolomic methods, and construct a multidimensional
database. The collected multiomics data will be analyzed in the Q core by quantum computing combinedwith AI to identify “quantum signatures” associated with the given phenotypes. Subsequently, thesesignatures will be evaluated in the Bio-2 core in collaboration with the Bio-1 core, using connectomics,
organoid, and structural biology techniques to validate the cause-effect relationships. An imaging
metabolomics team will operate at the interface between Bio-1, 2, and Q to detect small metabolite-derived
nuclear magnetic signals in situ at high sensitivity and spatial resolution, and identify the function of
microbiome-derived metabolites in the multiorgan networks. By accelerating the reverse translation cycle,
we will achieve and exploit novel discoveries in human biology to optimize the functioning of the hostmultiorgan system, reduce unfavorable or pathological conditions, and promote healthy longevity.
2) Interdisciplinary research: In recent years, it has become clear that the microbiome has a significant
impact on human health and organ systems. Microbiota exerts such effects primarily by producing tens of
thousands of unique chemicals (metabolites). However, the vast majority of metabolites (>99%) have notbeen annotated structurally and functionally (thus remaining unidentified “dark matter”). In addition, thedifficulty in accurate and high-throughput analysis of the community action of microbiota and their
metabolites has hindered efforts to define the mechanistic connections between the microbiota and hostphenotypes. Moreover, a comprehensive understanding of complex human biology requires an integrative
analysis of multiple levels of data from the genome, transcriptome, metabolome, together with microbiome.
However, it has been extremely challenging to infer causal molecular networks using multiomics data,
underscoring the importance of continuing to develop new approaches. Quantum computing represents
an exciting frontier with significant potential for discovery in the field of biological sciences, yet several
challenges remain, such as improving accuracy, fault tolerance, and lack of practical applications in life
sciences. Therefore, the Bio2Q WPI will harness quantum computing to shed light on the black box
separating the complex system involving multiple organs and the microbiome, and determine scientificcausal relationships. Establishing an algorithm/pipeline that fully utilizes the power of quantum computing
will pave the way for significantly improving the discovery process in biological sciences. Suchinterdisciplinary research requires the training of young scientists capable of collaborating acrossdisciplines. To foster such scientists, graduate students and postdoctoral fellows in the fields of biology(Bio-1, Bio-2) and computing (Q) will be mentored by multiple PIs across cores and laboratories.
(3) Global Research Environment and System Reform
1) International research environment: International up-and-coming multidisciplinary young researchers
will be recruited by a dedicated recruitment team based on the policy that is designed to ensure fair andobjective selection and decision processes. The working language will be English. We will ensure diversity
among Bio2Q researchers by having a variety of nationalities, genders, and ages, with the goal of having
at least 30% international and 50% female researchers. The administrative and support staff will help all
researchers in a way that they can devote themselves to their research. From the outset of the WPI project,a total of more than 3,000 m2 will be available for the center at Shinanomachi Campus, with 1,300 m2 as
the core facilities of a “globally visible” research center, which will include open labs, center support offices,

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and community space. After opening the WPI center, we will relocate and expand the center by considering
the construction of a new building on Shinanomachi Campus in anticipation of a facility that will allow
researchers to work together under one roof. In addition, a virtual research environment will be established
to bring together research activities using web conferencing systems and other data-sharing tools, creatinga strategy for close daily communication among researchers of Keio University and satellites (RIKEN,
CIEA, Harvard, MRB-LMB, NTU, Rockefeller, MIT, Yale, NYU, Broad Institute, and Stanford).
2) Center management and system reform: The center will be an independent research institute under
the administrative jurisdiction of Keio University. The Center Director will be appointed and dismissed by
the President of Keio University. Decisions regarding the general management of the center will be at thediscretion of the Center Director. We will establish a support office that will cover all facets of the center,
including intellectual property, DX, early career researcher training, and fundraising. In order to make thecenter self-sufficient and sustainable, the host institution will work to support the acquisition of externalfunding, strengthen intellectual property management, and establish a governance system that ensurescompliance while allowing freedom of research. Compensation will be determined by the Center Director
in line with a global standard (those implemented by the National Institutes of Health, USA) and basedon evaluations of research performance and other factors. An Advisory Council consisting of about fiveinternational scientists will be independently established to evaluate the scientific progress of the centerand provide advice regularly.
(4) Values for the Future1) Generating and disseminating the societal value of basic research
The mission of the center is to contribute to the sustainable development of society by creating knowledge
that leads to improved prophylactics and therapeutics for promoting healthy aging. We are committed topromoting the translation of basic research findings into practice in relevant healthcare settings. We willencourage researcher entrepreneurship and industry-academia collaboration. To this end, we will createa team dedicated to active outreach and publicity activities. We will develop ways to share the details of
our research findings and their value, particularly to the younger generation via lectures, workshops, andsocial media.
2) Fostering next-generation human resources linked with higher education
The center will strive to create positive feedback loops where faculty, researchers, and students areencouraged to work freely beyond academic disciplines. To achieve this objective, three Graduate Schoolsof Medicine, Pharmaceutical Sciences, and Science and Technology will establish a joint cross-disciplinary
graduate English program tentatively named STaMP (Science and Technology, and Medicine, Pharmacy)
in FY2023, inviting PIs and early career researchers from the center to participate in graduate education.
PIs will be qualified to supervise graduate research at STaMP, and students will be able to receive
guidance from multiple mentors across the different graduate schools. Keio University entered into a basic
research and education agreement with RIKEN and the Central Institute for Experimental Animals (CIEA).
The center will leverage these agreements to build stronger feedback loops to foster talent and expand
joint research opportunities. In addition, undergraduates and high school students will be considered as
potential WPI researchers, and we will encourage their participation in the activities of the center.
3) Self-sufficient and sustainable center development
The Bio2Q center will be a manifestation of the university's goal of "creation of convergence of knowledge"
and will serve as a model international, interdisciplinary, and autonomously growing research center. After
the WPI grant period ends, the center will remain in place in the form of the Institute for Advanced Studies(tentative), which will function as a "globally visible" research center. Keio will continuously uphold
university-wide commitment by bridging faculties/graduate schools across departments and enhancing avirtuous cycle. We continue to aim to translate research results into society via industry-governmentacademia collaboration and startup supports. Keio will implement structural reform to employ excellent
researchers at all career stages, and foster early career researchers via graduate education, etc. Throughthe above actions, Keio aims to serve as a model for international research centers at private universities,

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which have to generate their own financial resources in contrast to national universities.

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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

Research Center ProjectCenter name:
Human Biology-Microbiome-Quantum Research Center (Bio2Q)
Host institution: Keio University
Head of host institution: Kohei Itoh, President of Keio University
Prospective center director: Kenya Honda, Professor, Keio University 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 directors: Oltea Sampetrean (Assistant Professor) and Haruhiko Siomi(Professor) Keio University School of Medicine
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 theobjectives of the WPI program.

1. Mission Statement: We will establish a new life science research institution (Human BiologyMicrobiome-Quantum, namely the “Bio2Q” Research Center) aimed at furthering our understandingof how humans process external environmental information and maintain homeostasis by dispersing
and integrating signals among cells/organs, at resolutions higher than those achieved so far. We willaddress the question of how human homeostasis is regulated by the epithelial, immune, nervous, andmetabolic systems, with an emphasis on microbiome analysis. We will conduct multimodal analysesof human specimens by leveraging microbiome, genomic, and metabolomic approaches. Further, we
will develop a novel pipeline that implements quantum computing together with artificial intelligence(AI) to robustly analyze the collected multiomics data and uncover novel multiorgan interaction
pathways. The causality of the associated pathways will be verified through state-of-the-art
technologies in structural biology, connectomics, organoids, and humanized animal models. Our
mission is to forge a new interdisciplinary research area that will lead to groundbreaking progress in
elucidating the regulatory mechanisms of biological homeostasis in humans. In the long term, we willdevelop new prophylactic/therapeutic approaches to promote healthy longevity.
2. Identity: In humans, homeostasis is
maintained through complex interactions
between multiple organs. This interaction
includes the microbiome, which exists on
every external surface of the body, and theresulting information is converted, regulated,
and utilized in a coordinated manner. Under
the direction of a world leader in microbiome
research, our center will draw from theexperience of top experts in multiple life
sciencedisciplines
in
the
Bio-1
(Multidimensional data analysis) and Bio-2(Homeodynamics mechanistic analysis) coreunits. Furthermore, the center will implement
a quantum computing (Q) core to support
these Bio cores, reducing the time it takes todiscover biological pathways and bring scientific breakthroughs from bench to bedside. The Q core is
the only team in Japan that can perform both annealing and gate-based quantum computing and willbe the first to address complex biology and multidimensional omics data. Thus, our center will function
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

as a unique and highly competitive research institution that will establish a new interdisciplinary
research field by blending human biology, microbiome, and quantum computing research with thegoal of decoding the human multiorgan homeostatic interactions.
3. Goals of the program: To accomplish our mission, the collaborative team will focus on six main
goals: 1. Accumulate multiomics data from humans (including those from centenarians) and modelorganisms (animals/cells) and compile a multidimensional database. 2. Elucidate the structure andfunction of microbiome-derived metabolites. 3. Refine imaging metabolomics and structural biology
to promote in situ functional analysis of metabolites in organs and cells. 4. Develop quantum
computing-based algorithms and pipelines to analyze the complex interactions between multiple
organs and microorganisms. 5. Establish research approaches that can model the interface between
the environment and epithelial, immune, and nervous systems by advancing organoid technology andanimal models and elucidate the mechanisms underlying the conversion of information from external
environmental factors into internal signals. 6. Invent new technologies in connectomics and structural
biology to understand the organized complexity and dynamic multiorgan interactions, including gutbrain communication.
By achieving these goals, we will generate a new entity of life science and decipher causal
relationships in multiorgan and microbiome interactions in humans during health and disease, with aparticular emphasis on understanding of microbiome-derived metabolites, microbiome-epithelialinteractions, gut-brain communication, and healthy longevity in a way that cannot be accomplishedby conventional approaches.
2) World-Leading Scientific Excellence and Recognition2) -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, theproject’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)

Title of Research Area: Human multiorgan-microbiome homeostatic interactions
The importance of the target research field: Homeostasis in humans is maintained by a complex
circuitry of interactions between multiple organs connected by the vascular, nervous, immune, andmetabolic systems. Accumulating evidence suggests that this complex network confers robustness
against external perturbations. Biological functions (outputs) are appropriately regulated in response
to external environmental changes (inputs), and the breakdown of multiorgan networks results inchronic diseases. However, fundamental gaps in knowledge and several technical bottlenecks remain
regarding the complex interplay between organs. The human body is not merely a collection ofdifferent parts. Whenever the hierarchy changes from the genome to cell to tissue/organ/organ toindividual, the higher organized levels show emergent properties not apparent in the sum of theproperties of the lower levels. Information is dispersed, integrated, and transmitted in a feedback loop
between the lower and upper layers. To understand such extremely complex interactions,conventional approaches that focus primarily on single organ/cell networks ultimately fall short.
A typical example of a multiorgan network is the direct projection of nerves from the intestine
to the central nervous system (“gut-brain axis”). Recent research has shown that nutrient metabolism
after digestion and absorption is regulated via the central nervous system. However, the pathways
involved in the metabolic control of dietary nutrients are likely far more complex than currently
understood. Within the defined space of a living organism, signals are likely distributed throughKeio University-2
Human Biology-Microbiome-Quantum Research Center (Bio2Q)

multiple pathways, thereby achieving optimization and robustness. In addition to metabolism, theautonomic nervous system controls immunity and inflammation by innervating various peripheralorgans, such as the intestine, thymus, spleen, and bone marrow, and sends afferent signals fromperipheral organs to the central nervous system. However, the synaptic structures between theautonomic nervous system and peripheral organs remain largely unknown.
Moreover, every external surface of individuals, such as skin and intestine, harbors trillions of
microorganisms (collectively defined as the microbiome), whose function profoundly affects human
homeostasis. Multi-million-dollar nationwide projects, such as the Human Microbiome Project (HMP),
have revealed associations between the state of the microbiome and various human conditions anddiseases that exceed previous predictions, including inflammatory bowel disease, cancer, diabetes,
obesity, Parkinson's disease, cognitive impairment, and neuropsychiatric and developmental
disorders. Furthermore, the efficacy of fecal microbiota transplantation therapy has been
demonstrated in several diseases, making the human microbiome a new attractive therapeutic target.
However, the mechanism of action of the microbiome remains largely unknown. In particular, themicrobiome is thought to exert its function by producing tens of thousands of unique bioactive
metabolites by converting host/diet-derived natural products; however, the vast majority of
metabolites (>99%) have not been annotated structurally and functionally (thus remaining unidentified“dark matter”). In addition, unlike infectious diseases caused by a single pathogen, the physiological
functions of the microbiome are mostly exerted by a community of multiple bacterial species. However,none of the currently existing systems can effectively and accurately decipher which members of the
microbiota causally act as effector microbes and how the combinations of microbial metabolites areprojected into the interorgan network and translate into phenotypes.
Therefore, to clarify the details of the complex multiorgan and microbiota networks, it is necessary
to develop new research approaches using multiple modalities as well as a workflow that integrates
a large amount of information from diverse interacting components and leads to a systems-level
understanding.
Rationale to develop a WPI center: The conversion mechanism from external information to internal
biological signaling, and the complex networks connecting the immune, neural, and metabolic
systems cannot be fully addressed by conventional research approaches. In addition, it is difficult todecipher and verify the mechanisms that translate the functions of the microbiome into the hostphenotypes. The most challenging aspect of current microbiome research is understanding thestructure and function of microbial metabolites. We developed an unbiased metabolic pipeline that
detected tens of thousands of metabolites. However, only a handful of their functions (i.e., their
receptors and subsequent conversion mechanisms into host phenotypes) have been identified.
Furthermore, effective computational analysis methods for integrating multiomics data from multiple
organs and microbiomes are yet to be established. Despite AI-driven technologies such as deeplearning being state-of-the-art, further development in the computational sciences is necessary tofacilitate the analysis of multi-variable, small-sample size, multimodal, and multiorgan data.
The current situation, however, is gradually improving due to the development of cutting-edge
technologies. For example, metabolomics, which captures metabolite diversity and dynamics throughadvanced mass spectrometry, and organoids, which facilitate semi-permanently culturing of humantissue stem cells, have led to significant progress in the field of microbiome and human biology.
Likewise, epigenomics, which targets transposon-mediated modifications, and connectomics, which
combines virus-mediated tracing of neural networks and in situ structural biology techniques, have
revolutionized our understanding of the interactions between multiorgan systems. In addition,
quantum computing coupled with AI has been attracting attention in biological research. Quantum
computing employs quantum bits and quantum mechanical principles for processing information in a
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

superposition of 0s and 1s and is expected to answer a number of complex biology-related questions.
In the case of comparing multidimensional data sets, for example, it may be useful to translate network
structures into an ultra-high-dimensional quantum Hilbert space by quantum computing to understandthe molecular and biological features (“quantum signatures”) associated with the given phenotype. By
applying AI and quantum computing in a biological space, we expect to discover potential causal
relationships that have previously been difficult to determine.
A group of world-leading researchers across multiple disciplines have now gathered at Keio
University. By fostering scientific excellence, we believe that we can synthesize a new life sciencefield that integrates human biology, microbiome research, and computational science. We will collectmultiorgan multiomics data (including microbiome data) associated with human pathological andhealth conditions and conduct data mining and evaluation using multimodal biological technologies
combined with AI and quantum computing. Based on the insights obtained into the mechanisms
underlying multiorgan interactions and the maintenance of homeostasis, we aim to develop newtreatment strategies and biomarkers for promoting healthy longevity.
Other world-class research centers for microbiome and human biology research:
1) Stanford, ChEM-H: Stanford ChEM-H brings together chemists, biologists, engineers, andclinicians to understand life at the molecular level and apply this knowledge to improve human health.
Similar to Bio2Q, ChEM-H collects and processes human samples and conducts in-depth analyses.
2) Cleveland Clinic Discovery Accelerator (a joint Cleveland Clinic-IBM Center): The Cleveland Clinic,a US-based clinic that provides medical care, research, and education, has formed a 10-year
partnership with IBM to utilize AI and quantum computing technologies in medical/life science
research.
3) The University of Chicago, Duchossois Family Institute (DFI): The DFI aims to investigate themicrobiome to reduce susceptibility and/or enhance resistance to a range of human diseases andinflammatory conditions.
4) The Broad Institute: The Broad Institute is a biomedical and genomic research center where
physicians, geneticists, and molecular, chemical, and computational biologists launch innovative
projects, invent new technologies, build computational tools, and develop new therapeutics.
5) UCSF, The Benioff Center for Microbiome Medicine: The center's collaborative community
leverages the unique potential of the human microbiome to predict health outcomes and to create
microbiome-based therapeutics for a wide variety of gastrointestinal, skin, and neurological diseases,
with the goal of bringing these treatments to patients in the shortest time possible.
The strength of Bio2Q is comparable to that of those world-renowned institutions because it
possesses several cutting-edge technologies and unique resources, including:
1. Gnotobiotic pipeline: A particular strength of the Bio2Q is that we have developed an effective
gnotobiotic screening system to track the causal effects of biologically-relevant microbiota moleculesand strains with host-modulatory capabilities. Bio2Q is home to one of the world's largest germ-freeanimal facilities, with full-time technicians and embryo transfer specialists to maintain about 150
isolators capable of producing more than 1,500 gnotobiotic mice a month. An in vivo system isessential for testing microbes directly, as microbiota members generally act as a community tocooperatively produce metabolites that affect host physiology, a scenario that can be recapitulated
and rigorously studied in gnotobiotic animals.
2. Germ-free common marmoset monkeys: Non-human primates are critical for translational
research to bridge the gaps between rodents and humans. Common marmosets have several
advantages, including human-like brain architecture and function with complex social and cognitive
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

behaviors. Moreover, the gut microbiota composition and metabolome in marmosets are similar to
those in humans. Sasaki at CIEA, a satellite of Bio2Q, has succeeded in establishing an effective
method to generate and maintain germ-free 1. Germ-free animal facility
4. Centenarian cohort
marmosets for the long term under sterile
conditions. Germ-free marmosets are suitable foranalyzing the effects of the microbiota on
neurodegenerative and aging-associated diseases.
3. Humanized mouse models: In addition to NOGbased humanized immune mice, CIEA recently
developed “humanized liver mice” in which a herpes
simplex virus type 1 thymidine kinase transgene isexpressed within the liver on the immunodeficient
NOG background and human hepatocytes arestably transplanted. The humanized liver mice
mimic the profiles of intestinal and plasma
metabolites and the gut microbiota components,
and can therefore a powerful tool for studying hostmicrobiome interactions.

2. Germ-free marmosets

5. Metabolomics

3. Humanize liver mice

(Liver)5. Organoid technology
5. Connectomics

Humanizedliver NOG

0

1.5 0

5

NOG

Human mitochondria

GSH

UDP-glucuronate

4. Centenarian cohort: Centenarians, or individuals who have lived more than a century, represent
the ultimate model of successful longevity associated with decreased susceptibility to agingassociated illness and chronic inflammation. The Center for Supercentenarian Medical Research at
Keio University has been following and collecting clinical information and blood and fecal samples
from a cohort of more than 1,000 centenarians, including those over 110 years old("Supercentenarian") over 20 years.
5. Organoid, connectomics, metabolomics, computing expertise: Sato pioneered thedevelopment of organoid technology and established >1,000 lines of human organoids from healthy
individuals and patients at Keio University. This organoid biobank confers key advantages to Bio2Q
over the other centers. Augustine, who found the Center for Functional Connectomics in Korea, hasbeen a leader in the field of connectomics. Yuzaki is one of the first to discover that the C1q
complement family functions as a novel synapse organizer in the central nervous system. By using
connectomics tools, Yuzaki has clarified where and how the C1q family proteins control synapse
formation and maturation. Yuzaki and Aricescu have created a synthetic synaptic organizer (termed
CPTX), by combining the structural elements of natural synaptic organizers. CPTX effectively treats
symptoms of mice with Alzheimer's disease and spinal cord injury. Arita has developed a non-targetedmass spectrometry platform to elucidate the structural diversity of >8,000 lipid species (10 times less
was defined previously) and is leading the Lipidome Atlas project. In addition, Keio University is oneof the few institutions in the world capable of gated and annealing quantum computing. These cuttingedge technologies and resources will confer key advantages to Bio2Q over the other centers.
Collectively, Bio2Q is uniquely positioned to be a world-leading institute as it integrates cutting-edge
technologies, including microbiomics, lipidomics, imaging metabolomics, connectomics, organoids,
quantum computing, etc., which enable practical causality-driven basic sciences. As Honda has been
exchanging information and collaborating internationally in microbiome research for many years withMichael Fischbach from ChEM-H, Ramnik Xavier from the Broad Institute, and Eric Pamer from DFI,
Bio2Q can accelerate microbiome and human biology research in collaboration with these institutes(Fischbach and Xavier will participate in Bio2Q as international collaborators).
2) -2 Research objectives and plans
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

* Describe in a clear and easy-to-understand manner to the general public the research objectives that your project seeks to achieveby the end of its grant period (in 10 years). In that process, describe what world-level scientific and/or technological issues are you
seeking to solve, and 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 research center will establish a new life science research area to discoverand verify human homeostatic multiorgan and microbiome interaction mechanisms that have not yet
been elucidated. By further refining microbiomics, metabolomics, organoid technology, in situ
structural biology, and connectomics, we will establish a research platform that can model theinterface between the environment and the human body. Further, we will elucidate the mechanisms
underlying the conversion of external environmental changes (including the microbiome) into internalsignals, and examine the associated multi-organ regulatory networks (the gut-brain axis in particular)
at a greater resolution than currently prevalent. We will also innovate computational techniques toextract previously unexplored biological pathways from multidimensional multiomics data. The goalsof the center are to explore new cross-disciplinary paradigms in multiorgan and microbiota interactions
through integration of emerging technologies in biology and computational sciences. By doing so, wewill establish a new field in the life sciences that is unreachable by conventional methodologies, andidentify “causal” relationships in homeostatic multiorgan interactions, particularly in the context of thegut-brain axis and healthy longevity. In the long term, we will develop new therapeutic and preventive
modalities based on rational design, such as microbiota manipulation, bacterial design, dietaryintervention, and artificial synaptic connector therapy, to contribute to creating a society that supports
healthy longevity across the life course.
Research plan: We will establish three core units designed to accelerate the discovery and validation
workflow to identify multiorgan and microbiome interactions: Bio-1, Multidimensional data analysis
core (Core Director: Makoto Arita); Bio-2, Homeodynamics mechanistic analysis core (Core
Director: Toshiro Sato); and Q, Quantum computing core (Core Director: Shu Tanaka). These threecores will share technologies, expertise, and pipelines to streamline data generation, mining, andevaluation. The Bio-1 core will analyze human multiorgan samples and model organisms by
integrating human microbiome, genomic, epigenomic, and metabolomic methods, and construct a
multidimensional database. The collected multiomics data will be analyzed in the Q core by quantum
computing combined with AI to identify “quantum signatures” associated with the given phenotypes.
Subsequently, these signatures will be evaluated in the Bio-2 core in collaboration with the Bio-1 core,using connectomics, organoid, and structural biology techniques to validate the cause-effectrelationships. An imaging metabolomics team will operate at the interface between Bio-1, 2, and Q to
detect small metabolite-derived nuclear magnetic signals in situ at high sensitivity and spatial
resolution, and identify the function of microbiome-derived metabolites in the multiorgan networks. By
accelerating the reverse translation cycle, we will achieve and exploit novel discoveries in humanbiology to optimize the functioning of the host multiorgan system, reduce unfavorable or pathologicalconditions, and promote healthy longevity.
Bio-1: Human multidimensional data analysis core: The Bio-1 core will collect human multiorgan
samples associated with health, disease, and aging, and analyze them from multiple perspectives.
The information will be shared in the center and satellites to enable breakthroughs.
Human disease analysis team (Seki, Yoshino): The clinical picture of chronic diseases andconditions as observed in clinical practice is extremely diverse, and a comprehensive understanding
derived from a large amount of patient information is essential to obtain a complete picture of thedisease concept. Together with the center's collaborators, the team will obtain clinical samples andinformation on cancer, diabetes, obesity, neuropsychiatric disorders (Parkinson's disease, dementia,
and depression), developmental disorders (autism spectrum disorder), allergic diseases,
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

inflammatory bowel disease, and aging. For example, Seki has created a multicenter database that
includes more than 1,000 patients with Parkinson's disease (Seki, Parkinsonism Relat Disord 2013).
Parkinson's disease is rapidly increasing in an aging society and has been considered a systemic
disease. The gut microbiome has attracted attention for its influence on the pathogenesis of
Parkinson’s disease and drug metabolism. Optimization of treatment and provision of tailor-mademedicine based on the evaluation of the microbiota is paramount for improving medical care forpatients with Parkinson's disease. In addition to Parkinson’s disease, Keio University Hospital has
collected blood and clinical data from over 10,000 patients with inflammatory bowel disease andapproximately 1,000 centenarians (including those over 110 years old). Centenarians aged 100 years
and older are known to be less susceptible to age-related diseases, such as hypertension, diabetes,
obesity, cancer, and infectious diseases. There are centenarian-specific members of the gut
microbiota (Sato, Nature 2021), which might not be merely a consequence of adaptation to aging,rather actively contribute to maintaining homeostasis, resilience, and successful aging. Clinicalinformation and specimens will be shared with the Bio-1, Bio-2, and Q cores, and analyzed frommultiple perspectives.
Microbiome Team (Honda, Huh, Tuganbaev, Atarashi): The human body is colonized by microbes
from all three domains of life, with the gastrointestinal tract exhibiting the greatest microbial densityand diversity. Gut microbes outnumber the host by over 25-fold in terms of genetic composition.
Unsurprisingly, this vast microbial ecosystem interacts intimately and, for the most part, mutualisticallywith its human host, performing essential metabolic functions. While sequence-based microbiomewide association studies provide correlative support for the notion that the microbiota influences
human health and disease, they address neither the causality nor the directionality of the hostmicrobiota relationship. Therefore, we have shifted toward causational studies to identify bacterial
species that directly contribute to human homeostasis in specific ways (important examples are
Atarashi, Science 2013; Atarashi, Cell 2015; Tanoue, Nature 2019; and Sato, Nature 2021). In
particular, the combination of two complementary reductionist approaches, that is, gnotobiotic andmetabolite-based, has enabled a detailed mechanistic understanding of the microbiota-mediatedmaintenance of homeostasis and multiorgan systems, in which specific bacterial species and theirproducts play critical roles. In the WPI program, we will create a more effective feedback cycle
between the gnotobiotc study and the rigorous mechanistic studies, ultimately enabling for theidentification of causally effective and therapeutically applicable minimal microbes and microbial
products. The "gut-brain communication" is a typical example of a multiorgan network. It has beenreported that the intestinal information, particularly that from the gut microbiome, is delivered to thecentral nervous system, and CNS sends signals back to peripheral organs to control their functions.
Recent evidence suggest that this Gut-brain axis affects the pathogenesis of several diseases,
including Alzheimer's and Parkinson's diseases. We will interrogate the molecular and cellular basisof the gut-brain communication. We will particularly horn in on the intestinal enteroendocrine cells.
Enteroendocrine cells are known to "chemosense" the intestinal contents via GPCRs. They also havea structure called neuropod, which forms synapse-like structure with the vagus nerve. We believe thatelucidating this synapse-like structure will be the best first step in determining the basis of the gutbrain connection. We will 1) elucidate the signaling pathway from the intestinal tract (namely the gut
microbiota) to the CNS by tracing anatomical pathways and 2) define their physiological functions. To
do so, we will advance culture techniques along with high resolution mass spectrometry that will
provide an additional lens for identifying small molecules correlated with diseases and specificconditions. Moreover, in collaboration with the Metabolomics Team, we will compile a metabolomics
database specific to the microbiome. We will determine the bacterial enzymes that are responsible
for the production of the given metabolites through a series of steps, including isolation of bacterial
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

strains, sequencing bacterial genomes, creating mutant strains, and analyzing the effects of the lackof specific genes in the microbiota on the host using the gnotobiotic pipeline. Moreover, incollaboration with other core members, we will elucidate the molecular and cellular mechanisms
underlying gut-brain crosstalk, the interaction of the microbiota with genomic mobile elements, andthe influence of the microbiota on the mucosal barrier (gut and skin) stem cells. We will also bridge
circadian biology and microbiology to uncover how multiple organ systems of our body dynamicallyinteract with the microbiome throughout a circadian cycle thus adding a dimension of time to thedefinitions of homeostasis and disease. Indeed, the quantity of bioactive small molecules that cancross the epithelial barrier at any given moment is not constant but: a) is diurnally fluctuating
increasing up to three-fold at peak vs trough; b) is regulated by microbiome (Tuganbaev Cell 2020).
Therefore, the temporal understanding of host-microbiome interactions will lead to the developmentof novel type of intervention strategies. Much like wave interference, diurnal rhythms of microbes andthe host can be utilized in combinatorial ways to rationally maximize therapeutic or minimize side
effects of microbiome-derived metabolites or orally administered drugs on the host.
In addition, in collaboration with the Q core, we will build a new pipeline to understand thecommunity action of multiple bacterial species using AI and quantum computing. Honda, Atarashi,
Sampetrean, and Tuganbaev have world-class strengths in the technologies required for microbiome
analysis (e.g., culture techniques to propagate difficult-to-culture or previously unculturable organisms,
gnotobiotic techniques, and commensal bacterial gene manipulation techniques). Huh is a worldleading scientists in the fields of immunology and gut-brain axis research. Combining the state-of-theart gnotobiotic expertise from the Honda lab with the neuroimmunology strength of the Huh lab willlead to the identification of mechanisms of action by which the bacterial community interacts with hostcells, including epithelial cells and immune cells, to affect health and disease in humans. In addition,
Mucida (Rockefeller University), Littman (NYU), Xavier (Broad Institute), Fischbach (Stanford
University), Iwasaki (Yale University), Devlin (Harvard University), and Kajimura (Harvard
University), with whom Honda has collaborated for many years, have joined as international
collaborators. The microbiome is a key component of the human biology, and decoding its impact on
the immune system, metabolism (including drug metabolism), aging, and gut-brain interactions will
be accelerated in this collaborative team.
Metabolomics Team (Arita, Soga): Advances in non-targeted lipidomics technology developed by
Arita and colleagues have revealed the existence of a far greater variety of lipid molecules in living
systems than previously thought (Tsugawa, Nat. Biotechnol. 2020). The diversity of molecular species
and modifications of lipids has the potential to generate a wide variety of biological information asfunctional elements. Indeed, the identification of new functional lipids often leads to a newunderstanding of biology and pathophysiology. In this project, by combining non-targeted mass
spectrometry and molecular spectrum networking technology (which supports structural estimates of
unknown molecules), we will identify new lipid molecular species that are uniquely produced by the
microbiota. To verify the structure-activity relationship of functional lipids and their causal relationshipwith the given phenotypes, we will chemically synthesize lipids, including structural isomers, andevaluate their biological activities by conducting a wide range of bioassays. Moreover, we will develop
a computational mass spectrometry platform that facilitates the annotation of metabolites byintegrating the collision cross-section and MS/MS spectra. We will advance MS imaging technology
to visualize the localizations of more than 1,000 molecular species of lipids. This spatial lipidomics
platform will enable the visualization of functional lipid distribution in cells and organs in vivo.
Most molecules from central carbon and nitrogen metabolism are hydrophilic (e.g.,
phosphorylated sugars, phosphorylated carboxylic acids, carboxylic acids, amines, amino acids,
nucleic acids, nucleosides and nucleotides). Despite their importance, no analytical method has been
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

developed to cover all these metabolites because of their high polarity, non-volatility, and difficulty in
identification. Furthermore, the coexistence of over 1,000 metabolites with similar physical andchemical characteristics in the cell complicates their analysis. Focusing on these characteristics, Sogadeveloped a metabolomic profiling method based on capillary electrophoresis mass spectrometry(CE-MS) of polar and charged metabolites (Soga, Proteome Res. 2003). CE provides fast andeffective analysis, whereas MS provides high sensitivity and selectivity. The CE-MS method has
several advantages, such as its low sample consumption and the ability to easily detect charged
compounds. The utility of this method has been exemplified by the discovery of low-molecular-weightbiomarkers for several diseases (Yoneshiro Nature 2019). Building on these methods, we will develop
a highly sensitive and high-throughput metabolomic profiling method and single-cell metabolomics
method. Our goal is to discover new biological regulation mediated by bacterial metabolites (bothhydrophobic and hydrophilic metabolites) and to comprehensively understand host-microbe
interactions in multiorgan systems.
Genome Dynamics Team (Siomi, Ishigaki): An extraordinary abundance of transposable elements(TEs) is one of the most striking aspects of mammalian genomes. Their ability to mobilize and insert
anywhere in the genome can cause mutations that are generally detrimental to the host. TEs may
also play a major role in mammalian biology by forming gene regulatory networks as part of the ‘self.’
Barbara McClintock, who discovered TEs in the late 1940s, realized that TEs are not only mobile
genetic elements but are “controlling elements” because of their regulatory influences on neighboring
gene expression and function. The activation of TEs in response to environmental stresses induces
mutations and/or epimutations (epigenetic modifications) that initiate a highly programmed sequenceof events within the cell to cushion the effects of the stress and could help the organism adapt to newenvironmental conditions. Recent studies support the idea that the host immune system uses TEs tocommunicate with microbiota, which controls tissue homeostasis and inflammation. With theresources available within the WPI program including tissue organoids and microbiome cultures,
Siomi will address how TEs sense the microbiome to initiate the host immune response using stateof-the-art (epi)genomics tools and bioinformatics.
Millions of genetic variants define the phenotype of each individual. Variants in cell type-specificenhancers influence the transcriptome, proteome, metabolome, and, eventually, more complex
phenotypes (e.g., immune cell functions and host-microbiome interactions). Therefore, a precise
understanding of the functional readouts of genetic variants can help elucidate the molecular basis ofhuman biology. Ishigaki will investigate how genetic variants influence cell type and tissue specificmolecular phenotypes using state-of-the-art technologies such as organoids, single-cell multiomics
platforms, and CRISPR single base-editing.
Bio-2: Homeodynamics mechanistic analysis core
Reverse translation studies will be performed on human multiorgan samples using organoids andanimal models along with Bio-1, and causal relationships will be tested based on inferences obtainedwith the Q-cores.
Organoid Team (Sato): The intestinal epithelium plays a pivotal role in maintaining homeostasis
through nutrient absorption and anti-bacterial protection. Deregulation of these epithelial functions
leads to an imbalance in gut microbiota associated with systemic disorders, such as chronic
inflammation, obesity, and cancers. However, owing to the paucity of experimental systems, thebiological mechanism by which epithelium regulates gut microbiota and host homeostasis remains
unclear. Sato and Clevers (Hubrecht, now Roche) developed organoid technology that enables ex
vivo analysis of the human intestinal epithelium and host-microbe interactions, which provides a
critical functional platform for the causality assessment. The expertise in technical development andKeio University-9
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rich insights into the stem cell biology of the Sato group will create a robust competitive edge.
The intestinal epithelium consists of various cell types, and each cell type expresses a diverse
array of receptors corresponding to gut microbes and their metabolites. This many-to-many
relationship is further complicated by potential epigenetic alterations by gut microbes. To tease out
such chaotic configurations, the Sato group, in collaboration with the Genome dynamics team and Q
core, will identify pathways by which external inputs induce specific biological phenotypes at thesingle-cell level. Enteroendocrine cells in the intestinal epithelium are known to sense various
metabolites derived from gut microbes and exhibit unique neuroendocrine and metabolic responses.
Using co-culture of organoids with non-epithelial cells such as immune cells and neurons, the Satogroup will explore how the environmental cues modulate organ functions via epithelial interactions
with neural, endocrine, and metabolic systems, in coordination with the Metabolome and Microbiome
teams and the Neuroregulation team. The group will also collaborate with the Structural biology teamto analyze the interactions between epithelial receptors and gut microbiota-derived metabolites at thestructure level.
The Sato group will procure tissue samples from patients and establish disease organoid models
with the Human disease analysis team to facilitate an understanding of disease pathobiology and thedevelopment of therapeutic strategies. In collaboration with the Humanized animal model team, theSato group will streamline an in vivo experimental platform and provide its access to all team members.
The group will further work with the Imaging metabolomics team to survey clinical human or patient
data and analyze their consistency with organoid and humanized animal model data.
Neuroregulation Team (Yuzaki, Minagawa, Augusine): In recent years, attempts have been madeto elucidate all functional and structural connections between neurons in the brain via a “connectomics”
approach in international frameworks such as the Brain Initiative. The Augustine Group will apply
functional connectomics approach, by which neuronal activities are stimulated or inhibited byillumination while monitoring Ca2+ changes in target tissues, for mapping projection neurons inlymphoid tissues. The Yuzaki group aims to apply existing and newly developed connectomics tools
to elucidate brain-gut junctions. For example, various metabolites produced by the microbiome, as
well as nutrients and bile acids, are sensed by receptors expressed by enteroendocrine cells (EECs)
scattered in the intestinal epithelium. EEC signals are transmitted to the nucleus tractus solitarii (NTS)in the medulla oblongata via the sensory vagal nerve and further integrated with various kinds ofinformation in the higher-order centers in the brain to control visceral, cognitive, and emotional
functions, which are relevant to certain psychiatric and neurological disorders. To fully understand therelationship between the microbiome and the nervous system, it is essential to elucidate each of thefollowing steps: 1) how metabolites produced by the microbiome are sensed by EECs, 2) how EECs
communicate with sensory vagal nerves, and 3) how signals from the NTS are integrated in the higherorder centers. To achieve these goals, the team will first develop a viral vector toolkit to specificallymanipulate gene expression in different subpopulations of EECs and vagal nerves. In addition, in
collaboration with the Q core, the team will establish a pipeline for computational analysis ofmultidimensional data obtained using microbiome, genomics, and metabolomics approaches, as well
as functional imaging of the vagal nerve and higher-order centers. Cognitive and motor functional
abnormalities in animal models of psychiatric and neurological disorders, such as Alzheimer’s disease
and autism spectrum disorders, will also be quantified and integrated into the database. The team will
also collaborate with the Humanized Animal Model Team and the Organoid Team to establish aplatform for visualizing the activity of EECs and the vagal nerve using genetically encoded Ca2+
sensors in response to the administration of metabolites derived from the microbiota. The Augustinegroup will perform in vivo imaging of immune cell trafficking in the CNS to elucidate the effect of
microbiome and its metabolites on immune cells in the brain. The effects of the microbiome and its
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metabolites on animal behavior will be further examined by inhibiting or activating specificsubpopulations of EECs, lymphoid tissues and the vagal nerve with chemogenetic tools in vivo. The
Augustine and Yuzaki groups have previously developed a technique for tracing neuronal networks
in the CNS using viral vectors. Both groups have ample experience using optogenetic andchemogenetic tools to alter the function of specific neuronal circuits to establish a link between
synaptic functions and animal behavior. Thus, the team will establish a causal relationship between
the microbiome and neurological and neuropsychiatric disorders by integrating data on the nervous
system, animal behavior, and multiomics.
The Yuzaki group has developed CPTX, an artificial synaptic connector based on the structure ofmolecules identified at CNS synapses in collaboration with the Structural Biology Team (Aricescu andSuzuki). CPTX administration induces rapid synapse formation in vivo and effectively reduces thesymptoms in Alzheimer's disease and spinal cord injury mouse models (Suzuki, Science 2020). The
group also developed a technique called the split-TurboID method to identify molecules associatedwith cell-cell adhesions using contact-dependent proximity labeling followed by high-resolution LCMS (Takano, Nature 2021). Autonomic nerves in the intestinal epithelium are not distributed randomly
as previously thought, but form synapse-like adhesion structures with specific EECs. However, themolecules involved in the formation and maintenance of such synapse-like structures remain unclear.
By applying the split-TurboID method, the group will identify structures between the autonomic nerves
and EECs and their molecular components. Similar to CPTX, which can induce CNS synapses, thegroup will develop new therapeutic tools to artificially modify the brain-gut connection. The integrated
brain-gut correlation database will be used to enable predictive simulations of the effects of such tools.
Over the years, Minagawa has collected cortical brain activity data from infants using optical
topography. Furthermore, the group intends to analyze microbiome data in conjunction with corticalactivity in children with autism spectrum disorders. International collaborator Choi (MIT) will
investigate the relationship between inflammation and autism spectrum disorders. The
Neuroregulation Team will also obtain microbiome and metabolome data in various age groups inconjunction with brain activity data, which will be provided to the Q and Bio-1 cores.
Structural Analysis Team (Aricescu, Suzuki): Enteroendocrine cells express several orphan G
protein-coupled receptors (GPCRs) with unknown ligands. GPCRs are among the best candidates
receptors for functionally undefined metabolites produced by the microbiota. The Aricescu group has
solved the crystal structures of a variety of membrane proteins including the heteromeric GABA
receptor (Sente, Nature 2022). Aricescu and Suzuki will collaborate with the Microbiome Team andthe Neuroregulation Team to elucidate the microbiome-host interface, bacterial membrane structure,and the structure of GPCRs responsible for interaction with bacterial metabolites.
X-ray crystallographic analysis of highly purified proteins has enabled single-particle analysis
under non-crystallizing conditions. However, it has become clear that membrane proteins such as
GPCRs and synapse-forming molecules, which function stably in the presence of lipids and otherproteins, undergo conformational changes when isolated as single particles. Thus, in situ structural
analysis of molecules in an intact lipid environment is essential. At the WPI center, in situ structural
analysis technologies will be developed in collaboration with the Organoid Team and the Humanized
Animal Model Team of the Bio-2 core.
Humanized Animal Model Team (Sasaki): The gut microbiome compositions in humans and miceare quite different, and certain members of the human microbiota cannot colonize the mouse intestine
upon transplantation, which might be due in part to the differential liver-derived metabolites. Indeed,mice and humans have differential profiles of liver cytochrome P450s as well as intestinal bile acidcompositions and other liver-derived metabolites. To overcome such a species specificity, we havedeveloped “humanized liver mice” in which a herpes simplex virus type 1 thymidine kinase transgene
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

is expressed within the liver on the highly immunodeficient NOG background and human hepatocytes
are stably transplanted (Hasegawa, BBRC 2011 and Uehara, Drug Metab Pharmacokinet 2022). The
humanized liver mice exhibit significantly different profiles of intestinal and plasma metabolites andthe gut microbiota. By generation of germ-free and gnotobiotic humanized liver mice, we caninvestigate mechanisms of homeostasis regulated by microbiota and enterohepatic circulation.
The common marmoset is a nonhuman primate experimental animal closely related to humans
and a useful model animal that is genetically manipulatable (Sasaki, Nature 2009, Sato, Cell Stem
Cell 2016). We have recently succeeded in generation of genetically modified Alzheimer's diseasemodels (Sato, bioRxiv) and germ-free marmosets (Inoue, Research Square 2021). We also
developed an automated behavioral monitoring system (Yurimoto, bioRxiv). Moreover, by using
embryo splitting technics, genetically identical twins of the Alzheimer's model can be created toanalyze the interaction between intestinal microbiome and neurodegeneration and behavioral
changes under germ-free and conventional conditions, which provides a molecular and cellular basis
underlying gut-brain communication in nonhuman primates, independent of genetic background. We
will collect multimodal data using whole-brain imaging, fMRI, mass spectrometry imaging, behavioral
tests, and metabolomics from marmosets in health, disease, and aging.
Imaging metabolomics Team (Suematsu, Hishiki): The Team aims to refine and advance
multidisciplinary imaging metabolomics using three different modalities: imaging mass spectrometry(IMS), high-power and wide-open (11.7 Tesla/22 cm bore) functional MRI, and surface-enhanced
Raman imaging (SERS). For two decades, Suematsu and Hishiki devoted their efforts to developing
IMS technology to visualize metabolites and hormones responsible for the maintenance of organ
homeostasis and immunological responses. By using 13C- or 15N-labeled substrates, IMS can reveal
the spatial and temporal biotransformation of glucose, glutamate, etc. The 11.7-Tesla fMRI will define
the anatomical distribution of metabolites through diffusion-tensor tractography. Theoretically, thefMRI can map metabolite distribution at 100 m spatial resolution. Water constitutes almost 70% of
the body and serves as a major source of proton signals. We will utilize fMRI with a water suppression
device to visualize NMR signals derived from metabolites. By combining these technologies together
with germ-free mice, germ-free marmosets, and humanized liver mice, we will visualize the distributionof bioactive metabolites and explore how the microbiota affects the host physiology. Goldnanoparticle-based large-area SERS, which was establish by Suematsu group, can be used tovisualize the spatial distribution of several metabolites including reactive sulfur species, volatile fatty
acids, and small molecular gaseous compounds such as CO, CO2, NOx, and hydride/hydrogen (H/H2) (Suematsu, JCI 1995; Shiota, Nat Commun 2018). In vitro studies have revealed that thesecompounds are actively utilized as nutrients and signaling molecules by anaerobic microbes, andpossibly as host macromolecules (Kabe, Nat Commun 2016). In addition to these infrastructures, the
IM Team will provide key technologies including high-performance affinity nanobeads for chemical
biology, which can be used to mine candidate metabolites that can interact with the intestinal epithelial
cells and/or immune cells. Chemical biology can further reveal the identity of receptors of individual
metabolites. Collectively, using multidisciplinary imaging metabolomics and chemical biology, we will
decipher metabolite-mediated multiorgan regulatory networks in health and disease.
Q: Quantum computing core
The Q core will play a fundamental role in integrating data obtained from the Bio-1/2 cores and perform
high-precision analysis using both gate- and annealing-model quantum computing techniques.
Quantum computing has attracted considerable attention owing to its calculation efficiency andrepresentational power. However, issues in finding the efficient solution to various problems remain.
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

Data distribution in quantum latent space
Although various techniques have been
Encoder
Decoder
implemented, calculation errors owing toOmics data
environmental noise are inevitable.
･･ ( ･ |･)･ ( ･|･ )LatentMoreover, because practical applications
variables
Compilationin biological and medical biology have notbeen explored rigorously, the immediatechallenge is to find tasks in various fieldsof biological sciences in which quantum
computing can be applied. In the first five
years, we will develop new research
Quantum latent spacemethods utilizing quantum computers that
apply to human biology. We will develop Using variational Autoencoder (VAE) and quantum computing, the omics data obtained from clinical or basic research can beplotted in a quantum latent space. This may facilitate visualization of differences between data ("Quantum signature"), such as
black-box optimization using quantum physiological vs. pathological conditions, or before and after taking medications.
annealing, which is the result of Tanaka's
research described below, into a method applicable to human biology. In addition, we will identify
bottlenecks in applying quantum algorithms for gate-model quantum computing to human biology andpropose improvements for the application of quantum algorithms for gate-model quantum computing
to human biology. In the next five years, we will apply the developed methods to the data obtained
from the Bio-1 core and achieve discovery results that will contribute to multi-organ circle research,which will be connected to the research in the Bio-2 core.
Quantum AI, which combines gate-model quantum computing with conventional AI, is expected tolead to more accurate heuristic methods by combining the advantages of both. This will establish amethod for extracting “quantum signatures” that lie behind the circuitry of multi-organ molecular andcellular interactions associated with a given phenotype, potentially with high speed and accuracy (seeabove figure). The number of qubits in gate-model quantum computers has been increasing rapidly
in recent years, and the dimension of the variables that can be handled in the problem is increasing
exponentially. Substantial improvements in error correction systems will be made, and the number ofalgorithms will be increased in a gate-model quantum computer, with a corresponding increase in thecapability of handling complex quantum circuits and the potential for its application in biomedical
sciences. Keio University Quantum Computing Center has put forth a significant effort to advancegate-model quantum computing and has made several research findings on quantum AI (Nakaji, Sci
Rep. 2021; Kishi, IEEE J. Emerg. Sel. 2022). In the WPI, Sakakibara will analyze multidimensional
human multiorgan multiomics data obtained from Bio-1 using non-negative matrix factorization on a“quantum space” defined by qubits, extract quantum signatures, and feed them back to Bio-2. The
data from the microbiome, metabolome, and genomic analysis of human multiorgans are sparse andhave tens of thousands of dimensional matrices. Matrix factorization in quantum space can rapidly
decompose them into low-dimensional factor matrices, that is, “quantum signatures”. Kawaguchi andYamamoto will develop exploratory algorithms that can deal with data structures obtained from the
Bio-1 core (i.e., small number but multivariate structures) by taking advantage of the highrepresentational capability in the feature space. For example, by extending a method utilizing
quantum kernels to capture the relationships among variables (Kawaguchi, arXiv, 2021), algorithms
that can estimate causal structures more accurately than conventional methods will be developed toprovide accurate hypotheses, which will then be linked to Bio-2.
Annealing-model quantum computing called “quantum annealing” is a promising method for
efficiently solving “combinatorial optimization problems’’. However, most of the current research on
quantum annealing is limited to investigating basic problems in mathematical optimization. Tanaka
has been working on a proof-of-concept in several applications, mainly in industry-academia
collaborative research, such as web advertisement serving optimization (Tanahashi, J. Phys. Soc.

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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

Jpn. 2019), network analysis (Yoshimura, IEICE Trans. Inf. Sys. 2021), and stable structure searches
for multiple polymers. Tanaka has also developed a black-box optimization method that drastically
expands the range of applications using quantum annealing (Kitai, Phys. Rev. Research 2020).
Building on these research findings, Tanaka and Kawaguchi will establish a fast and accurate method
to solve many-to-many combinatorial optimization problems behind multiorgan algebras by quantum
annealing. For example, in collaboration with Bio-1, we plan to extend our network analysis method
using quantum annealing to discover functionally similar metabolites with distinct structures. In
addition, we propose black-box optimization methods and stable structure search methods to predict
potential pathways for a given metabolite with high efficiency. In collaboration with Bio-2, we will
discover and test potential mechanisms in multiorgan networks.
Through these studies, we will establish critical application methods for quantum computing in thebiomedical sciences. Because medical biology deals with a complex system that has a nonlinear,
non-equilibrium, and multi-hierarchical nature, providing examples of applications of quantum
computing will have an immeasurable impact on the quantum computing field.
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. Regarding the composition of the center’s personnel, describe measures to obtain diversity
such as gender balance.
* 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: Bio2Q will build a research structure with the 7 core values
described below, having at least 5 international PIs or Jr PIs who reside on site. In parallel, we
consider the long-term vision of the center. We will endeavor to build a system that can attract andtrain promising early career researchers from around the world. Our educational system will include
mentoring by center PIs and the establishment of a joint program between the Graduate School of
Medicine, Graduate School of Pharmaceutical Sciences, and the Graduate School of Science andTechnology, which will expand the scope of study for students and foster the development of future
WPI researchers. We underscore the importance of providing ample support through ouradministrative and research support organizations so that researchers can fully dedicate themselvesto their research. The responsibilities of these support organizations include preparing to accept
international researchers, organizing events, and handling administrative procedures, such as
research fund management that researchers otherwise have to handle themselves.
We will ensure diversity among the researchers at the WPI center by having a variety ofnationalities, genders, and ages represented, with the goal of having at least 30% international
researchers and 50% female researchers. The center is expected to comprise approximately 120
members in total, including 30 PIs and junior PIs (including 5 international PIs or Jr PIs who reside onsite), 10 international collaborators, 50 postdocs and graduate students, and 30 research support andadministrative staff. English will be used as the official language of the center.
Core values of the center:
Bio2Q will build a research structure with the following 7 core values.
1. Excellence and professionalism: Bio2Q delivers work of the highest quality and professional
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standards.
2. Collaboration and sharing of knowledge: The three Cores share technologies, expertise, andpipelines to streamline data generation, mining, and evaluation.
3. Transparency and integrity: Bio2Q encourages transparency, openness and reproducibility inscience, as well as transparency in decision-making processes, except where confidentiality is strictly
required.
4. Innovation and sustainability: Bio2Q is committed to discovering new talent and new ideas,
attracting and learning from them, and stimulating new approaches and new ways of thinking.
5. Social implementation: Bio2Q values and accelerates research activities toward social
implementation.
6. Diversity and globalization: Bio2Q strives to recruit in a focused manner to attract top talent while
ensuring gender and cultural diversity. These are essential ingredients for a creative, exciting andsuccessful work environment, and will help ensure our competitiveness on the international stage.
7. Education and fostering the next generation: Bio2Q creates an environment where graduate
students and early career researchers are encouraged to learn and collaborate freely acrossdisciplines.
Researchers and Satellites:
Core leader
In collaboration with the Director
Bio-1
Administrative Director
Metabolome
Multidimensional Data
(Honda) and Deputy Directors/Core team
Analysis Core
T. Soga
M. Arita(Keio U)
(Keio U)
directors (Arita, Sato, and Tanaka), 11
Director
O. Sampetrean(Keio U)
Principal Investigators (PIs) (15 PIs in Microbiome
total, including 3 international PIs and 2 teamInternational collaborators
K. Honda J. Huh
K. Atarashi/Advisors(Keio U)
(Keio U)(Harvard)(Keio U)female PIs) and 8 Jr PIs will work together
at the three research cores. In addition, 10 Genome
Human disease
analysis teaminternational collaborative researchers dynamics
team
D. Mucida
D. Littman
A. Iwasaki(Rockefeller, (NYU, HHMI) (Yale, HHMI)
H. Siomi
K. Ishigaki
M. Yoshino M. Seki
HHMI)
(Keio U)/advisors will participate in the team to(RIKEN)(Keio U)
(Keio U)promote research collaboration. The home
Bio-2
Homeodynamics Mechanistic Analysis Core
research institutes of PIs who participate
R. Xavier
M. Fischbach S. KajimuraCore leader(Broad, MIT) (Stanford)(Harvard, HHMI)
Imaging
in Bio2Q from institutions other than Bio2Q
metabolo
Organoid-mics
team
are called “satellites.” The Central Institute teamM. Suematsu T. Hishiki
T. SatoYC HsuG. Choi
H. Clevers
S. Devlin(Keio U)(CIEA)
for Experimental Animals (CIEA) and(Keio U)(Harvard)(MIT)(Roche)(Harvard)
RIKEN, with which an agreement for
Humanized
Structural
animalQ
research collaboration has already been biology
model
team
Quantum Computing Core
team
E. Sasaki
R. Aricescu K. Suzuki
reached, will function as domestic satelliteCore leader(CIEA)(MRC-LMB) (MRC-LMB)
institutes,
not
only
for
research
collaboration but also as human resource Neuroregulation
S. Tanaka
N. Yamamoto Y. Sakakibara H. Kawaguchi(Keio U)
(Keio U)
(Keio U)development institutions for graduate team M. Yuzaki Y. Minagawa G. Augustin(Keio U)
(Keio U)
(Keio U)
(Nanyang Tech U)
students and postdocs. The Medical
Research Council Laboratory of Molecular
Biology (MRC-LMB) in UK and Harvard Medical School in the USA will function as overseas bases
for Bio2Q. It is worth noting that Augustin has extensive experience with developing and operatinginternational research center and programs, such as the Center for Functional Connectomics in Korea
as part of the World Class Institute program and international research programs at the Duke-NUS
Medical School and Lee Kong Chian School of Medicine.
Sampetrean and Siomi will work together as Administrative Directors and provide a wide rangeof supports to the Director as well as other PIs. This two-person system will enable rapid coordination
between the three departments and the satellites, and provide comprehensive support and agile
management. Sampetrean is a neurosurgeon and basic scientist involved in brain tumor andmicrobiota research. She is a rare multilingual researcher who is fluent not only in Japanese and
Jr PI

Jr PI

T. Tuganbaev

Admin
director

Jr PI

Jr PI

Jr PI

Jr PI

Jr PI

Jr PI

Keio University-15
Human Biology-Microbiome-Quantum Research Center (Bio2Q)

English but also in 6 other languages. She will head up external operations, whereas Siomi will be incharge of internal affairs and provide continued support to Sampetrean.
Bio-1: Multidimensional data analysis core (Core director: Arita)
Human Disease Analysis Team: Morinobu Seki (Keio Med, Jr PI) and Mihoko Yoshino (Keio Med, Jr
PI). Two clinical coordinators will be hired to facilitate clinical sample collection and ethicalapplications.
Microbiome Team: Kenya Honda (Keio Med.), Jun Huh (Harvard), Timur Tuganbaev (Keio Med.), Koji
Atarashi (Keio Med., Jr PI), International Collaborators [Dan Littman (NYU), Daniel Mucida(Rockefeller), Ramnik Xavier (Broad Inst.), Michael Fischbach (Stanford), Akiko Iwasaki (Yale),
Shingo Kajimura (Harvard), Sloan Devlin (Harvard), and Ya-Chieh Hsu (Harvard)].
Metabolome Team: Makoto Arita (Keio Pharma. Sci.) and Tomoyoshi Soga (Keio IAB).
Genome Dynamics Analysis Team: Haruhiko Siomi (Keio Med.), Kazuyoshi Ishigaki (RIKEN, Jr PI).
Bio-2: Homeodynamics mechanistic analysis core (Core director: Sato)
Organoid Team: Toshiro Sato (Keio Med.), International collaborator [Hans Clevers (Roche)].
Neuroregulation Team: Michisuke Yuzaki (Keio Med.), Yasuyo Minagawa (Keio Literature), George
Augustine (Nanyang Technological University), International collaborator [Gloria Choi (MIT)].
Structural Analysis Team: Radu Aricescu (MRC-LMB), Kunimichi Suzuki (MRC-LMB, Jr PI).
Humanized Animal Model Team: Erika Sasaki (CIEA).
Imaging metabolomics team: Makoto Suematsu (CIEA), Takako Hishiki (Keio Med, Jr PI).
Q: Quantum computing core (Core director: Tanaka)
Shu Tanaka (Keio Sci. Tech.), Naoki Yamamoto (Keio Sci. Tech.), Yasufumi Sakakibara (Keio Sci.
Tech.), Hideaki Kawaguchi (Keio Sci. Tech., Jr PI).
General management of the center:
The Planning and Administration Office is responsible for the overall management of the center,
including the development of the center’s rules and regulations, management of facilities, andreporting to relevant ministries and agencies. In addition, in cooperation with the digital transformation(DX) promotion coordinator, the office will be in charge of online research meetings and other events
to ensure that our activities are not confined to the center.
The Finance Office will manage the annual budget of the center and implement measures tomake the center self-sustaining, support the acquisition of external funds, solicit donations, etc.
The Personnel and Public Relations Office will primarily be responsible for recruiting early career
researchers. The office will be responsible for consistency in the center’s PR activities so that it can
inform international recruitment, contract negotiations, and hiring. We also consider outsourcing
professional services to support international researchers in traveling to and from Japan, as well as
helping them settle after arriving.
The Coordination Office will be responsible for providing general support for PIs’ activities,
including international PIs, to ensure that their research goes smoothly.

Keio University-16
Human Biology-Microbiome-Quantum Research Center (Bio2Q)

The Data Sharing and Governance Office will present an approach to sharing data in ways thatwill enable smooth collaboration between researchers, including those outside of Japan, and will
establish an appropriate data management system in compliance with the laws and regulations forresearch using clinical data obtained
from Keio University Hospital and otherinstitutions.
The Intellectual Property Office willverify legal regulations, evaluate theappropriate intellectual property, andassess and negotiate licensing whenconcluding joint research agreementswith companies to make the center
self-sustaining.
The
intellectual
property field is expected to include
research related to drug discovery, IT(e.g., life science apps), and medical
devices.
The DX Promotion Office will
promote virtual research environments
and focus on sharing the center’sfindings, recruiting international early
career researchers, overseeing public
outreach, and transitioning the center
to a paperless environment incoordination with other offices.
Advisory council: An Advisory Council consisting of about five international scientists will be
independently established to evaluate the scientific progress of the center and provide advice
regularly. In addition, the Center Director shall appoint Advisors who evaluate scientific progress andprovide suggestion to the center. International collaborators can also serve as advisors. We plan to
appoint Eisuke Yoshida of the Keio Faculty of Business and Commerce to oversee organizational
management, and Takehiro Ohya of the Faculty of Law to oversee ethical, legal, and social issues(ELSI). We also plan to hire other staff, such as editors of well-known journals, to assist with researchplanning and publishing.
a) Principal investigators (full professors, associate professors, or other researchers of comparable
standing)* Paste onto table a) in Appendix 7.

(persons)
At beginning of
project
Researches from within the hostinstitution
Foreign researchers invited fromabroadResearchers invited from otherJapanese institutions
Total principal investigators

At end of FY 2022

Final goal
(Date: March, 2025)

10

10

10

3

3

4

2

2

2

15

15

16

Keio University-17
Human Biology-Microbiome-Quantum Research Center (Bio2Q)b) Total number of members* Paste onto table b) in Appendix 7.

At beginning of projectAt end of FY 2022

Number of
persons

Number of
persons

Researchers%

32

Final goal
(Date: March, 2025)
Number of%
persons%

32

90

Overseas researchers

13

40.6

13

40.6

28

31.1

Female researchers

8

25.0

8

25.0

45

50.0

Principal investigators

15

15

16

Overseas PIs

3

20.0

3

20.0

4

25.0

Female PIs

2

13.3

2

13.3

2

12.5

Other researchers

17

17

74

Overseas researchers

10

58.8

10

58.8

24

32.4

Female researchers

6

35.3

6

35.3

43

58.1

Research support staffs

13

13

17

Administrative staffs

6

6

11

Total number of people

51

51

118

At beginning of projectAt end of FY 2022

Number of
persons

Number of
persons

Doctoral students%

0

Expected employment

Final goal
(Date: March, 2025)
Number of%
persons

%

0

0

-

40

0

-

40

100.0

The number of doctoral students indicated in the lower table can also include those in the upper table of b) Total numbers.

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 (FY2017-2021).

H29(2017)

H30(2018)

Japanese PIs

990

2,823

1,302

1,481

1,813

8,409

1,682

Overseas PIs

780

2,959

829

334

540

5,442

1,088

1,770

5,782

2,131

1,815

2,353

13,851

Total

R1(2019)

R2(2020)

R3(2021)

Total

Average

2,770(Million yen)

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 (FY20222026).
* 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.

Year

R4
(2022)

R5(2023)

R6(2024)

R7(2025)

R8(2026)

R9(2027)

R10(2028)

R11(2029)

R12(2030)

R13(2031)

total
amountWPI Grant

650

700

700

700

700

679

658

637

616

595

6,635

Funding fromthe host
institution

256

534

536

538

512

531

551

570

589

608

5,225

Research Expenses
from Competitive
Funds & Other
Sources

498

1,047

1,110

1,127

1,157

1,187

1,267

1,297

1,326

1,406

11,422(Million yen)

Keio University-18
Human Biology-Microbiome-Quantum Research Center (Bio2Q)

WPI Grant
1. Personnel expenses: PIs, Jr PIs, international collaborators, University Research Administrators(URAs), administrative staff, postdocs, graduate students.
2. Project promotion expenses: Research environment maintenance (for the renovation of open labs,
center support offices, community spaces, germ-free mouse facilities, germ-free marmoset facilities,
and cryo-electron microscopy (cryo-EM)-related facilities), travel and living support, contractor
expenses, and center website expenses.
3. Travel expenses: Travel expenses for international collaborators and newly hired postdocs.
4. Equipment expenses: Cryo-electron microscopy (cryo-EM)-related equipment.
Funding from the host institution
1. Personnel expenses: Center director, PIs, Jr PIs, administrative directors, full-time technicians,
URAs, and administrative staff.
2. Project promotion expenses: Renting space for the center, utility expenses for spaces used for thecenter initiative.
Research expenses from competitive funds & other sources
1. Personnel expenses: Researchers and research assistants hired for competitively funded projects
associated with the center.
2. Project promotion expenses: Expenses related to promotion necessary for competitively funded
projects associated with the center.
3. Travel expenses: Domestic and international travel expenses for competitively funded projects
associated with the center.
2) -5 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
and creating new field(s) by the fusion.

We expect that the technologies and results generated by the fusion of Biology, Microbiome, andComputing will affect other fields in multiple ways. Applications with a wide impact will include establishing
new therapies, preventive modalities, and biomarkers. We believe that our efforts will also help forge theentire research field of biology and Q-computing and produce several innovative technologies.
Establishing workflows of how to identify multiorgan and microbiome interactions and how to use quantum
computing to advance biological knowledge can be applied to other fields and will set a precedent increating new examples of interdisciplinary fusion.
In recent years, it has become clear that the microbiome has a significant impact on human health andorgan systems. Microbiota exerts such effects primarily by producing tens of thousands of uniquechemicals (metabolites). However, the vast majority of metabolites (>99%) have not been annotatedstructurally and functionally (thus remaining unidentified “dark matter”). In addition, the difficulty in accurate
and high-throughput analysis of the community action of microbiota and their metabolites has hinderedefforts to define the mechanistic connections between the microbiota and host phenotypes. Moreover, acomprehensive understanding of complex human biology requires an integrative analysis of multiple levelsof data from the genome, transcriptome, metabolome, together with microbiome. However, it has been
extremely challenging to infer causal molecular networks using multiomics data, underscoring theimportance of continuing to develop new approaches. Quantum computing represents an exciting frontierwith significant potential for discovery in the field of biological sciences, yet several challenges remain,such as improving accuracy, fault tolerance, and lack of practical applications in life sciences. Therefore,
the Bio2Q WPI will harness quantum computing to shed light on the black box separating the complex
system involving multiple organs and the microbiome, and determine scientific causal relationships.
Establishing an algorithm/pipeline that fully utilizes the power of quantum computing will pave the way forsignificantly improving the discovery process in biological sciences. Such interdisciplinary research
Keio University-19
Human Biology-Microbiome-Quantum Research Center (Bio2Q)

requires the training of young scientists capable of collaborating across disciplines. To foster such
scientists, graduate students and postdoctoral fellows in the fields of biology (Bio-1, Bio-2) and computing(Q) will be mentored by multiple PIs across cores and laboratories.
3) Global Research Environment and System Reform3) -1 System for advancing international research* Describe your concrete plan for building an international research center including the makeup of its foreign researchers,
establishment of oversea satellites, 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.
* Describe measures to help foreign researchers sustain and strengthen their activities under conditions when international exchange islimited.

Plan for building an international research center: We will ensure diversity among Bio2Q
researchers by including a variety of nationalities, genders, and ages, with the goal of having at least
30% international researchers and 50% female researchers. We will provide sufficient support forinternational researchers and their families to ensure a smooth start to their lives in Japan. Startup
funding will be provided for international PIs so that they can promptly start their research at the center.
Compensation will be determined in line with a global standard (those implemented the National
Institutes of Health, USA), and not bound by university conventions. Through these measures, we willkeep the center attractive for up-and-coming young scientists. The center structure will be developed
within three fiscal years following the start of the project. We will increase opportunities to obtainresearch grants, such as by joint application for overseas foundation grants, thereby enhancing theinternational nature of the center's activities.
Strategy for recruiting international researchers: The Personnel and Public Relations offices willconduct public relations activities and create a system to recruit motivated postdoctoral and otheryoung scientists from around the world throughout the year. Starting in the first year of the project, we
will develop international recruitment programs and establish a system for reviewing and accepting
applicants in accordance with the recruitment agreements and regulations of the center. In particular,
we plan to strategically recruit 4-5 international Jr PIs within the first two years of the project.
Measures to help foreign researchers: We assume that there will be situations in whichinternational PIs cannot physically come to Japan because of restrictions arising due to the COVID19 pandemic. In such cases, state-of-the-art DX technologies such as virtual conferencing and clouddata storage system will be used to enable the PIs to engage in research activities from remotelocations. We plan to create a virtual institute environment (the so-called “cyber one-roof”) to enablefrequent, in-depth communication between researchers who would otherwise have trouble physicallyworking at the center. We will also utilize a range of media, including social media, to share the latest
findings at the center, create a network, and attract global interest from around the world.
3) -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 who can facilitate the use of English in the work process 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 (e.g., allocation of adequate staff support to handle
paperwork and other administrative functions) including your procedure and time schedule.
* Describe your strategy, procedure and timing for periodically holding international research conferences or symposiums.

To promote globalization, we will secure and train personnel in English language proficiency andresearch administration skills. We will also promote DX to streamline working processes to support
the globalization of the center and other research activities. The support office will take care ofadministrative procedures such as research grant management, preparation for events, andprocedures for accepting international researchers. In the first and second years, the center willdevelop its facilities, establish rules within the center, and formulate a structure for research support
Keio University-20
Human Biology-Microbiome-Quantum Research Center (Bio2Q)

and administrative offices.
The center will regularly hold an international symposium gathering PIs and top researchers
annually. To attract more participants and save costs with lower burden of preparation, webconferencing will be actively utilized for various meetings and discussions. Along with the researchmeetings, workshops will be organized for undergraduates and graduate students to facilitate
interaction between them and top-level researchers.
3) -3 Center management and system reform* Describe the role of the center director and the administrative director.
* Concretely describe your concept for establishing the center’s administrative organization, the center’s decision-making system andhow authority will be allocated between the center director and the host institution. (Describe concretely the mechanism for decision
making when the person in charge of management and the person in charge of research and education in the center are different, anddescribe the responsibility relationship between the two.)* 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.

Role of the center director and administrative directors: The center will be an independent
research institute under the administrative jurisdiction of Keio University. The Center Director will be
appointed and dismissed by the President of Keio University, who acts as both Keio’s chief executive
officer and chairman of the board of trustees. The decision-making authority for the overallmanagement of the center is left to the discretion of the Center Director to achieve highly flexible andagile management at the center. In day-to-day operations, the authority of the PIs, research cores,
and divisions appointed by the Center Director will be clearly defined, and free and vigorous research
activities will be prioritized. The Deputy Directors will support the Director and work with the PIs andother researchers to achieve research goals and create new research fields. Administrative Directors
will strengthen collaboration with internal and external stakeholders and work with host institutions
and external organizations to develop strategies and plans for stable management of the center.
On the other hand, compliance measures, such as research ethics and biosafety, as well as
accounting procedures, are supported by the administrative office of the School of Medicine. For
issues that may arise at the center that cannot be resolved within the center, the Office forInterdisciplinary Research Initiatives at the Headquarters for Research Coordination and
Administration (RCA) will consider the issue and solve it as a university-wide problem. RCA will also
provide support to take successful examples within the center and apply them across the departments.
In this way, the Center Director will be given a great deal of discretionary authority to carry out center
activities with confidence and a feeling of security. RCA also regularly reviews center activities andprovides feedback as necessary. The host institution will be involved in preventing the abuse of poweron the part of the Center Director, and if there is a situation that is not expected to improve,
replacement will be considered at the discretion of the President of Keio University.
System for evaluating research and merit-based compensation: The center will hierarchicallyevaluate researchers and research results once a year: The Center Director will evaluate the Deputy
Directors, and subsequently, the Deputy Directors will evaluate the PIs, Jr PIs, and postdocs. The
evaluation will be based on the overall achievements in terms of publications, research presentations,acquisition of research funds, fostering young researchers, and contribution to society. The centercan determine the salary amount according to the performance evaluation within the scope of various
labor laws, without being bound by internal conventions. In terms of institutional support, we plan tooffer a competitive employment package by exempting researchers from compulsory retirement
regulations and by introducing an incentive reward system for individuals out of the funding that they
have obtained.
3) -4 Research environment* Concretely describe how equipment and facilities, including laboratory space, will be provided in a manner appropriate for a “world
premier international research center.” Include your procedure and timing.

Keio University-21
Human Biology-Microbiome-Quantum Research Center (Bio2Q)

* Describe measures taken with regard to the research environment to sustain and strengthen research activities under conditions wheninternational exchange is limited.
* Concretely describe how the center will consider arranging for its researchers to participate in the education of graduate students.
* Describe new measures to improve or abolish existing systems and practices in the host institution toward optimizing the center’s
research environment.
* Describe your measures other than those described above for ensuring 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.

Equipment and facilities, including laboratory space: From the outset of the WPI project, morethan 3,000 m2 will be set aside for the center on Shinanomachi Campus, including open labs, PI
offices, center support offices, and a community space. In particular, 1,300 m2 in the Center for
Integrated Medical Research Building and 540 m2 in core facility of Keio Medical School will be used
as a “globally visible” research center. In addition, a core facility (540 m2) of Keio Medical School,
outfitted with the latest research equipment, will be made freely available to all WPI researchers. In
the first year of the project, we will start by installing cryo-electron microscopy-related equipment,
which will be the core of the center's activities, to accelerate the implementation of structural analysis.
Germ-free animal facilities (for mice and marmosets) will also be prepared to facilitate microbiome
studies.
Simultaneously, we will focus on developing a best-in-class computing environment for analyzing
and processing vast amounts of human biological data. In 2018, Keio University established the IBM
Q Network Hub, becoming the only organization in Asia that has access to IBM’s best quantum
computer. Together with seven industrial partners, Keio has been recognized as the world's mostimpactful quantum computer software and algorithm development center, with an unprecedented
mastery of IBM’s latest quantum chips, which are evolving rapidly. Because of active collaborations
with universities and research institutes in Europe and the U.S., we will be able to accelerate theanalysis of the vast amount of multiomics data acquired at the center using quantum computing in
addition to state-of-the-art AI. Although IBM is developing a gated-based quantum computer, we will
also have access to a cloud-based quantum annealing technique, which excels in combinatorial
optimization problems.
After the center opens, existing spaces will be reallocated as research develops, and facilities will
be expanded and further developed as needed. As part of the Keio University Mid-Term Plan 20222026, Shinanomachi Campus, where the center will be established, will be developed as a “globally
visible” research center and will continue to drive innovation at Keio University in the future, even after
the WPI grant period ends. As the WPI program develops, we will consider the ideal facilities required
for researchers to work under one roof and assess the transformation of the center’s research
environment, including the construction of new research buildings on Shinanomachi Campus as partof campus development in line with university-wide plans for construction.
Sustaining research activities in conditions where international exchange is limited: If a researcher
is unable to physically stay at the center because of the COVID-19 pandemic or other reasons, they
will be able to maintain and advance their research through regularly scheduled meetings. Methods
for sharing research information will be designed early in the first year of the project, and a system
will be established to manage and share raw research data on the cloud, leveraging online
collaboration tools such as Dropbox and Box to establish a virtual laboratory space that will enable
regular communication and sharing of research progress.
For researchers belonging to other campuses, a room will be set up in the center to facilitatesmooth collaboration with other researchers belonging to the Bio2Q. For overseas PIs, a secretary incharge will be appointed, and researchers residing in Japan at the same research core will provide
support for their research activities, thereby creating a mechanism to promote WPI research activities,
both remotely and when visiting Japan, without delay. When overseas researchers visit Japan, the
WPI office will provide support for their arrival in Japan and their daily life.
Keio University-22
Human Biology-Microbiome-Quantum Research Center (Bio2Q)

Researchers' participation in graduate education: By establishing a joint cross-disciplinary
graduate English program tentatively called STaMP (Science and Technology, and Medicine,
Pharmacy) between the Graduate School of Medicine, Graduate School of Pharmaceutical Sciences,and Graduate School of Science and Technology, the WPI center will create a "place of resonance"
where faculty, researchers, and students from the three graduate schools can directly interact with
one another. PIs affiliated with the center will be qualified to supervise graduate students at any of
the graduate schools for medicine, pharmaceutical sciences, or science and technology. This will
enable each graduate student to work with multiple mentors and receive guidance that transcends
graduate school boundaries. We expect that these measures will create a virtuous cycle that will leadto more findings in core research units, which will, in turn, lead to more students and early career
researchers coming to the center. In addition, Jr PIs and postdocs at the center will be able to gain
educational and teaching experience by regularly working together with graduate students on theirresearch projects. Since graduate education is conducted across graduate schools, PIs and early
career researchers are expected to expand their knowledge of other academic fields and forge newcollaborations through their participation in graduate education at the center.
Improvement of existing systems and elimination of customs: The university will position thecenter as a place where it can implement new initiatives to optimize its research environment. The
center will be designated as a special zone to enable the employment of excellent researchers fromJapan and abroad (including individuals who are beyond the retirement age). WPI faculty member
salaries will be determined flexibly based on performance. Project researcher salaries will be
determined by the Center Director based on PI evaluations. This arrangement will allow us to employ
world-class researchers regardless of age. The headquarters of RCA, a university-wide organization,
will be responsible for promoting and expanding research collaboration at the center and will createa system for connecting undergraduate faculties and graduate schools using the center as a platform.
Keio University is committed to creating a comprehensive research environment befitting a premierinternational research center.
4) Values for the future4) -1 Generating and disseminating the societal value of basic research* Describe concretely and quantitatively the center’s policy for widely disseminating the societal significance and value stemming fromthe results of its basic research to the general public.

Innovation through intellectual property: The center will establish new life science methodologies
for discovering and verifying uncharted multiorgan homeodynamics. The basic research performed
will generate knowledge that will contribute to preemptive medicine and healthy longevity care in asociety where people are healthy throughout their lives and contribute to a sustainably growing
society. The process of intellectual property creation and licensing of basic research results will bestrengthened. We will promote industry-academia collaboration to translate research findings to theclinic with the help of the Clinical and Translational Research Center at the Keio University Hospital.
We will also promote researcher entrepreneurship to promote the social implementation of intellectual
property. This initiative will also be supported by the center's URAs and Keio’s Office for Open
Innovation and Office of Research Development and Sponsored Projects. The WPI program will beconnected with the COI-NEXT program "A Health Commons Center to Empowering Social Wellbeing" (Host Organization: Keio University) to create a cycle that emphasizes the importance of basic
research in a new light and generates funding for human resource development.
Outreach: Sharing the details of our research, findings, and their value, is of paramount importance.
We plan to build a dedicated outreach team led by URAs with research experience and specialized
knowledge, hire professionals with backgrounds in content management, and create an attractive
Keio University-23
Human Biology-Microbiome-Quantum Research Center (Bio2Q)

website with engaging content. Information will be published and shared publicly across different
media, including social media, to disseminate our contribution to the realization of a bioeconomy
society that aims to solve environmental and medical problems. As the center aims to seek a way toconnect biotechnology with quantum computing, sharing the outcome from this unprecedented
collaboration with other organizations and the public will provide valuable insights and contribute to
the development of new applications for quantum computing technology. In addition, we will develop
ways to attract interest in research from the younger generation through open campus days targeting
junior and senior high school students via events that will combine lectures and workshops.
4) -2 Fostering next-generation human resources linked with higher education* The center should be a platform for establishing a research system in which new interdisciplinary domains can be created within a richinternational environment. Describe concretely and quantitatively the initiatives to be taken to foster young researchers, including
doctoral students, through participation in such a research system within the center.

As academic fields become increasingly diversified and specialized, it is essential to promoteinterdisciplinary research by creating positive feedback loops that transcend academic disciplines topursue disruptive innovations. As such, in conjunction with higher education, we plan to establish a
joint cross-disciplinary graduate program tentatively called STaMP in FY2023 (the official language isEnglish). Because each of the Keio graduate schools exists on separate campuses, the physicaldistance has made it a challenge to implement collaborative programs. However, the center will createa virtuous cycle in which faculty, researchers, and students from the three graduate schools caninteract directly with one another. The Keio University Center for Quality Assurance in Higher Learning
will provide comprehensive support for the planning and operation of STaMP. It is important that we
foster these positive feedback loops in an open environment, where graduate students and early
career researchers are encouraged to collaborate freely across disciplines. Keio University hasentered into a basic research and education agreement with RIKEN in 2008, followed by acomprehensive cooperation agreement with the Central Institute for Experimental Animals (CIEA) in
2016. The center will leverage these agreements to build stronger feedback loops to foster talent andexpand joint research opportunities. Furthermore, as detailed below, STaMP will, in the future, be
integrated into the Institute for Advanced Studies (tentative), which will consist of a group ofinternational and interdisciplinary research centers and institutes modeled after the WPI center.
1) Shared mentor program: We plan to implement a system for graduate students to receive
guidance from multiple mentors in graduate schools. Mentors will not only participate in researchguidance, but also join degree reviews and promote research in their respective graduate schoollaboratories and at research institutions abroad. We expect this system to not only promote thedevelopment of interdisciplinary researchers, but also to encourage interdisciplinary research among
mentors through their graduate student mentees. The faculty members of the Graduate School of
Medicine, Graduate School of Pharmaceutical Sciences, and Graduate School of Science andTechnology who are not part of the WPI center will be actively registered as members of the STaMP
Graduate School Committee as the center develops, allowing them to take part in research guidance
and personnel exchanges that transcend academic disciplines.
2) Research internship program: We will establish a system that allows graduate students to internat other laboratories (within their graduate school, at another graduate school, or overseas) for up to
six months. PIs and WPI offices can assist graduate students in selecting a laboratory, but thedecision will be ultimately left to the student.
3) Symposiums and retreats organized by graduate students and early-career researchers:
International symposiums and retreats will be organized and held approximately once a year at theinitiative of early career researchers, including graduate students and postdocs, with support from PIs
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

and the WPI administrative offices. We hope that these symposiums and retreats will lead to thecreation of researcher networks that will extend across academic disciplines.
4) Cross-listed graduate workshops: We will establish workshops, including lectures and practical
exercises, as programs for acquiring the skills and knowledge required of early career researchers
who can work across academic disciplines. Workshops will be open not only to graduate students,
but also to undergraduate students and early career researchers. Upon completion, participants will
receive a certificate signed by the three deans of STaMP graduate schools. For example, in the
Presentation Workshop, an international lecturer will present in English on how to give a presentation(oral, poster, or online), followed by practical training in small groups (e.g., four groups of five students
each year) with PIs from the three graduate schools participating as tutors for each group. In the
Medical Bioinformatics Workshop, participants will receive lectures and take part in practical training
on genome analysis, gene expression analysis, and image analysis. PIs from each of the three
graduate schools will be in charge of lectures and online training.
5) Accepting undergraduate students from the Faculty of Science and Technology and theFaculty of Pharmacy to conduct their graduate research at the School of Medicine: Unlike theFaculty of Medicine, undergraduate students at the Faculty of Science and Technology and theFaculty of Pharmacy participate in graduate research. Although students were previously acceptedon an irregular basis, we plan to accept approximately 20 undergraduate students each year, incoordination with the Medical Educational Center at the School of Medicine as part of this new center.
We expect that the master’s and doctoral program students who experience this kind of crossdisciplinary graduate research will lead this center in the future.
6) High school outreach program: The center will support high school outreach programs that are
already in place at each of Keio’s undergraduate faculties to foster the future leaders who will help
drive the next generation of research at the center.
4) -3 Self-sufficient and sustainable center development* The center needs to become self-sufficient and sustainable after the funding period of 10 years ends. Describe the host institution’s
mid- to long-term plan and schedule for supporting the center’s development, including the reform of the host institution’sorganization, the provision of personnel with priority allocation of tenured posts to the center, fundamental financial support, andmaterial support including land and buildings.

Reorganization to become self-sufficient and sustainable: The center will be positioned as anindependent research institute under the administrative jurisdiction of Keio University. In the future,
we will establish the Institute for Advanced Studies (tentative), which will consist of a group ofinternational and interdisciplinary research centers and institutes modeled after the WPI center. As
an intramural special zone within the university, we will implement various bold measures to enhanceresearch, ensure independent management, and attract the attention of researchers from around theworld for its research performance, environment, support systems, and the ability to obtain funding.
After reaching a consensus on these issues, we will reorganize existing cross-departmental research
centers and institutes at the university, consolidating and optimizing resources into the Institute forAdvanced Studies by reallocating operational expenditure budgets, staff, and facilities. As social
norms and values continue to undergo dramatic changes, we advocate a "Convergence ofKnowledge" format that integrates the humanities and social sciences, which will serve as the nucleus
for creating the future of Japan and will be the driving force for the evolution of the university into aspace that nurtures the world's leaders. Entry into the Institute for Advanced Studies will be based on
the same criteria as the WPI center, requiring an impact and presence that attracts frontline
researchers from around the world. While strict entry requirements will be set for research centers
and institutes to receive accreditation, various incentives will be provided to affiliated researchers. By
promoting the systems and policies of the Institute for Advanced Studies across the university, the
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

institute will become a driving force for Keio University to make further progress as a research
university.
Provision of personnel with priority allocation of tenured posts to the Center: Researchersaffiliated with the WPI or the Institute for Advanced Studies may also remain affiliated with their homeinstitutes (concurrent appointment). Simultaneously, through the above-mentioned organizational
reforms, we will be able to allocate or increase the number of tenured positions, and we will develop
a system for establishing several tenured positions at the Institute for Advanced Studies at thediscretion of the President of Keio University. These positions will be allocated to contribute to thesustainable development of the center through tenure-track positions for early career researchers andthe acceptance of promising researchers from outside the university and overseas, primarily throughthe generational succession of PIs and the acquisition of external funding to exponentially improvethe center’s reputation.
In addition, we will promote the existing system of Advanced Research Project Professors(externally funded fixed-term faculty members not subject to compulsory retirement regulations). The
income of the center (external funds) will also be used to bring 'world knowledge' from outside theuniversity to the center and leveraged to further acquire external funding. Graduate students who
participate in this center through the Early-Career Researcher Development Program at the Centerfor Quality Assurance in Higher Learning will be treated as researchers and paid an appropriate salary
to broaden the center’s base and ensure its sustainable development.
Mid- to long-term plan and schedule to support the center’s development: The establishment
and operation of the Institute for Advanced Study will be a part of the core project of Keio University
following three goals specified in the “Mid-Term Plan 2022-2026”: 1. creation of convergence ofknowledge needed to lead society through collaboration between the humanities and naturalsciences; 2. organic growth as a research university; 3. establishment of a ‘globally visible’ research
center that can attract frontline researchers from around the world. These initiatives will remain inplace in the form of the Institute for Advanced Studies after the WPI grant period ends. The operational
budgets of the Institute for Advanced Studies are provided to maintain a secure and well-performing
environment for researchers. We support the translation of research findings into social contributions
and the acquisition of competitive research fundings with minimal interference. Furthermore, we plan
to build updated infrastructures and commit to operating the institute where both international anddomestic researchers can fully dedicate themselves to their research. Specifically, the university will
support various new initiatives to secure research fundings. At the start point of WPI center, Keio
University will bear a portion of the personnel expenses for PIs and other researchers (approximately
150 million yen/year) as well as the cost of renting space (approximately 300 million yen/year). All
indirect expenses from public funds will be used to develop and improve the research infrastructureof the center (regarding private funding from companies, etc., 30% indirect costs will be charged).
Through these measures, approximately 200 million yen will be available to the center in the final yearof the project. Personnel expenses for the center's research and administrative support teams under
this grant will be gradually reduced from the project’s sixth year onward and will be halved in the final
year (we expect to use approximately 360 million yen/year). By gradually shifting financial resources
to external funds, and indirect expenses/overhead to be secured as detailed above, we estimate that
it will be possible to maintain the center even after the WPI grant period ends, but we will invest
university operational expenditure as necessary to achieve the project proposal.

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Center Director's Vision
I began my research career fascinated by the complexity of the immune system and later focused on thesite where immune cells are the most active - the interface with the external environment, the mucosal surface.
I realized that about 100 trillion symbiotic microorganisms (the microbiome), with their one million genes,
functioned as if they were a single organ, profoundly influencing immune homeostasis. Given that the numberof human genes is only 27,000, one can readily appreciate the functional impact of the microbiome. Moreover,the microbiome is an essential part of a multiorgan network that includes not only the mucosal immune
system but also the entire immune system, along with the nervous, metabolic, and cardiovascular systems.
Over the past decade, our own research, as well as next-generation sequencer-based large-scale projects
including the human microbiome project (HMP), have uncovered significant associations between various
diseases and the human microbiome. Moreover, the success of fecal microbiota transplantation, in which
healthy human feces are transplanted into patients, revealed that the microbiota is manipulatable and is a goodtherapeutic target. However, despite the global development/progress of microbiome research, only a handfulof studies have been able to identify truly “causative” bacterial species that causally contribute to diseaseprogression or regression. Most of the research does not go beyond the “correlation” between gut microbiota
and host phenotype. As a result, drug development still largely depends on empirical experiences. In infectious
diseases, which are caused by a single pathogen, a standard practice is to isolate the responsible microorganism,
infect animals with it, and see if it recapitulates the disease. In contrast to infectious diseases, the physiological
functions of the microbiota are exerted by a “community” composed of multiple bacterial species. Therefore,
it is critical to understand which combinations of bacteria constitute a functional unit. Current methodologies,
however, are not best suited to the identification of such a functional unit at high throughput. Thus, themicrobiome still remains the “dark matter” of the human body. To overcome this limitation, we have developed
a unique approach that goes beyond the data-driven approach and instead narrows down the complex
microbiota to minimal consortia that exert critical functions in the target phenotype. By taking full advantage
of our strengths in the field of microbiome research (e.g., microbial culture techniques, gnotobiotic techniques,
metabolomics, etc.), we have made seminal contributions in the microbiome field by identifying immuneactivating microbial consortia. However, there is a limit to what a single laboratory can reveal about the highly
complex network of the microbiome and multiple organs.
The human body’s homeostasis is maintained through “multiorgan homeodynamics”, a complex
interaction that connects multiple organs throughout the nervous, immune, metabolic, and digestive systems,
in which the microbiome plays a central role. The interactions between multiple organ systems likely enable
the optimization of biological processes. However, conventional analyses of single networks of cells or genes
cannot fully reveal the details of this complex interplay. In particular, mechanisms underlying the signal
conversion of external to internal biological information, as well as the intricate network connecting theimmune, neural, and metabolic systems, are difficult to decipher by conventional analyses. Invention of new
methodologies are required to elucidate the extremely complex and dynamic interactions within the multiorgan
network by a reductionist yet integrated approach. Recent technological innovations promise to help solve thispredicament. Metabolomics can now characterize metabolite diversity and dynamics, and organoid technology
ensures the semi-permanent culture of human tissue stem cells, leading to major breakthroughs in humanbiology research. Furthermore, epigenetic analyses targeting transposons and connectomics analyses of neuralcircuits are both powerful tools for elucidating multiorgan homeodynamics. In addition, artificial intelligence(AI), represented by deep learning, is becoming a cutting-edge tool in biological science. In particular, quantum
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

computing is a new technology that uses quantum bits, which can achieve the superposition of the 0 and 1
states and thus has a far higher representational power than traditional computers. Therefore, by combining
quantum computing together with AI and by projecting super multiomics data onto high dimensional quantum
Hilbert spaces, we expect to solve more complex tasks and discover hidden features of complex multiorgan
network structures. Furthermore, quantum computing can be powerful to accelerate research through the rapid
generation of highly valid hypotheses. The cooperation of experts in various fields and the integration of AI
and quantum computing will thus enable discovering, inferring, and verifying novel causal relationships
between the microbiome and multiorgan networks. We firmly believe that by harnessing this kind of integrated
research, it will be possible to elucidate the mechanisms underlying the conversion of external environmental
changes (including the microbiome) into internal signals, and examine the associated multiorgan regulatory
networks (the gut-brain axis in particular) at a greater resolution than currently prevalent.
To this aim, we will establish a research center that can integrate all the above-mentioned technologies. We
propose the Human Biology-Microbiome-Quantum Research Center (Bio2Q) as a new WPI center thataims to decipher human multiorgan homeodynamics by collecting multiomics and microbiome data associatedwith various human diseases, development, and aging, and by combining quantum computing technology and
AI. Pioneers in the fields of Biology, Microbiome, and Quantum will collaborate to address the problem of
biological signal conversion and to forge a new life science field based on the elucidation of the mechanismsof organ homeodynamics. The Bio2Q Center will comprise three research core units: Bio-1:
Multidimensional Data Analysis Core, Bio-2: Homeodynamics Mechanistic Analysis Core, and Q:
Quantum Computing Core. The three cores will function cooperatively to overcome the bottlenecks ofcurrent research and to establish a new methodology in human biology and microbiome research. The new
methodology will not only become a gateway to exploring various biological phenomena but will also have asignificant impact on the health and medical industry.
Keio University is already bringing together researchers with world-class expertise in microbiome,organoid, metabolome, transcriptome, and connectome technologies. We aim to make our organization highly
attractive to top-class international students and postdocs and a starting point for the transformation into a
globally competitive center. In line with the aim of Bio2Q, I have selected a core of 14 top-class scientists. I
have enlisted the help of the Central Institute for Experimental Animals and RIKEN, which function as
domestic satellites. In addition to 3 international PIs, our proposal has attracted the participation of 10
international outstanding collaborators in the fields of immunology, microbiology, neuroscience, informatics,
biochemistry, metabolism, stem cell biology, and structural biology. Their home institutes (Harvard, NTU,
MRC-LMB, Rockefeller, MIT, Yale, NYU, Broad Institute, and Stanford) will function as overseas satellites.
Furthermore, we believe that the establishment of the WPI Center is an excellent opportunity to promote
innovation within Keio University as well. By crossing department barriers and working closely withinternational centers, the WPI Center will accelerate the university’s globalization. In conjunction with theongoing digital transformation (DX), we will significantly improve old-fashioned administrative and meetingsystems. By enhancing researcher support such as intellectual property acquisition and contracts, support for
writing papers in English, and public relations, we will create an environment where researchers can focus
more on their own research. At the same time, we will review the progress of each core unit and projects andreflect the results in the evaluation of researchers and budget. We will also flexibly adjust the system byincorporating new themes and consolidating or eliminating research teams. We are confident that this center
will establish itself as a true “world-class research center” and serve as a platform for fostering the next
generation of domestic and international researchers.
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Host Institution’s Commitment
June 1, 2022
To MEXT
Keio University
Kohei Itoh, President
I confirm that the measures listed below will be carried out faithfully and concretely as follows
regarding “(Human Biology-Microbiome-Quantum Research Center (Bio2Q))” 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, while showing that the center contributes toachieving the host institution’s missions, etc.

※Describe how the center will contribute to achieving the host institution’s missions, enhance the founding spirit/philosophy of thehost institution, and contribute to realizing the objectives of its operation, etc.
※Describe the center’s role within host institution’s own mid-to-long-term strategy.

Keio University has a clear mission set forth by its founder, Yukichi Fukuzawa. In the university’sfounding principles, Fukuzawa calls on those in the Keio community "to go on to become leaders ofsociety." Now, more than 160 years after the university’s establishment, ‘society’ implies an‘international society,’ and WPI will provide indispensable motivation for the development of theuniversity. Thus, we guarantee that comprehensive support will be given to the WPI center.
Our Mid-Term Plan 2022–2026 was formulated as a concrete measure to achieve this goal. As apractical project to realize our mid-term plans for research, the Bio2Q center aims to become a worldclass research center for interdisciplinary research comprising three research cores. It will bring
together internal and external research resources and serve as a leading example of our vision for atruly international research center. We will establish a related graduate school program to educate
world-leading experts in these fields as the university aims for “organic growth as a research
university.” The formation of this center presents a great opportunity for the university to promote its
outstanding efforts both internally and externally.
The center will be an independent research institute under the administrative jurisdiction of Keio
University, and in the future, we will establish the Institute for Advanced Studies (tentative), which willconsist of a group of international and interdisciplinary research centers and institutes modeled after
the WPI center.
The establishment and operation of the Institute for Advanced Study will be part of the core projectsof Keio University following three goals specified in the Mid-Term Plan 2022–2026: 1. creation of
convergence of knowledge needed to lead society through collaboration between the humanities andnatural sciences; 2. organic growth as a research university; 3. establishment of a ‘globally visible’
research center that can attract frontline researchers from around the world.
The operational budgets of the Institute for Advanced Studies will be provided to maintain a secure
and well-performing environment for researchers. We will support the translation of research findings
into social contributions and the acquisition of competitive research funding with minimal interference.
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

Furthermore, we plan to build updated infrastructure and are committed to operating an institute where
both domestic and international researchers can fully dedicate themselves to their research.
Specifically, the university will support a variety of new initiatives to secure research funding.
2)

Provide a mid-to-long-term policy on the direction of the host institution’s operatingorganization, one that includes the reform of the institution’s existing organization in waysthat will achieve the center’s independence and create a permanent place for it within theorganization. A concrete plan must be established and a schedule set for carrying out the
restructuring of the host institution’s organization.
※Describe your mid-to-long-term policy on the direction of the host institution’s operating organization and provide a concrete planand schedule.

The Bio2Q center will be under the administrative jurisdiction of Keio University. The Center Director
will be appointed and may be dismissed by the President of Keio University, who acts as both Keio’s
chief executive officer and chairman of the board of trustees. Decisions regarding the generalmanagement of the center will be left to the discretion of the Center Director, making for a highly agile
structure that facilitates rapid decision-making.
We are considering establishing several international advanced research organizations modeled
after this center in the future. Together, they will serve as special research zones within the university
under the tentative name of “Institute for Advanced Studies,” which will be incorporated as permanent,
independent research organizations by restructuring and integrating existing organizations andcentralizing resources as necessary, including the Bio2Q center.
The following is a schedule of various support and reforms toward self-sustaining operations of the
Bio2Q center.
1. The Center for Integrated Medical Research Building at Shinanomachi Campus will be usedas the main base of operations from the outset of the WPI project, with 3,000 m2 of research
space—equivalent to approximately 300 million yen/year in rental fees—will be provided tosupport the center’s activities. Once the center is established, we will expand the amount of
space by reallocating existing spaces according to research progress. At the same time, wewill consider securing more space for the center on Shinanomachi Campus as part of campus
development in line with university-wide plans for construction.
2. A portion of the personnel expenses for Principal Investigators (PIs) and other researchers(approx. 150 million yen/year) will be covered by Keio University. After establishing the Bio2Q
center, we will work to obtain various funding sources to achieve financial independence, suchas accepting joint corporate researchers on the condition that they bear research costs andsoliciting donations through crowdfunding and other means. In addition, through the Office forOpen Innovation, our internal organization for industry-government-academia collaboration,
we plan to share research findings with companies and obtain royalties by promoting social
implementation, thereby gradually reducing the amount of funding needed through this grantin the sixth year and beyond. We also plan to increase the allocation of a wide range of externalfunds, indirect expenses, and overhead costs.
3. The Center for Quality Assurance in Higher Learning was newly established in Keio University
in April 2022. Through it, a joint cross-disciplinary graduate English program tentatively called
STaMP (Science and Technology, and Medicine, Pharmacy) is slated to launch in FY2023,
which will be an opportunity to enhance the cross-disciplinary academic programs acrossundergraduate faculties and graduate schools.
4. We will secure and train personnel with English-language proficiency and researchadministration skills to promote globalization in administrative departments that support
research activities. We will promote digital transformation across administrative departments,
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

secure resources by streamlining and improving workflows, and establish an International
Affairs Section within the Office of Research Development and Sponsored Projects by FY2024
to support the globalization of this center as well as other research.
5. We will promote research data management as part of our digital transformation efforts. By
FY2024, we will establish a system of support services for our data management plan (DMP)and simultaneously build a research data infrastructure that works with this system in order tocontribute to the global research commons through open science.

3)

Describe the host institution’s concept for allocating it’s basic and other budgets andprovide sufficient support for carrying out the center’s operation and research activities,
including necessary human, financial, and system support. In addition, when utilizing
external funds other than the WPI grant for the center’s operation and research activities
toward realizing the missions of the host organization, show the relationship between thecenter and the other external funds.
* If a prospect exits for utilizing external funds other than the WPI grant for the center’s operation and research activities, indicate
the application/acquisition status of the relevant external funds and the relationship between them and the center. (If the following
programs are included, be sure to describe them. Their relationship to the center can be illustrated if appropriate.)
・ WISE Program(Doctoral Program for World-leading Innovative & Smart Education, ・ Supereminent Program for Activating
Regional Collaboration (SPARC), ・ Open Innovation Platform for Industry-Academia Co-creation (COI-NEXT), ・ Center of
Innovation (COI) Program, ・ Program for Promoting Regional Revitalization by universities as Center of Community (COC+
Program)

We will provide maximum assistance to make the center more attractive to researchers by
establishing a system for comprehensive support services that enable global researchers to focus on
their research. These services will include support for legal matters, intellectual property, digitaltransformation, early-career professional development, fundraising, and more. The center director,
three deputy directors, two administrative directors, and a dedicated team of administrative support
staff will be established inside the organization. Keio University will bear the personnel expenses offaculty members affiliated with the university. The School of Medicine, other undergraduate faculties,
and campus administrative departments will also assist in the center’s operation. The external funds
obtained by PIs affiliated with the Bio2Q center will exceed 700 million yen each year. Combined with
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

the allocation of indirect expenses, this will ensure resources beyond the amount subsidized by the
WPI Grant. Keio will also look to donations, fundraising, and other forms of financial support.
In terms of institutional support, we plan to offer a competitive employment package that attracts
excellent researchers from all over the world by exempting them from compulsory retirement
stipulations based on internal university regulations and by introducing an incentive reward system
for individuals out of the funding that they have obtained.
The aforementioned STaMP program will be promoted at the Bio2Q center and linked to the crossgraduate school training program under the Support for Pioneering Research Initiated by the Next
Generation (JST-SPRING) program, which was adopted in FY2021, to enhance the professional
development of early career researchers. Moreover, we will collaborate with the Keio-led project of“A Health Commons Center to Empowering Social Well-being” as part of the JST Program on Open
Innovation Platform for Industry-Academia Co-creation (COI-NEXT). The collaboration will aim torealize an ecosystem where research funds are obtained through joint corporate research, researcher
entrepreneurship promotion, and social implementation of intellectual property.
We expect to allocate external funding obtained by PIs to the research activities at the Bio2Q centerin addition to the funding from the WPI. Amounts of external funding obtained by PIs are shown in the
Figure below.

4)

Provide for the independent operation of the center including after the WPI grant period
ends. Provide necessary support to include the long-term provision of human and financial
resources, facilities, equipment and other elements needed to retain the center as a “World
Premier International Research Center.” Also, secure and provide from an early stage of thecenter’s establishment the infrastructure needed for it to carry out its activities (e.g. land,
research facilities and equipment, research space), and do so with a commitment tocontinually maintaining this infrastructure after the WPI grant period ends.

To ensure our continued independent operation as an internal special research center after the WPIgrant period ends, we will secure human resources externally, support overseas researchers upon
review and expansion of internal research funding, and secure an ongoing supply of research talentby training early career researchers through the center's activities. Moreover, we will continue to
implement the personnel and financial support measures listed in measure #3 after the WPI grant
period ends. Once the Bio2Q Center opens, existing spaces will be reallocated as research evolves,and facilities will be further expanded and constructed as needed. As the WPI progresses, we will
Keio University-4
Human Biology-Microbiome-Quantum Research Center (Bio2Q)

consider the ideal facilities required for researchers to work under one roof and assess thetransformation of the center’s research environment, including the construction of new researchbuildings on Shinanomachi Campus.
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 the center’s operation.

The Center Director will exhibit strong leadership and manage the center independently with theability to exercise their authority on issues pertaining to personnel matters, budget execution,
accepting research funding, and other matters within the center. The center will have two
Administrative Directors, one responsible for external operations and one for internal affairs, enabling
rapid coordination with other departments and comprehensive support and agile management.
If any issues that may arise at the center cannot be resolved within the center, the Office forInterdisciplinary Research Initiatives at the Headquarters for Research Coordination and
Administration (RCA) will take up the issue and solve it as a university-wide problem. The RCA will
also provide support to take successful examples within the center and apply them across theuniversity. This will result in a structure where the Center Director will be given a great deal of
discretionary authority to carry out center activities with confidence and a certain peace of mind. The
RCA will also regularly review center activities and provide feedback as necessary. The hostinstitution will be involved in preventing abuse of power on the part of the Center Director, and if there
is a situation that is not expected to improve, replacement of the Center Director will be consideredat the discretion of the President of Keio University.
6)

Provide support to the center director by coordinating with other departments regarding
assigning researchers to the center and creating an effective environment for the center
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.

Keio University aims to conduct leading interdisciplinary research and has set forth a mid-term plan
for research to “promote collaboration between the humanities, social sciences, and natural sciences,
strengthen cooperation among graduate schools, and create integrative knowledge to lead society.”
Based on this philosophy, the Bio2Q center will provide a place for outstanding internal researchers
across all of Keio’s campuses. In addition, personnel expenses will be allocated to reduce theeducational and administrative workload placed on academic faculty members and provide anenvironment where PIs can better focus on their research activities.
The activities of the Bio2Q center, from application to its actual formation and operation, will be
carried out in collaboration with the Office for Interdisciplinary Research Initiatives at the RCA, which
will act as a conduit between the center and Keio’s undergraduate and graduate schools throughwhich feedback on outstanding research can flow. The entire university will build the structuresneeded to support the center’s efforts to grow into a place that can aggregate the knowledge andexpertise of researchers from various disciplines.
7)

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).

In addition to a new administrative office dedicated to the Bio2Q center, we will actively promote
the internationalization of research support services. For example, we will establish an International
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

Affairs Section within the existing Office of Research Development and Sponsored Projects to findand train professionals with English-language proficiency and a working knowledge of contracts,
intellectual property, and review procedures. A new employment system will allow researchers who
have made internationally visible achievements and are expected to continue to make further
progress after the mandated retirement age of 65 to work at the center regardless of their age. Keio
University will position the center as an integrative knowledge hub by linking the center with various
programs for the professional development of early career researchers, which will help train the next
generation of researchers and build a pipeline of talent to the center.
8)

Provide other types of assistance to give the center maximum support in achieving its
project and in becoming a world premier international research center in both name anddeed.

We will provide support for the development of a global research network and use international
recruitment to appoint a wide variety of international researchers with an emphasis on respecting
diversity. The various research data generated and collected at the Bio2Q center will be disclosed
and shared to the extent possible through a platform for the utilization of research data promoted by
Keio University as part of its digital transformation of research, leading to innovation potential beyond
the research conducted at the center. Conversely, in response to the new global-scale risks
associated with internationalization and open research, we will ensure that the prerequisites for aninternational research institution are met, including ensuring research integrity and further
strengthening our security export control measures. Through the WPI, Keio University will raise theawareness of its academic faculty and administrative staff and educate its students, ensuring theimplementation of university reforms to establish the university as a world-class research institution.
9)

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 the departments throughout
its organization.

The Advisory Council, which will be organized by the President of Keio University and includes
external parties, will consist of more than 50% non-Japanese members and will conduct regular
evaluations of the activities and achievements of the Bio2Q center. In addition, outstanding efforts will
be shared with the RCA and disseminated throughout the university. In particular, the center facilities
will strengthen the global infrastructure of the host institution as a whole by serving as the impetus toincrease internal English-language proficiency, strengthen the management of intellectual property,
drive innovation, and promote startups. The center will be a model for the operation of a world-classresearch center for subsequent research organizations within the university to follow. It will also serveas an example for other world-class research organizations at private universities, which have togenerate their own financial resources in contrast to national universities.
10) (For host institutions that already have an existing WPI center and/or Academy center) Fully
support and sustain the existing WPI and/or Academy center and advance its development
as a world premier international research center, while being capable of fully supporting the
new center at the same time.

Not applicable.
11) (For host institutions that already have an existing WPI center and/or Academy center) Take
the initiative to spread the existing centers’ good system reform results to other departments
throughout the host institution and apply them to implementing the host institution’s own
reforms.

Not applicable.
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Human Biology-Microbiome-Quantum Research Center (Bio2Q)

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 2022.
・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 Investigators."

Name

Age

Current affiliation

Specialization(Department/ School/Institution) ・Title

Effort *(%)

1 Kenya Honda *53

Keio University School of Medicine・Professor Microbiome, Immunology

90

2 Toshiro Sato *49

Keio University School of Medicine・Professor Gastroenterology

90

3 Makoto Arita *52

Keio University Faculty of Pharmacy・Professor

Lipid biology, Lipidomics

80

4 Shu Tanaka

41

Keio University Faculty of Science andTechnology・Associate Professor

Quantum annealing,
Statistical mechanics,
Computational physics

80

5 Haruhiko Siomi *62

Keio University School of Medicine・Professor Epigenetics

6 Michisuke Yuzaki *62

Keio University School of Medicine・Professor

Neuroscience,
Synaptopathy

80

7 Jun Huh *48

Department of Immunology/ Harvard
Medical School・Associate Professor

Microbiome and
Neuroimmunology

10

8 Erika Sasaki

55

Department of Marmoset Biology andMedicine/ Central Institute for Experimental
Animal・Director

Laboratory animal
science, Reproductive
biology

80

80

80

9 Yasuyo Minagawa

51

Keio University Faculty of Letters・Professor

Developmental cognitive
neuroscience,
Developmental
psychology,

Alexandru Radu
Aricescu *49

Neurobiology Division/ MRC Laboratory of
Molecular Biology, Cambridge, UK・
Programme Leader

Neuroscience &Structural Biology

10

11 Tomoyoshi Soga *62

Keio University Faculty of Environment andInformation Studies・Professor

Analytical chemistry,
Metabolomics, Cancer
metabolism

80

12 Naoki Yamamoto *45

Keio University Faculty of Science andTechnology・Professor

Quantum computation,
Quantum control

50

10

13

Yasubumi
Sakakibara

61

Keio University Faculty of Science andTechnology・Professor

Bioinformatics

70

14

Makoto Suematsu*

64

Live Imaging Center, Central Institute forExperimental Animals・Director
Biochemistry
Keio University School of Medicine・Professor

80

15George Augustine*66

Neuroscience & Mental Health/Lee Kong
Chian School of Medicine/Nanyang
Technological University・Professor

30

Neurobiology

Notes

Satellite (Central Institute forExperimental Animals)

Satellite (Central Institute forExperimental Animals)* 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.)(Keio University) - 1

Human Biology-Microbiome-Quantum Research Center (Bio2Q)