2023

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Contents
Connect molecules, create value, and change the world

Director’s message

4

ITbM at a glance5

Members and organization

6

Research groups

8

Centers

14

ITbM administration

15

Research environment

16

Towards globalization

17

ITbM’s female scientists

19

ITbM outreach20

Graduate Program of Transformative Chem-Bio Research (GTR)

21

Research

22

WPI centers and support

38

3

Director's message
Changing the world with molecules
Looking back through history, we can see therevolutionary impact of life-saving drugs like penicillin andvital research tools such as green fluorescent protein.
Our dream is to change the world through molecules, andby fusing state-of-the-art synthetic chemistry, biology
and theoretical science, ITbM has developed a range ofpromising bio-functional molecules during its first ten years.
Many of these molecules have been commercialized andutilized to discover the molecular mechanisms of importantbiological events.

beyond our imagination. If we can utilize the power of suchmolecules to elucidate fundamental biological functions inplants and animals, we will be able to maximize their ability
to grow, reproduce, and adapt to the environment, as well as
understand and overcome various diseases.
Curiosity has always been the driving force behind
research at ITbM. We will open up new frontiers with thepower of molecules through curiosity-driven interdisciplinary
research. We will nurture a new generation who can pioneer
new science at the interface of multiple disciplines andattract top global researchers to face fresh challenges.

Our earth faces a number of critical issues that are vital to
the sustainable future of humankind, such as achieving foodsecurity, combating climate change, protecting ecosystems
and ensuring healthy lives. In ITbM's second chapter, 'ITbM
2.0', we will further accelerate and expand our research
to solve these important social issues with the power ofmolecules. Novel molecular structures harbor new functions

Takashi Yoshimura
Director, Institute of Transformative Bio-Molecules4

ITbM at a glance
Interdisciplinary research between chemistry and biology
The Institute of Transformative Bio-Molecules (ITbM) at
Nagoya University (NU) in Japan, is an international research
institute that conducts interdisciplinary research between
chemistry and biology. ITbM was selected in October 2012
as one of the centers of the World Premier International
Research Center Initiative (WPI), a ten-year program fundedby the Japanese Ministry of Education, Culture, Sports,
Science and Technology (MEXT).

research area on the boundaries of chemistry and biology.
By taking full advantage of our strengths, ITbM has been
conducting ‘needs-inspired’ basic research and explored
new research areas of “plant chemical biology”, “Striga”,“chemical chronobiology”, and “chemistry-enabled live
imaging” at the beginning of ITbM, “ITbM 1.0”. Going forwardwith its mission/goal of developing transformative biomolecules, ITbM set the strategy “ITbM 2.0”, and started thefollowing challenges: “chemistry-enabled plant adaptation”,“parasitic plants”, “clock diseases”, “chemistry-enabledbioimaging”, “nanocarbon chemistry and biology”, and“climate change resilience”. These endeavors will address
various social issues regarding the environment, foodproduction, and medical technology.

Officially launched in April 2013, ITbM's goal is tocreate a new interdisciplinary field of research through thecollaboration of cutting-edge synthetic chemistry, animal/
plant biology, and theoretical science, as well as to deliverbio-molecules that change the way we do science and welive, i.e., “transformative bio-molecules”.

ITbM has become a truly exciting and internationallyvisible institute where new interdisciplinary fields of research
are emerging and new molecules are being born every day.
Although some activities have been limited since FY2020
due to the COVID-19 pandemic, our dream of changing theworld with molecules is clearly bearing fruit. ITbM’s challenge
continues.

Many transformative bio-molecules have been developed
up to now, such as the discovery of penicillin, and thedevelopment of the highly effective anti-influenza drug,
Tamiflu.
At ITbM, chemists, biologists and theoreticians arecollaborating side by side to design, synthesize and evaluate
new transformative bio-molecules, and to generate a new5

Members and organization
ITbM gathers world-leading researchers in the fields ofsynthetic chemistry, biology, and theoretical science, andthey work together to conduct interdisciplinary research.
In 2013, ITbM started with ten PIs (7 from NU, 3 fromoverseas), and added three more PIs (1 from NU, 2 fromoverseas) by 2016 to further advance its research. In 2022,
under the initiative of the new Director, ITbM is working on
research that contributes to human health, with a view ofrecent global climate changes and data science. With a viewto promoting diversity, ITbM has appointed a new PI andthree junior PIs who are necessary to tackle these researchareas, and will take on the challenges for the next 5-10 years.
To enable world-class researchers to participate in
ITbM as overseas PIs, ITbM has introduced the Co-PI
system. Through this system, ITbM employs brilliant young
researchers as Co-PIs who work full-time at ITbM while
cooperating with the overseas PIs. This system enables
the overseas PIs to carry out their-own research at ITbM
with continuity, and has contributed to improving the global
visibility of ITbM. Co-PIs were also allocated to PIs at Nagoya
University (NU PIs) to enable them to focus on their research.

6

One of the keys is the Administrative Department ofresearch. ITbM's research activities are supported by many
capable and dedicated staff in ITbM.

ITbM, especially the members of the Research Promotion
Division (RPD) and the Strategic Planning Division (SPD). The
RPD finds inventions and scientific discoveries from eachresearch group at an early stage and achieves mainstream
recognition from society through diverse activities such as
public relations, science visualization, and so on. The SPD
promotes technologize ITbM’s research results throughapplication of patents and academia-industry collaboration.
The RPD also has the capability to provide local support
to ITbM’s foreign researchers and their families, enablingthem to fully concentrate on their research. ITbM’s four
sub-centers (Chemical Library Center, Live Imaging Center,
Peptide Protein Center, and Molecular Structure Center) also
make significant contributions to ITbM’s interdisciplinary

As international collaboration has been considerablyenhanced by ITbM’s internationalization and global visibility,
ITbM has strategically expanded its collaboration networkand strengthened international collaborative relationships
with existing partners such as the Center for Selective C-HFunctionalization (NSF, US), RIKEN Center for Sustainable
Resource Science (CSRS, Japan), Institute of Chemistry(IoC) at Academia Sinica (Taiwan), and Kenya Agricultural& Livestock Research Organization (KALRO, Kenya). In
2020, the IoC Itami lab was launched and a faculty staff wasallocated.

7

Research groups: ChemistryBode-Oishi Group
Jeffrey W. Bode
Position

Research interests
WebsitePrincipal Investigator; Professor, ETH Zürich

Synthetic chemistry, protein synthesis, chemical biology
https://bode.ethz.ch/Research overview: The chemical synthesisof proteins can be accomplished by peptide
ligation reactions. In our own research, weShunsuke Oishi(Co-Principal Investigator) have developed a new amide-forming reactionof α-ketoacids and hydroxylamines (KAHA
ligation) that allows the synthesis of proteins by
combining peptide segments under aqueousconditions without coupling reagents or side
chain protecting groups. Rendering the synthesisof proteins – including highly modified derivatives
and covalent protein–protein conjugates – asroutine and convenient as bacterial protein
expression is the long term goal of our research
program.

Crudden-Nambo Group
Cathleen M. Crudden
Position

Research interests
Favorite molecule
WebsitePrincipal Investigator; Professor, Queen's University
Asymmetric synthesis, organometallic catalysis, nano materials
BINAP (chiral ligand)http://www.cruddengroup.com/

Research overview: Research in the Cruddengroup focuses on catalysis and materials
Masakazu Nambo(Co-Principal Investigator) chemistry. We are interested in developing
new reactions to prepare interesting organic
molecules, in particular reactions that areenantioselective or enantiospecific. With ourcollaborators at ITbM, we aim to investigate
the biological activity of these molecules forapplications in the pharmaceutical and agriculturalindustries. We are also interested in the use ofcarbon–based molecules as ligands for metal
surfaces and nanomaterials comprised of gold
and other metals. With our collaborators at ITbM
and other institutions across the world, we aim toinvestigate the applications of these materials invarious fields, including catalysis and biologicalimaging.

Itami Group

Kenichiro Itami

Faculty members:
Hideto Ito
Akiko Yagi
Kazuma Amaike
Hayato Yamada
Atsushi Usami
Ayaka Ueda
Affiliated researchers:

Shinya Hagihara
Kei Murakami
Takehisa Maekawa

Position
Research interests
Favorite molecule
WebsitePrincipal Investigator; Professor
Synthetic chemistry, catalytic chemistry, materials chemistry
Benzenehttp://synth.chem.nagoya-u.ac.jp/

Research overview: The ultimate goal of the Itami
group is to develop “transformative molecules”,
innovative functional molecules that make a marked
change in the form and nature of science andtechnology. With such a goal in mind, the work of
the Itami group has centered on catalyst-enabling
synthetic chemistry with broad directions. The
emphasis is on the development of new catalysts

8

for solving challenging synthetic problems, forrealizing super-efficient chemical syntheses, for highdemand molecule activations, and for producing
as-yet unexplored molecules of significant interest in
various fields.

Designing and making molecules
Ooi Group

Takashi Ooi
Position

Faculty members:
Kohsuke Ohmatsu
Yoshitaka Aramaki
Tsubasa Nakashima

Research interests
WebsitePrincipal Investigator; Professor
Organic synthesis and catalysis
http://www.chembio.nagoya-u.ac.jp/labhp/organic3/

Research overview: We have been creating abold stream of research on the molecular designof various organic ion pairs and their rational
structural modifications for eliciting uniquefunctions as molecular catalysts, providing asolid basis for the safe and sustainable supplyof useful organic compounds. At ITbM, wedevelop innovative molecular catalysts that canrevolutionize organic reactions and chemical
syntheses in order to not only provide sustainablechemical processes, but also accelerate thediscovery of transformative bio-molecules
as a reliable means for solving problems offundamental biological significance.

Yamaguchi Group
Shigehiro Yamaguchi

Faculty members:
Masayasu Taki
Masahito Murai
Soichiro Ogi
Tatsuya Mori
Affiliated researcher:

Aiko Fukazawa

Position
Research interests
WebsiteVice-Director of ITbM; Principal Investigator; Professor
Physical organic chemistry, fluorescent molecules
http://orgreact.chem.nagoya-u.ac.jp/

Research overview: We work on a variety of
topics in the fields of main group chemistry
and physical organic chemistry. In particular,
the emphasis is placed on the construction of
new π-conjugated scaffolds, which is crucial
for pursuing the photo/electronic functions oforganic molecules. At ITbM, we are pursuing
the challenge of designing and synthesizing

9transformative fluorescent π-conjugatedmolecules for bioimaging applications. A numberof fascinating fluorescent molecules have beendeveloped so far, not only for optoelectronic
applications like OLEDs (organic light-emitting
diodes), but also for biological applications suchas fluorescent probes.

Research groups: Biology
Frommer-Nakamura Group
Wolf B. Frommer
Position
Research interests
Favorite molecule
WebsiteMasayoshi Nakamura(Co-Principal Investigator)

Faculty members:
Satomi Kanno
Akira Yoshinari

Principal Investigator; Professor, Heinrich Heine Universität Düsseldorf,
Max Planck Institute for Breeding Research, Köln
Molecular biology, biochemistry, chemical genomics
isorhamnetin-3-O-β-D-glucopyranosidehttps://www.itbm.nagoya-u.ac.jp/frommer-nakamura/Research overview: The research in the
Frommer group at ITbM is carried out inthe following four areas: (i) engineering ofgenetically encoded biosensors and sponges
for in vivo biochemistry; (ii) characterization of
the determinants of interactions between small

molecules and transporters to help identifying
novel drugs and agrochemicals; (iii) search for yet
unidentified receptors for small molecules; and(iv) chemical genomics and imaging of processes
related to cellular growth and dynamics.

Kamikouchi Group
Azusa Kamikouchi
Position

Faculty member:
Matthew Paul Su

Research interests
WebsitePrincipal Investigator; Professor, Graduate School of Science
Neuroscience, Insect Physiology, Neuroethology, Acoustic communication
https://www.bio.nagoya-u.ac.jp/~NC_home/index3.htm

Research overview: Kamikouchi conducts
pioneering research using fruit flies as a model
for studying hearing. Utilizing neuroanatomical,
neuroimaging, and behavioral analyses, she
has led ground-breaking investigations into thefunctional properties of the fruit-fly auditory system,
uncovering a number of similarities to equivalentmammalian systems. At the ITbM, she will extend
these findings to mosquito hearing research.

Mosquitoes carry infectious diseases that killhundreds of thousands of people each year. Hearing
plays an essential role during the mating behaviorof these mosquitoes, and thus provides a promisingtarget for controlling their behaviors. At ITbM, shewill be involved in developing molecules that caneffectively disrupt hearing function by elucidating thefundamental molecular bases underlying mosquito
hearing.

Kay-Hirota Group
Steve Kay
Position

Research interests
WebsiteCollaborating Researcher; Professor, University of Southern California
Chronobiology, chemical biology
https://www.itbm.nagoya-u.ac.jp/en/kay-hirota_group/

Research overview: By using the resourcesof clock modifying compounds and genes inTsuyoshi Hirota
combination with state-of-the-art technologies(Co-Principal Investigator)
at ITbM, the Kay-Hirota group aims to discover
Faculty member:“transformative bio-molecules” that will revolutionize
Megumi Hatori
clock research and ultimately benefit humanhealth. A unique combination of molecular, genetic,
genomic, biochemical, and chemical biology

10

approaches will allow us to reveal key regulatory
processes of the circadian clock and define
molecular links between the clock and rhythmic
regulation of physiology and behavior. Proof-ofconcept chemical probes will provide valuable tools
to control clock function in a conditional mannerand also act as starting points for developing
therapeutics for circadian clock-related disorders.

Elucidating the function of molecules
Kinoshita Group
Toshinori Kinoshita
Position

Faculty members:
Yohei Takahashi
Yusuke Aihara
Koji Takahashi
Affiliated researcher:

Norihito Nakamichi

Research interests
WebsitePrincipal Investigator; Professor
Plant molecular biology
http://plantphys.bio.nagoya-u.ac.jp/en/

Research overview: Our research focuses onunderstanding the mechanism of how plants adapt
and respond to ever-changing environmental
signal. Stomata is the key in this process - since
the pair of guard cells surrounding stomatal pores
regulate CO2 uptake for photosynthesis and water

loss from leaves in response to environmental
signals. We have been studying signaling pathways
responsible for stomatal opening and closing, andhave identified the key components that regulate
this behavior. To elucidate the full signaling pathwayof stomatal opening and closing, we are using
genetic, biochemical and physiological approaches
to uncover the full mechanism. Our discovery willallow generation of plants with high productivity anddrought tolerance, simply through the regulation of
stomatal openings.

Laohavisit Group
Anuphon Laohavisit
Position

Research interests
WebsitePrincipal Investigator; Designated Associate Professor
Plant Signaling, Plant Physiology
https://www.itbm.nagoya-u.ac.jp/en/members/group/a-laohavisit.php

Research overview: Plant signaling is central toplant physiology, from plant development to stressresponses. Due to their sessile lifestyle, plants needto sense and respond appropriately to various
stimuli in different environmental conditions. By
using a multi-disciplinary approach, our group aims
to 1) identify novel, endogenous and exogenous,
signaling molecules 2) unravel their perception
and their signaling mechanisms, and 3) determine

their biological roles in plants. Such knowledge
will enable us to exploit and manipulate beneficial
signaling pathways through biology-based andchemistry-based rational designs in collaboration
with other research groups. A better understandingof how plants sense and respond to different stimuli
will facilitate the way to grow plants in today’s
fluctuating environment.

Mizuta Group
Yoko Mizuta
Position

Faculty member:
Hidenori Takeuchi

Research interests
Favorite molecule
WebsitePrincipal Investigator; Designated Assistant Professor (YLC)
Plant reproduction, Imaging, Pollen, Gene modification
Fluorescent proteins
https://www.itbm.nagoya-u.ac.jp/en/members/group/y-mizuta.php

Research overview: Even a small flower bloomingon the side of the road has a magnificent dramaof life hidden in it. We are trying to understandmolecular mechanism of plant reproduction by using
a microscopic imaging and genetic engineering
technologies. Especially focusing on pollen, thegenes and the mechanism of pollen tube attraction

11

have been studied. We also developed methods fordeep imaging inside a flower, genetic modification,and regulation of germ cells. By understanding how
seeds are produced, my research aims to enrich
our lives by increasing food production and plant
breeding.

Torii-Shimotohno Group
Keiko Torii
Position
Research interests
Favorite molecule
WebsiteAkie Shimotohno(Co-Principal Investigator)
Affiliated researcher:

Naoyuki Uchida

Collaborating Researcher; Professor, The University of Texas at Austin;
Investigator, Howard Hughes Medical InstitutePlant development, cell-cell communication, peptides
LRR-RLK (plant kinase receptor), caffeine
https://www.plant-stomata.org/

Research overview: In the Torii-Shimotohno
group, we strive to probe signaling dynamics
and manipulate plant development via integrated
approaches of synthetic cell biology, chemical
biology, physiology and molecular genetics.
Fully leveraged on ITbM’s core strengths andambitious mission to fuse catalysis chemistry andplant & animal biology, we aim to: (i) design small

molecules to highjack inter- and intra-cellularsignaling networks; and develop fluorescentprobes to visualize signaling dynamics (synthetic
cell biology); (ii) design and screen for small
molecules to manipulate plant growth (chemical
biology); and (iii) elucidate the functions of ligandreceptor pairs in plant development upon variable
environmental stimuli (developmental genetics).

Tsuchiya Group
Yuichiro Tsuchiya
Position

Faculty member:Research interests
WebsitePrincipal Investigator; Designated Professor
Chemical biology in plants
https://www.itbm.nagoya-u.ac.jp/Tsuchiya_G_HP/main.html

Akira Morikawa

Research overview: The goal of our research is tosave African farmers from a parasitic plant Striga
hermonthica that has been causing a huge problem
to crop production in Africa. The damage causedby the single species is devastating, as 10 billion
USD worth of crops have been lost every year fromthe African continent and 300 million people's lives
have been affected. We have been studying themechanism on how Striga identifies the presenceof host plants and am utilizing the information
to develop small molecules to destroy the hostparasite communication. Using chemical genetics,
I am trying to elucidate the signaling mechanism ofstrigolactones (SLs), which are released from thehost root and stimulate Striga seed germination.

Yoshimura Group
Takashi Yoshimura
Position

Research interests

Faculty members: Favorite molecule
Taeko Ohkawa
Naohiro Kon
Tomoya Nakayama
Junfeng Chen

WebsiteDirector of ITbM; Principal Investigator; Professor
Animal integrative physiology, chronobiology, systems biology
DHEA (anti-aging supplement)
https://www.agr.nagoya-u.ac.jp/~aphysiol/en_index/

Research overview: Cyclic environmental changes
such as day-night and seasonal cycles control
all organisms on earth. To better adapt to these
cyclic events, organisms have developed internal
biological clocks during the evolutionary process. To
understand animals’ clever adaptation strategies to12environmental changes, we apply interdisciplinary
approaches to various animals that have highlysophisticated mechanisms. Our findings are
currently fueling development of transformative biomolecules that will improve animal production andhuman health.

Research groups: Theory
Calculating and analyzing molecules
Phung Group

Quan Manh Phung
Position
Research interests
Favorite molecule
WebsitePrincipal Investigator; Associate Professor
metalloenzyme, biomimetic chemistry, computational quantum chemistry
Ferrocene
https://www.itbm.nagoya-u.ac.jp/en/members/group/q-phung.php

Research overview: Our research focuseson understanding the electronic structure andreaction mechanism of metalloenzymes, which
are capable of selectively catalyzing a large
number of chemical reactions under physiologicalconditions, as well as countless biomimetic
systems with high catalytic activities. To this end,

we employ a wide variety of techniques, ranging
from low-cost density functional theory to novel,
highly accurate ab initio methods. Our goal is not
only to find general patterns in transition metalchemistry but also to make predictions and guide
new experiments for new chemical systems withhigh catalytic activity and selectivity.

Tama Group
Florence Tama
Position

Research interests
WebsitePrincipal Investigator; Professor
computational biophysics
https://sites.google.com/view/computationalbiophysicslab/

Research overview: Research in the Tamagroup focuses on the computational studies ofstructures and functions of large macromolecularassemblies. Dysfunctions of these bio-molecules
may result in severe diseases, and in orderto understand such diseases and develop
treatments, the functional mechanisms of thesebio-molecules need to be elucidated. To this goal,
Tama’s group 1) develops new computational
techniques to determine 3D structures anddynamics of biological complexes; and 2) works
in collaboration with experimental groups toelucidate functions of bio-molecules of interest.

Yanai Group
Takeshi Yanai
Position

Faculty members:
Kazuhiro Fujimoto
Masaaki Saitow

Research interests
Favorite molecule
WebsitePrincipal Investigator; Professor
Computational quantum chemistry
Nitrogen molecule and chromium dimer
https://www.itbm.nagoya-u.ac.jp/en/members/t-yanai/

Research overview: The heart of chemistrylies in the transformation of molecules. In the
Yanai group, we investigate transformationsof molecular systems through theoretical andquantum chemistry computational methods. The

13prime goal of our research is to elucidate theprinciples and mechanisms guiding chemicaltransformations, while recognizing the importanceof the role of electrons in these systems.

Centers
Accelerating ITbM's interdisciplinary researchLive Imaging Center

Chemical Library Center

Yoshikatsu Sato

Ayato Sato

Designated Associate Professor

Designated Associate Professor

The Live-imaging Center provides access ofProviding opportunities for researchers in different
disciplines and creating novel bioactive molecules toward
future transformative biomolecules.

advanced optical microscopes to everyone–from ITbM
members to researchers worldwide. We have many

cutting-edge optical microscopes for high-sensitivity

The ITbM chemical libraries consisting of 85,000
compounds have been created by selecting natural
products, pharmaceuticals, agrochemicals, and newly
synthesized compounds. In addition, the center
equips with an automated liquid handling workstation,clean bench, incubators, high performance liquid
chromatography-mass spectrometer (LCMS), and devices
necessary for synthetic chemistry, which are relevant to
conduct chemical biology research. To date, the centerhas provided more than 2.5 million compounds to over 250
collaborators, and are used by researchers in academia
and industry in Japan as well as around the world. The
center has and will play as a hub where synthetic chemists
bring the molecules and the biologists use them for theirassays, to create transformative biomolecules.

imaging, high-speed imaging, wide-field imaging, deep

imaging, and fluorescence lifetime imaging. Up to now,
researchers from 46 universities and research institutes

have used our centers and published 99 original research
papers. In addition to the supporting activities, wehave developed transformative bioimaging moleculesby collaborating with ITbM chemists, such as PREX 710,
Mito PB Yellow, and Kakshine. In order to create further

applications of these ITbM molecules, we are developing
original research on the mechanisms of plant development
and environmental response through Grant-in-Aid for
Scientific Research (KAKENHI), Moonshot Target 3(Cabinet Office), and CREST (JST) projects.

Molecular Structure Center

Peptide Protein CenterEmi Mishiro

Shunsuke Oishi

Designated Lecturer

Designated Assistant Professor

The Molecular Structure Center is equipped with
cutting-edge mass spectrometers and data analysis
software for the structural determination of organicand biological molecules synthesized by members of
ITbM. To facilitate analysis by ITbM members and otherresearchers, we will discuss the best analysis method foryour purposes.(1) High performance liquid chromatography
mass spectrometer equipped with a nanospray unit
for proteomics analysis (nanoLC-MS/MS); (2) Highperformance liquid chromatography-mass spectrometerequipped with a Fourier transformation spectrometerfor high accuracy synthesized molecules analysis (LCMS); (3) High performance gas chromatography-mass
spectrometer for metabolomics analysis (GC-MS); (4)Hydrogen/deuterium exchange mass spectrometer forprotein interaction analysis (HDX-MS); (5) Proteome
Discoverer software, etc.

The Peptide Protein Center provides tailor-madepeptides and proteins to the research groups at ITbM.
Using ligation chemistry developed by the Bode group,
we can prepare not only simple linear peptides, but also
cyclic peptides and synthetic proteins. Synthetic peptides
and proteins can be tailored to suit different needs
by incorporating chemical functionalization. We havesuccessfully incorporated novel fluorescent molecules
developed by the Yamaguchi group and unnatural aminoacids synthesized by the Ooi group into synthetic peptides
and proteins. We envision that these unique compounds willbe transformative for research at ITbM.

State-of-the-art equipment and technologies are available
in all centers. External access to the four centers can bearranged upon request.

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ITbM administration
Promoting ITbM's interdisciplinary research
The ITbM Administrative Department plays a crucial rolein supporting ITbM. Three divisions have been established:
Management Division, Research Promotion Division (RPD)
and Strategic Planning Division (SPD).

seminars, workshops and meetings, along with internal/
external communities. In order to promote the social
implementation of the technologies developed at ITbM, theSPD was established as a spin-out from the RPD in May
2016. SPD plays a role in contributing to society by feeding
research outcomes into society. SPD supports evaluationof inventions, patent applications, collaborative researcheswith domestic and overseas companies, license agreements,
strategic construction of partnerships with companies aiming
for industrialization/commercialization, running the ITbM/
GTR Consortium and establishment of venture business,
etc. Both RPD and SPD consisting of members who holdadvanced degrees in science/engineering, support andpromote ITbM research activities from basic to social stage
consistently and seamlessly, cooperating with each otherand using the expertise, resources and skills, to receive
international recognition as a research center that conducts
interdisciplinary research between chemistry and biology.

The Management Division consists of the General
Affairs Unit and the Accounting Unit, both of which performfunctions similar to those of a university administration. The
General Affairs Unit is responsible for the development of
ITbM's policies, the organization of PI meetings, personnel
management and labor relations, as well as welfares. The
Accounting Unit is in charge of matters related to research
grants, as well as the handling of financial budgets that
include personnel expenses, honoraria, travel expenses, andsupplies.
The RPD is to create a bridge between researchers anduniversity administration, and is involved in a wide rangeof activities (press release, science visualization, and soon) in ITbM. This includes support in the discovery of new
seeds for collaborative research and obtaining research
grants, support for overseas researchers' everyday life
in Japan, and overall promotion of the institute throughthe organization of various events, such as symposia,

The ITbM Administrative Department provides both
English and Japanese support to all ITbM members, bothoverseas and Japanese researchers. ITbM aims to create aninternational atmosphere, where researchers are comfortable
and able to fully focus on their research.

Spreading to
the society
Globalization

Discussion

Application

Publication

PublicrelationsIntellectual
properties

Accounting Unit:- research grants- handling of the finacial budget etc.
General Affairs Unit:- making ITbM guidelines- organizing PI meetings- personnel management- labor relation- welfares etc.

Research
Promotion
Division(RPD)

Education

Socialacceptanceindustrialization

Strategic
Planning
Division(SPD)
Management
Division

Collaborative
researches

Society
Seamless
SupportLaboratory

15

Research environment
Promoting "mixing" of different fields
ITbM has set up Mix Labs to remove the physical barriers
between research groups and to enhance interdisciplinary
research across various fields and groups. Unlike traditionallabs, where the labs are usually separated according toresearch groups, the Mix Labs incorporate large spaces,
where researchers and students from different backgrounds
share the same space and can have discussions on a daily
basis. Each PI is in charge of their own research group.
Nevertheless, the flexible interaction that exists between
different research groups enables dynamic mixing ofresearch that goes beyond the boundaries of conventionalframeworks. Using “molecules” as the common keyword has
advanced the understanding between different disciplines.

The ITbM Research Award was established to promoteinterdisciplinary research proposed by young researchers
working in the Mix Lab. The award provides start-up
funding and is granted to outstanding collaborative research
projects that are proposed by a team of researchers fromdifferent fields, which consist of at least one ITbM researcher(non-PIs). Many of the selected proposals have become
representative projects at ITbM.
ITbM’s new research building that reflects the Mix Lab
concept was completed in March 2015. The building’s
whole area space is 7,934 m2 and is a 6-storied buildingthat consists of two sets of Mix Labs and Mix Offices. Thelabs and offices make up a 2-layer structure, where the Mix
Offices are an open space over the windows that has a goodview of the Mix Labs situated below.

The Mix Labs have played an immense role in advancing
collaborative interdisciplinary research at ITbM, as thefaculty, postdoctoral researchers and students are able tocommunicate across different fields and put their research
proposals immediately into action. A large number ofinterdisciplinary research themes have emerged from young
researchers in the Mix Labs, and some of the researchoutcomes have already been released as patents andpublications, as well as commercialization of reagentsthrough technology transfer to industries.

The center is also equipped with a kids’ room to assist
researchers with children, as well as refresh spaces, anda wooden deck in order to enable interactions between
members. ITbM Tea break Meetings are held weekly tofacilitate communication between members of the institute.

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Towards globalization
International symposia and awards
Tsuneko & Reiji Okazaki Award

ITbM is organizing a number of international symposia andawards each year. Through these international events, ITbM
is establishing a strong network with leading researchers
in the fields of synthetic chemistry, animal/plant biology
and theoretical sciences. These activities are part of ITbM’s
globalization strategy, which aims to enhance globalization.

The Tsuneko & Reiji Okazaki Award was established in2015 by ITbM in memory of the great achievements of Dr.
Tsuneko Okazaki, Special Professor of Nagoya University
and the late Dr. Reiji Okazaki, Honorary Professor of Nagoya
University. Drs. Okazaki are known for their discovery of the
Okazaki Fragments, which are short DNA fragments thatare formed during DNA replication, and have contributed toadvancing the field of molecular biology. Their efforts havealso inspired subsequent generations of researchers. The
Okazaki Award is an international award that is presented
each year to a young leading scientist, who has madesignificant contributions in the field of life sciences throughunique approaches and techniques.

International Symposium on Transformative BioMolecules (ISTbM)
ITbM organizes its international symposium each year in
Nagoya by inviting world-leading researchers who carry out
research in ITbM’s related fields. ISTbM contributes to theestablishment of ITbM’s international network and promotesinternational research collaborations.

Nagoya Medal of Organic Chemistry

Hirata Award

The Nagoya Medal of Organic Chemistry is an international
award that was established in 1995 by Dr. Ryoji Noyori,
Special Professor of Nagoya University, and Dr. Hisashi
Yamamoto, Honorary Professor of Nagoya University, under
the support of the MSD Life Science Foundation (previously
known as the Banyu Life Science Foundation International).
Every year, the Nagoya Gold Medal is awarded to an organic
chemist who has made significant original contributions
to the field in its broadest sense, and the Silver Medal ispresented to a promising scientist based in Japan, whose
research has had a major impact on the field of syntheticorganic chemistry. From 2023, Dr. Takashi Ooi, a principal
investigator at ITbM, takes on the role of the Chair of the
Nagoya Medal.

The Hirata Memorial Lecture started in 2005 at Nagoya
University and is an international award granted eachyear to a rising star in the field of organic chemistry. Thisaward was established in memory of the outstandingachievements of the late Dr. Yoshimasa Hirata, an Honorary
Professor of Nagoya University. Dr. Hirata is known for the
discovery of many natural products, including tetrodotoxin, aneurotoxin found in puffer fish, and greatly contributed to theadvancement of natural product chemistry. Throughout theyears, the Hirata Memorial Lecture has been given by many
distinguished young chemists and has grown to become
an internationally recognized honor in organic chemistry.
From 2015, the Lecture has changed its name to the "Hirata
Award" and is organized by ITbM.

17

Institute of Transformative
Bio-Molecules (ITbM),
Nagoya University
Nagoya, Japan

Heinrich Heine University Düsseldorf (HHUD)
Düsseldorf, Germany
Max Planck InstituteKöln, Germany

Queen’s University
Kingston, Canada

RIKEN Center for Sustainable
Resource Science (CSRS)
Wako, JapanETH Zürich
Zürich, Switzerland
University of Southern California
Los Angeles, USA
The University of Texas at Austin
Austin, USA
Academia Sinica
Nankang, Taiwan

National Science Foundation
Center for Selective
C–H Functionalization(NSF-CCHF)
15 institutions across USA

Partnerships and global networks
ITbM has collaborations with institutions worldwide. In
addition to the universities/institutes where the overseas PIs
hold posts (ETH Zürich, Queen’s University, The University ofTexas at Austin, University of Southern California, Heinrich
Heine University Düsseldorf, and Max Planck Institute), ITbM

Nurturing young researchers is a key mission of ITbM
and critical for our future development. ITbM financially
supports Ph.D. students going abroad and has sent 39 Ph.D.
students on overseas exchanges (as of March 2021). A
notable number of postdoctoral researchers have carried out

is collaborating closely with the National Science Foundation
Center for Selective C–H Functionalization (NSF-CCHF,
Center Director: Dr. Huw Davies, Emory University), the
RIKEN Center for Sustainable Resource Science (CSRS) andInstitute of Chemistry, Academia Sinica. Joint workshops areheld with these collaborating institutes. In addition, student
and faculty exchanges are ongoing between ITbM and CCHF.

research at ITbM, and are currently in outstanding academic
and industrial positions in Japan and overseas. The ITbM
spirit is everywhere and ITbM has been recognized as a key
hub in the global talent pool.

Academia Sinica
Nankang, Taiwan
18

ITbM's female scientists
ITbM has also been proactive in appointing and promoting
female researchers. Including three female PIs, there are 22
female researchers at ITbM, representing 32% of the total
number of researchers as of March, 2023.

Nature Plants (2019).
Many of ITbM's female scientists have been appointed
to academic positions and students have won prestigious
awards for their research, such as the L'Oreal-UNESCO
Award for Women in Science. ITbM students have won thisaward two years in a row.

Female scientists at ITbM have been recognized nationallyand globally for their high-quality science, published in highimpact journals such as Nature Chem (2014), Nature (2015),

19

ITbM outreach
ITbM has strategically established a wide range ofmore than 5,000 high school students in two years (FY2017
and 2018), and ITbM organized many outreach events forthe general public (more than 50 outreach events everyyear). These events are not only effective in fostering futurescientists (high school students), but also in encouraging theyounger generation, such as elementary school students,
including their parents, to develop curiosity about molecules.

networks, not only with top scientists, but also withjournalists, artists, high school teachers/students, and thegeneral public. Based on this network, ITbM has actively
organized various outreach activities, including scientificsymposia/seminars, exhibitions, public lectures, scienceeducation, etc. ITbM’s research activities were presented to20

Graduate Program of Transformative Chem-Bio Research
The best way to acquire real research power is to accumulate experience with promoting andaccomplishing exciting high-quality research on your own initiative
Our new graduate program, GTR (Graduate Program ofTransformative Chem-Bio Research), aims to train scholars
who will pioneer interdisciplinary frontiers in the areas ofchemistry and life science. In order to achieve sustainable
development of society, many challenges must be overcome,including environmental and energy problems, stable foodproduction, the development of materials leading to industrial
and technological innovations, and life science researchthat contributes to health. To address these issues faced byscience and society, the roles of chemistry and life science
research are becoming increasingly important. To breakthrough these issues, both advances in research in each fieldand promotion of interdisciplinary research are necessary.

The GTR program provides a practical course foracquiring these important research capabilities throughchallenge to exciting interdisciplinary research in diverse
research environments in which each student benefits fromthe guidance of two mentors.

Power to connect

Research power
to break throughTo bridge the gaps between traditional disciplines, weneed outstanding "research power to break through," which
consists of two elements: "the power to overcome" and"the power to connect." The former is based on experience,
confidence, and solid practical knowledge and skills that canbe fostered through promoting and accomplishing highquality research on important topics. On the other hand, thelatter leads to the creation of innovative ideas through freeand vigorous discussions across research fields.

Power toovercome

Sub field + Major field

Nagoya University:

Institute of Transformative Bio-Molecules (ITbM); Graduate Schoolof Science; Graduate School of Engineering; Graduate School of
Bioagricultural Sciences; Graduate School of Pharmaceutical Sciences

Cooperative Institutions:

RIKEN, Institute for Molecular Science, National Institute for Basic
Biology (Graduate University for Advances Studies); Kaneka Corp.;
Konica Minolta Inc.; Japan Tobacco Inc., Plant Innovation Center; ITbM
consortium (16 companies, 2019)http://gtr.itbm.nagoya-u.ac.jp/en/index.html

21

Research
Transformative Bio-Molecules

Carbon Nanobelt

23

SCL: Stomata Closing Compound24

SPL7: Sphynolactone-7

25

YLG: Yoshimulactone Green

26

PREX 710: Photo-Resistant Xanthene dye

27

MitoPB Yellow

28

DHEA: an endogenous steroid hormone

29

GO289: a new period-lengthening compound30

AMI-331: a casein kinase 1 inhibitor

31

AMOR: an ovular methyl-glucuronosyl arabinogalactan

32

ClearSee®: a rapid optical clearing reagent for whole-plant fluorescence imaging

33

PRK6: Tip-localized pollen-specific receptor-like kinase 634

Research Highlights

35

22

Bottom-up synthesis of carbon nanobelts for the
first time in the world

Molecules that will revolutionize the futurenanocarbon science

Carbon nanobelts are “short” carbon nanotubes
with a uniform structure. Because of its breathtaking
beautiful structure and potential as a future molecule,the synthesis of a carbon nanobelt, comprising a closedloop of fully fused edge-sharing flat benzene rings, hasbeen an elusive goal in organic chemistry for more than
60 years, before the discovery and synthesis of carbon
nanotubes.

Carbon nanobelts are a new form of carbon thatno one has ever seen before. As the history of thesoccer-ball-shaped fullerene (Nobel Prize in Chemistry,
1996) proves, a beautiful and new shaped molecule
led to unpredictable functions, applications, and/or
development at the time of discovery. Carbon nanobelt
is expected to expand its areas of activity by leaving its
home, ITbM. We believe “Functions follow Forms.”

The research group succeeded in the bottom-up
synthesis of carbon nanobelts for the first time in theworld from para-xylene (one of the components ofpetroleum) as a starting material through a synthetic
method they developed by themselves. Through various
analyses of carbon nanobelt (x-ray crystallography, UV
absorption, Raman spectroscopy, etc.), this molecule
could potentially serve as a seed for the preparation of
structurally well-defined carbon nanotubes. In addition,
carbon nanobelt was commercialized in 2018, andresearchers around the world are conducting appliedresearch by using this molecule.

Reference:“Synthesis of a Carbon Nanobelt” by Guillaume Povie,
Yasutomo Segawa, Taishi Nishihara, Yuhei Miyauchi,
Kenichiro Itami, Science 2017, 356, 172. DOI: 10.1126/
science.aam8158.

Itami Group23

SCL; molecules that prevent stomata from
opening

Closing pores to suppress wilting
By spraying these compounds on the leaves of roses
and oats, they revealed that the wilting of the leaves
under the dry condition was suppressed. This resultis expected to be used as molecules that keep the
freshness of cut flowers and flower arrangement, reducetransportation costs, and give drought tolerance against
practical plants.

Stomata are pores in the epidermis of plants which
open in response to sunlight, and the intake of carbon
dioxide and the release of oxygen and water are
regulated by stomata. For the pores to open, the plasma
membrane proton pump (H+-ATPase), which acts as anengine to open the pores, needs to be driven by light.
The ITbM research groups found compounds "SCL
(Stomatal Closing Compounds)" that inhibit stomatal
opening. These compounds exhibit stomatal closing
acidity through the inhibition of H+-ATPase and act in adifferent pathway from the phytohormone abscisic acid,
which closes the stomata.

Reference:“Identification and Characterization of Compounds that
Affect Stomatal Movements” by Shigeo Toh, Shinpei
Inoue, Yosuke Toda, Takahiro Yuki, Kyota Suzuki, Shin
Hamamoto, Kohei Fukatsu, Saya Aoki, Mami Uchida,
Eri Asai, Nobuyuki Uozumi, Ayato Sato and Toshinori
Kinoshita, Plant Cell Physiol. 2018, 59, 1568. DOI:
10.1093/pcp/pcy061.

Control

SCL

Kinoshita Group, Chemical Library Center

24

Innovative molecule, "Sphynolactone-7 (SPL7)"
toward solving food problems in Africa

such as bacteria in crops and soil, and can promote thegermination of Striga at extremely low concentration(1/1013-15mol/L). This activity is comparable to that of thenaturally occurring germination stimulator (strigolactone)
produced by the host plant, resulting in the artificial
strigolactone molecule with the highest activity so far.
Based on this result, we will conduct field tests of SPL7
against Striga that has caused heavy damage to thecrop production in Kenya and will verify them towardpractical use.

Striga is a plant which parasites on crops, causing thehost plants (grain) to die out. The parasitic plant "Striga,"
also known as "Witchweed," has had a significant
impact on crop production and its spread has becomea major threat in Africa. The ITbM research groupfocused on the germinating characteristics of Striga andsucceeded in developing an innovative molecule "SPL7"
for eradicating it. SPL7 is a molecule that strongly
induces germination of Striga so that, by using SPL7,
Striga is forcibly sprouted and died out before planting
the seeds of the host plant. By this method, we will
reduce the opportunity of invasion of host plants such as
grains and eventually eradicate it.

Reference:“A femto-molar range suicide germination stimulant
for the parasitic plant Striga hermonthica” by Daisuke
Uraguchi, Keiko Kuwata, Yuh Hijikata, Rie Yamaguchi,
Hanae Imaizumi, Sathiyanarayanan AM, Christin Rakers,
Narumi Mori, Kohki Akiyama, Stephan Irle, Peter
McCourt, Toshinori Kinoshita, Takashi Ooi, Yuichiro
Tsuchiya, Science 2018, 362, 6420. DOI: 10.1126/
science.aau5445.

Verification of SPL7 toward practical use in Kenya
SPL7 has little effect on the biological environment

SL-like molecules work as inducers of suicidal germination to purge the soil of
viable Striga seeds before planting the crop seed.
Kinoshita Group, Ooi Group, Irle Group, Molecular Structure Center

25

The successful discovery of a method forobserving the germination process of Striga

it bonded with the Striga seed’s receptor. This idea
focused on two properties: firstly, that the shape ofexisting fluorescent molecules resembled the shape ofgermination-stimulating molecules produced by hostplants, and secondly that the breaking down of thegermination-stimulating molecules would occur in aparticular place significant to the understanding of thegermination process. As a result of the development of
Yoshimulactone, as well as finding out when and where
the receptor is activated at the point of germination,
through using synthetic germination-stimulating
molecules and Yoshimulactone competitively it has
become possible to identify germination-stimulating
molecules, representing an immediate step forward inthis field of research.

The parasitic plant Striga has dealt a heavy blow to
the production of cereals in Africa. In order to eradicate
it, it is necessary to clearly understand the process bywhich it infects its host plant. Although it was alreadyunderstood that Striga responded to a molecule
released from the roots of the host plant, the mechanism
by which it did so was unclear. In order to understandthis germination mechanism, the ITbM research groupdeveloped a molecule known as Yoshimulactone thatwould produce a green fluorescence when exposed toa particular protein present in Striga. Through the use ofthis molecule, they were not only able to see in detail theprocess of Striga germination, but also find the protein(the receptor) that induced the germination.

Reference:"Probing strigolactone receptors in Striga hermonthicawith fluorescence" by Yuichiro Tsuchiya, Masahiko
Yoshimura, Yoshikatsu Sato, Keiko Kuwata, Shigeo Toh,
Duncan Holbrook-Smith, Hua Zhang, Peter McCourt,
Kenichiro Itami, Toshinori Kinoshita and Shinya Hagihara,
Science 2015, 349, 6520. DOI: 10.1126/science.
aab3831.

The story behind Yoshimulactone
In a now-legendary meeting, Mr. Masahiko
Yoshimura, at the time a graduate student, was eating
ramen with researchers when he was struck by an idea:
a molecule that would fluoresce at the exact point that

Itami Group, Kinoshita Group, Live Imaging Center, Molecular Structure Center

26

The super fluorescent dye that life scientists havebeen waiting for.

A wide range of practical applications, fromtracing a single molecule to deep tissue imaging

A variety of molecules have their own individual roles
in sustaining life. Fluorescence imaging is a powerfultool for understanding the dynamics of biologicalprocesses, including their functions, movements, andstructural changes. However, with existing imaging
technology which only makes use of visible light andultraviolet spectra, damage to cells due to exposure tolight and noise in images caused by autofluorescence(fluorescence produced by existing matter within theorganism’s structure) have been consistent problems.
In addition, since visible light can only reach a very
limited depth, it is not suitable for the observation ofblood vessels or internal organs. This problem can beovercome by making use of the near-infrared spectrum
instead. However, with the limited chemical andphotostability of currently available near-infrared dyes,
it has not yet been possible to make these observations
for anything other than a very short period of time.

The single molecule imaging method is a techniquethat involves marking the biomolecule that is to beobserved, for example a protein, with a fluorescent dye
and following it at the molecular level. The strong laser
beam required for this causes existing fluorescent dyes
to lose their color in a matter of seconds, but PREX 710
produces a detectable signal for over two minutes. In
addition, since near-infrared light can easily penetrateliving tissue, it is possible to observe deep biologicaltissue, such as capillary blood vessels in the brains of
mice, in 3D. It is not an overstatement to say that PREX
710, with its wide range of applications from single
molecule to deep tissue imaging, is a transformational
molecule in its field.
Reference:"A Highly Photostable Near-Infrared Labeling Agent
Based on a Phospha-rhodamine for Long-Term andDeep Imaging" by Marek Grzybowski, Masayasu Taki,
Kieko Senda, Yoshikatsu Sato, Tetsuro Ariyoshi, Yasushi
Okada, Ryosuke Kawakami, Takeshi Imamura, andShigehiro Yamaguchi, Angew. Chem. Int. Ed. 2018, 57,
32. DOI: 10.1002/anie.201804731.

The ITbM research group has successfully developed
a near-infrared dye, PREX 710, with exceptionally highchemical and photostability as a new tool for life science
research. When PREX 710 is used as a marker, it ispossible to observe a living specimen in a non-invasive
fashion for longer periods of time without noise, atechnology that researchers in both the life science andmedical fields have been eagerly waiting for.

Yamaguchi Group, Live Imaging Center27

A fluorescent molecule allowing the observation of
the mitochondrial inner membrane in living cells

A mechanism for dying only the inner membrane,
and high colorfastness

Mitochondria have an inner and outer membrane,with the inner membrane being made up of folds known
as ‘cristae’, a structure which increases the efficiency ofenergy production necessary for the cell. The structuralchanges of these cristae are heavily involved in cellfunctions and responses, but it has not been possible
to observe the cristae inside a living cell using existing
techniques.

MitoPB Yellow exhibits high fluorescence inhydrophobic environments such as lipid structures.
Based on the molecule’s particular properties, when
it gathers in the mitochondria, it is able to bond withproteins present in the inner membrane, and produces
a strong observable fluorescence. Because the pigment
is able to pass through the cellular membrane, it isable to highly selectively dye the mitochondria simply
by being added to the cell. Moreover, because it isextremely colorfast, it is possible to repeatedly capture
the same area with a strong laser such as that of a STED
microscope without the color fading. Thus, with the useof super resolution imaging, it is possible to observe
the changes in the structure of the cristae as a result of
mitochondrial fusion and swelling.

The ITbM research group has successfully developed
a highly colorfast fluorescent probe (MitoPB Yellow) thatspecifically dyes the mitochondrion’s inner membrane,
and with the use of a super high resolution STED
microscope able to pick out minute structures, weresuccessfully able to capture the fine details of thecristae within a living cell. Following the discovery ofthis molecule, it is hoped that it will find practical use
in the diagnosis and treatment of diseases related tomitochondrial damage.

Reference:“A photostable fluorescent marker for the superresolution live imaging of the dynamic structure of themitochondrial cristae” by Chenguang Wang, Masayasu
Taki, Yoshikatsu Sato, Yasushi Tamura, Hideyuki
Yaginuma, Yasushi Okada, Shigehiro Yamaguchi, PNAS
2019, 201905924. DOI: 10.1073/pnas.1905924116.

Yamaguchi Group, Live Imaging Center

28

From the screening of existing drugs, thediscovery of a molecule that can change thecircadian rhythm of mice

What is drug repositioning?
Although a large amount of money is currently spenton drug development, there is by no means a highsuccess rate. Drug repositioning is a method of findingout whether existing drugs, which are known to be safeand effective, can be used as new methods to treat
other diseases. By continuing to evolve this process, it ishoped that an existing drug can be used in the future totreat circadian rhythm disorders.

We all have a biological clock inside our bodies thatmarks out a rhythm of approximately one day. Thisis known as the circadian clock, and physiological
functions such as sleep, body temperature, bloodpressure and metabolism all align with this rhythm.
Thus, if the circadian clock becomes chronically out ofalignment, the risk of illness is increased. The elucidationof this process was so keenly desired in medicine
that the discovery of the molecular mechanism of
the circadian rhythm was awarded the Nobel Prize inPhysiology or Medicine in 2017.

Reference:“Identification of circadian clock modulators fromexisting drugs” by T. Katherine Tamai, Yusuke Nakane,
Wataru Ota, Akane Kobayashi, Masateru Ishiguro,
Naoya Kadofusa, Keisuke Ikegami, Kazuhiro Yagita,
Yasufumi Shigeyoshi, Masaki Sudo, Taeko NishiwakiOhkawa, Ayato Sato, and Takashi Yoshimura, EMBO
Molecular Medicine 2018, 10, 5, e8724. DOI: 10.15252/
emmm.201708724.

The ITbM research group, using drug repositioning,
tested over 1000 drugs to find molecules that could
speed up and slow down the circadian clock in humancells. Among the molecules found to increase its speed
is the important human hormone, also known as a
rejuvenating drug, dehydroepiandrosterone (DHEA).
When DHEA was mixed with the food of mice, it was
found to reduce symptoms of desynchronosis (jet lag).

Yoshimura Group, Chemical Library Center

29

The discovery of a new molecule that prolongs thecircadian rhythm of mammals

They found that when GO289 was administered to
cultured cells of acute myeloid leukemia, a blood cancer,
it heavily suppressed their multiplication by inhibiting
CK2. Thus, GO289 is expected to find use in medical
fields where the control of diseases influenced by thecircadian rhythm is desired, such as the suppression ofcancer cells.

The circadian clock controls a large number ofphysiological responses through the course of a single
day, starting with sleeping and waking. When thisfunction is disturbed, it is known to have a variety ofeffects, including diseases such as sleep disorders andcancers.

Reference:

The ITbM research team, using human cultured cells,
discovered a new molecule, GO289, that lengthens
the circadian rhythm. They found that it strongly andaccurately inhibited a kinase called casein kinase 2(CK2) in cells, and succeeded in observing its action at amolecular level using X-ray crystallography.

“Cell-based screen identifies a new potent and highly
selective CK2 inhibitor for modulation of circadianrhythms and cancer cell growth” by Tsuyoshi Oshima,
Yoshimi Niwa, Keiko Kuwata, Ashutosh Srivastava,
Tomoko Hyoda, Yoshiki Tsuchiya, Megumi Kumagai,
Masato Tsuyuguchi, Teruya Tamaru, Akiko Sugiyama,
Natsuko Ono, Norjin Zolboot, Yoshiki Aikawa, Shunsuke
Oishi, Atsushi Nonami, Fumio Arai, Shinya Hagihara,
Junichiro Yamaguchi, Florence Tama, Yuya Kunisaki,
Kazuhiro Yagita, Masaaki Ikeda, Takayoshi Kinoshita,
Steve A. Kay, Kenichiro Itami, and Tsuyoshi Hirota,
Science Advances 2019, 5, 1, eaau9060. DOI: 10.1126/
sciadv.aau9060.

Suppressing the multiplication of cultured acute
myeloid leukemia cells
CK2 participates not only in the control of thecircadian clock, but also in the cell cycle and cell death.

Kay-Hirota Group, Itami Group, Tama Group30

From searching for the target of a circadianrhythm lengthening molecule, to the discovery of theworkings of the plant biological clock

A discovery that changes the way we think about
biological clock evolution
In previously presented theories, it was thoughtthat different kinds of organisms – bacteria, molds,
animals, and plants – had each developed individual
biological clocks with proteins of different evolutionary
origins. However, in this research, it was found that
CK1 is present in plants, as well as animals and molds.
In other words, this discovery suggests that there is acommon protein connected to the biological clock, andshould encourage a re-evaluation of current evolutionary
theories related to time molecules.

In order to react to the day and night cycle andchanging of the seasons caused by the earth’s rotation
and revolution, all living things on Earth have acquired a
genetically encoded body clock, known as a circadianclock. While this evolutionary mechanism is wellunderstood in animals, plant chromosomes multiply
to two or three times their original number, and as
this results in the existence of many duplicate genes(multiple identical genes in one specimen), this has beendifficult to explain.

Reference:

The ITbM research group succeeded in discoveringa low molecular weight compound which changed therhythm of the plant circadian clock in thale cress, aplant with a high level of gene multiplicity. They foundthat the target protein, the casein kinase 1 (CK1) family,
was linked to the clock. Furthermore, they were able toidentify the directly CK1 controlled clock-related protein,
PRR. Based on this discovery, and combining the fieldsof biology and synthetic chemistry, they succeeded indeveloping a new molecule 100 times more effective
than CK1, known as AMI-331.

“Structure–function study of a novel inhibitor of thecasein kinase 1 family in Arabidopsis thaliana” by Ami
N. Saito, Hiromi Matsuo, Keiko Kuwata, Azusa Ono,
Toshinori Kinoshita, Junichiro Yamaguchi, and Norihito
Nakamichi , Plant Direct 2019, 3, 9, e00172. DOI:
10.1002/pld3.172.
“Casein kinase 1 family regulates PRR5 and TOC1 in
the Arabidopsis circadian clock” by Takahiro N. Uehara,
Yoshiyuki Mizutani, Keiko Kuwata, Tsuyoshi Hirota,
Ayato Sato, Junya Mizoi, Saori Takao, Hiromi Matsuo,
Takamasa Suzuki, Shogo Ito, Ami N. Saito, Taeko
Nishiwaki-Ohkawa, Kazuko Yamaguchi-Shinozaki,
Takashi Yoshimura, Steve A. Kay, Kenichiro Itami,
Toshinori Kinoshita, Junichiro Yamaguchi, and Norihito
Nakamichi, PNAS 2019, 116, 23, 11528-11536. DOI:
10.1073/pnas.1903357116.

Kinoshita Group, Kay-Hirota Group, Itami Group, Yoshimura Group, Molecular Structure Center31

Activation of pollen tubes for gamete delivery to
the ovule

Steps towards a new development in plant sugar
chain research

In flowering plants, pollen collects at the tip of thepistil, extending what are known as ‘pollen tubes’ down
through the pistil towards the ovules, which containthe egg cells. In order to avoid getting lost on their long
journey down the pistil, the pollen tubes must receive
signals which guide them towards the ovules.

The researchers then synthesized the disaccharide
they had found at the terminus, and added it to aculture medium containing pollen and an ovule. The
pollen tubes in this culture changed their direction of
growth towards the ovule. When the disaccharide was
not added to the culture medium, the pollen tubes
simply grew straight, their ends moving past the ovule.
This clearly indicates that AMOR is essential to pollen
tube guidance, living up to its name and acting as amatchmaker for the male and female plant gametes.

In mammals, the system known as ‘capacitation’,in which the male gamete is activated by an agent
originating in the female system, has long been
understood. In plants, the molecular mechanism bywhich pollen tubes, which transport the immobile plant
sperm cells, are activated, has remained a mystery.

The discovery of AMOR is expected to contributenot only to the study of plant fertility rates, but also newresearch into the role of sugar chains in signaling inplants.

Using Torenia fournieri as a model plant, ITbM
researchers succeeded for the first time in identifying
the pollen tube activator. The activator is made of aplant-specific sugar chain, arabinogalactan, with thetwo-sugar unit (disaccharide) at its terminus being theactive component. They named it Activation Moleculefor Response-Capability (AMOR).

Reference:“The AMOR arabinogalactan sugar chain induces pollentube competency to respond to ovular guidance" by
Akane G. Mizukami, Rie Inatsugi, Jiao Jiao, Toshihisa
Kotake, Keiko Kuwata, Kento Ootani, Satohiro Okuda,
Subramanian Sankaranarayanan, Yoshikatsu Sato,
Daisuke Maruyama, Hiroaki Iwai, Estelle Garénaux,
Chihiro Sato, Ken Kitajima, Yoichi Tsumuraya, HitoshiMori, Junichiro Yamaguchi, Kenichiro Itami, Narie Sasaki
and Tetsuya Higashiyama, Current Biology 2016, 26, 8,
1091-1097. DOI: 10.1016/j.cub.2016.02.040.

Higashiyama Group, Itami Group, Live Imaging Center, Molecular Structure Center

32

Overcoming the obstacles to fluorescencemicroscopy in plants

A truly innovative and easy to use reagent
Previously, it was necessary to thinly slice planttissues in order to observe their internal structures athigh resolution. The individual images would then haveto be reconstructed into a 3D image in a lengthy andcomplex process.

The discovery of fluorescent proteins has allowed
for rapid progress in the analysis of the functions andstructures of organic tissues through observation of the
behavior of proteins. An important part of this process ismaking the structure to be observed transparent so thatthe target protein can be seen.

ClearSee® changes this in one fell swoop. Now,
anybody can quickly and easily render plant tissuetransparent and observe its internal structure without
the need for special microscopy techniques. Since
its discovery, the researchers have further developed
it to be applicable to a wider range of plants andtissues, naming this improved version ClearSeeAlpha™.
ClearSeeAlpha™ is expected to become a valuable tool
for the acceleration of plant science research.

However, plant cells are a more difficult target for
fluorescence microscopy than animal cells, as they
contain autofluorescent substances such as chlorophyll,
and observation is further complicated by the refractive
index of other components such as the cell wall andsurrounding air.
Through chemical screening, researchers at ITbM
have discovered a highly effective surfactant thatremoves autofluorescence in plants while causing very
little tissue damage, and a second compound that
not only renders the observed tissue transparent but
also preserves the fluorescent proteins. When a plant
specimen was immersed in a solution of these twocompounds, its tissue was rendered transparent in just a
few days.

Reference:“ClearSee: a rapid optical clearing reagent for wholeplant fluorescence imaging” by Daisuke Kurihara,
Yoko Mizuta, Yoshikatsu Sato, Tetsuya Higashiyama,
Development 2015, 142 (23): 4168–4179. DOI: 10.1242/
dev.127613.
“ClearSeeAlpha: Advanced Optical Clearing for WholePlant Imaging” by Daisuke Kurihara, Yoko Mizuta,
Shiori Nagahara, Tetsuya Higashiyama, Plant and Cell
Physiology 2021, 62 (8): 1302–1310. DOI: 10.1093/pcp/
pcab033.

Higashiyama Group, Live Imaging Center

33

Search for a receptor

The two molecules’ structures vary between plants,
meaning that only the right key molecule can fit the rightlock molecule and thus ensuring that the correct typeof pollen fertilizes the ovule. Through understanding
the structure of the binding region, it is expected that
progress can be made in creating viable plant hybrids
whose breeding has been challenging. The discovery of
LURE and PRK6 represents a significant step forward on
the road to understanding the processes behind plant
reproduction.

In plant reproduction, the pollen tubes extend straight
down the pistil from its tip until they near the ovule,before changing the direction of their growth towards
the ovule until they make contact with and fertilize it.
The ovule (female) part of the plant releases LURE, a
pollen tube attractant, to guide the pollen tube towards
it. However, without a receptor on the pollen (male) side,
the pollen tube will not react, and will simply grow past
the ovule without fertilizing it.
Using Arabidopsis thaliana, ITbM’s researchers
found the receptor, PRK6, which senses LURE. They
discovered that the receptor contains several similaramino acid sequences, which work together to correctlyinterpret the attractor signal and control the growth andorientation of the pollen tube.

Reference:“Tip-localized receptors control pollen tube growth and
LURE sensing in Arabidopsis”by Hidenori Takeuchi
and Tetsuya Higashiyama, Nature 2016, 531, 245. DOI:
10.1038/nature17413.
"Structural basis for receptor recognition of pollen tube
attraction peptides" by Xiaoxiao Zhang, Weijia Liu,
Takuya T. Nagae, Hidenori Takeuchi, Heqiao Zhang,
Zhifu Han, Tetsuya Higashiyama & Jijie Chai, Nature
Communications 2017, 8, 1331. DOI: 10.1038/s41467017-01323-8.

Two molecules, one big step for plant
reproduction research
The researchers used X-ray crystallography to show
how LURE and PRK6 form a ‘lock and key’-like bond.

Higashiyama Group34

Research Highlights

Kinoshita Group

Yamaguchi Group

Stomatal CO2/bicarbonate Sensor Consistsof Two Interacting Protein Kinases, Raflike HT1 and non-kinase-activity requiring
MPK12/MPK4. (Science Advances 2022)

Diazulenylmethyl Cations with a Silicon
Bridge: A π-Extended Cationic Motif to Form
J-Aggregates with Near-Infrared Absorption
and Emission. (JACS 2022)

Yoshimura Group & CLC

Frommer-Nakamura & Tama GroupA pheromone that explains why puffer
fish spawn on beaches under moonlight.
(Current Biology 2022)

SWEET13 transport of sucrose, but
not gibberellin, restores male fertility in
Arabidopsis sweet13;14. (PNAS 2022)

Kay-Hirota & Tama Group

Itami GroupCRY2 isoform selectivity of a circadianclock modulator with anti-glioblastoma
efficacy. (PNAS 2022)

Synthesis, properties, and material
hybridization of bare aromatic polymers
enabled by dendrimer support. (Nature
Communications 2022)

35

Itami Group

Yamaguchi Group & LIC

A Möbius band constructed solely bycarbon atoms. (Nature Synthesis 2022)

A negative-solvatochromic fluorescentprobe for visualizing intracellular
distributions of fatty acid metabolites.
(Nature Communications 2022)

Kay-Hirota & Tama Group

Itami Group

Structural differences in the FAD-binding
pockets and lid loops of mammalian CRY1
and CRY2 for isoform-selective regulation.
(PNAS 2021)

A template for fast synthesis of
nanographenes. (Nature Communications
2021)

Frommer-Nakamura Group

Itami, Tama & Kay-Hirota GroupThe anchor and the sword: unlocking thesecrets of microtubule formation in plants.
(Nature Communications 2021)

Resetting the biological clock by flipping aswitch. (Nature Communications 2021)

36

Higashiyama Group

Kinoshita Group

Dynamics of the cell fate specifications
during female gametophyte development inArabidopsis. (PLoS Biology 2021)

A novel system for increasing rice crop
yield. (Nature Communications 2021)

Itami, Tama, Kay-Hirota Group & CLC

Itami Group

Photopharmacological Manipulation of
Mammalian CRY1 for Regulation of the
Circadian Clock. (JACS 2021)

A new synthesis method for threedimensional nanocarbons: Connecting
carbon by catalysis to create octagonal
structures. (Nature Catalysis 2020)

Kinoshita Group

Yoshimura Group & CLC

Training AI with synthetic data formeasuring crop seed shape Developmentof an efficient method to accelerate thedevelopment of machine learning models
for plant phenotyping. (Communications
Biology 2020)

Discovery of a drug to rescue winterdepression-like behavior. (PNAS 2020)

37

WPI centers and support
About WPIThe World Premier International Research Center Initiative(WPI) was launched in 2007 by the Japanese government's
Ministry of Education, Culture, Sports, Science andTechnology (MEXT). It is a ten-year funding program thataims to build globally visible research centers in Japan,eachwith a very high standard of research and an outstanding
research environment that will attract top researchers fromaround the world to come to work at these centers.

A total of 17 WPI centers have been selected acrossJapan up to now. Each center is being developed under thestrong leadership of the center director to realize the fourbasic goals of the WPI program: (1) Science: advancing
leading-edge research; (2) Fusion: creating interdisciplinary
research fields; (3) Globalization: establishing international
research environments; and (4) Reform: improving researchorganization.

Tohoku University
Advanced Institutefor Materials Research (AIMR)

Hokkaido University
Institute for Chemical Reaction
Design and Discovery (ICReDD)

Kanazawa University
Nano Life Science Institute (NanoLSI）

University of Tsukuba
International Institute forIntegrative Sleep Medicine (IIIS)

Kyoto University
Institute for Integrated
Cell-Material Sciences (iCeMS)

High Energy Accelerator
Research Organization
International Center for Quantum-field
Measurement Systems for Studies of
the Universe and Particles (QUP)

Kyoto University
Institute for the Advanced Studyof Human Biology (ASHBi)

National Institute for Materials Science
International Center for Materials
Nanoarchitectonics (MANA)

Osaka University
Immunology Frontier
Research Center (IFReC)

The University of Tokyo
Kavli Institute for the Physics andMathematics of the Universe (Kavli IPMU)

Osaka University
Premium Research Institute for
Human Metaverse Medicine(PRIMe)The University of Tokyo
International Research Center
for Neurointelligence (IRCN)

Kyushu University
International Institute for CarbonNeutral Energy Research (I2CNER)

Tokyo Institute of Technology
Earth-Life Science Institute (ELSI)
Keio University
Human Biology-Microbiome-Quantum
Research Center (Bio2Q)

Hiroshima University
International Institute for
Sustainability with Knotted
Chiral Meta Matter (SKCM2)

Nagoya University
Institute of Transformative Bio-Molecules (ITbM)

Supporting ITbM
ITbM will continue to conduct basic research to contributeto solving the major challenges facing global society. In order
to attract talented personnel, secure intellectual property,
and continue to generate advanced results in research andtechnology transfer, action is still needed after the ten-year
support from the WPI program ends in March 2022. Donations
to ITbM will help ensure that ITbM can continue to respond tosocietal challenges in the future.

NAGOYA UNIVERSITYFoundation page38

Editor-in-Chief: Takashi Yoshimura
Editor: Research Promotion Division
Design: Issey Takahashi
ITbM Brochure 2023 Published by the Institute of Transformative
Bio-Molecules (WPI-ITbM), Nagoya University, Tokai National Higher
Education and Research System

This brochure is for non-commercial use only. The information in this document is subject to change
without notice. This document and parts thereof must not be reproduced or copied without ITbM's written
permission, and contents thereof must not be shared to a third party nor be used for any unauthorized purpose.

39

Contact
Administrative Department,
Institute of Transformative
Bio-Molecules (WPI-ITbM),
Nagoya University,
Tokai National Higher Education
and Research System
Furo-cho, Chikusa-ku, Nagoya
464-8601, Japan
TEL: +81-52-747-6843
FAX: +81-52-789-3240
E-mail: office@itbm.nagoya-u.ac.jp

Nagoya University

Issued: March 2023
© 2023 Institute of Transformative Bio-Molecules