Welcome to CHIBA RESEARCH 2021, a publicationthat showcases the diverse and innovative work being

based medicine, three-dimensional holography, as well as
studies on how to achieve a fair and just society.

This issue introduces the twenty-two innovative projects current-(see page 10); and Shigeru Yoshida’s use of ghost-like

We hope you enjoy this issue of CHIBA RESEARCH and welook forward to sharing with you our latest research findings.

© iStock.com/BlackJack3D

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TABLEOF
CONTENTS

Guided by its motto “Always aim higher,” CHIBA UNIVERSITY strives to nurture

globally minded students who have broad outlooks. The university values academic diversity
and actively conducts leading-edge fundamental and applied research.

Top Research Program
Chiba University was founded as a national university in Japan in 1949, when Chiba Normal School,
established in 1874, merged with Chiba Medical College and several other educational institutions.
Currently composed of 10 faculties and 13 graduate schools, Chiba University is one of Japan’s largest
national universities, having about 11,000 undergraduate students, 3,500 graduate students and 3,500
faculty members on 4 campuses located near Tokyo. The main campus at Nishi-Chiba occupies an area ofalmost 400,000 square meters (100 acres) and is conveniently located between Tokyo Station (about
40 minutes by train) and Narita International Airport. The 850-bed University Hospital, a core hospital

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08

10

MUCOSAL IMMUNOLOGY AND
THERAPEUTICSINTERNATIONAL CENTER FOR
HADRON ASTROPHYSICSCHIRAL
MATERIALS SCIENCEFighting Pathogens at Their
Point of Entry

Revealing Hidden Messages fromthe Cosmos

Using Light to Establish a New
Field of Chiral Materials

for the region, is adjacent to the School of Medicine on the lnohana campus.

Research Incubator Program25

Humanities and Social Sciences
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15

CHIBA STUDIES ON GLOBAL FAIR SOCIETY
Forging a Fairer World

Improving Datasets Using Small Area Estimation
16

TRANSLATIONAL RESEARCH PROGRAM OFPSYCHIATRY AND PSYCHOLOGY
Cognitive Behavioural Theraphy
Comes of Age in Japan

17

20

NEXT-GENERATION THREE-DIMENSIONALDISPLAY AND MEASUREMENT

21

MULTIMODAL MEDICAL ENGINEERING

22

CENTER FOR INNOVATIVE MICROWAVE2730

PHYTOCHEMICAL PLANT
MOLECULAR SCIENCES

CANCER EPIGENOME CENTER

32

MEDICAL MYCOLOGY RESEARCH CENTER

33

MEDICINE FOR RARE DISEASES34

GLYCOMEDICINE RESEARCH CENTER

35

LABORATORY OF DDS DESIGN AND
DRUG DISPOSITIONIMAGING SCIENCE AND TECHNOLOGY

A Different Approach to Fighting Cancer

Manipulating Microbes for Human HealthInnovative Approach Offers Hopefor Intractable Problems

Sugar Science’s Immunotheraphy PlayBig Hopes for Nanotechnology Based
Drug Delivery Systems

FOR MATERIAL APPEARANCE AND AFFECT

Looking to Nature to Revolutionize Flight

Making Invisible Lymphedema Visible

31

REMOTE SENSINGINSECTS-INSPIRED BIG INNOVATIONLYMPHEDEMA MONITOR

Unlocking the Potential of Phytochemicals

Affect and Realness in Digital Images
24

COMMUNICATION

Medical and Pharmaceutical Sciences

Toward Image-Based Disease Diagnostics

The Next Wave in Remote Sensing

ADVANCED BONE-CONDUCTION
Bone-conductionTechnology beyond Hearing Aid

Living with People with Foreign Backgrounds

Future Images —More than Meets the Eye

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MIGRATION AND REFUGEE STUDIES

Science and Engineering

FOR INTELLIGENT MATERIALS

Catalyzing the Future of Smart Materials

SMALL AREA ESTIMATION
AND ITS APPLICATIONSOFT MOLECULAR ACTIVATION

36

INTERNATIONAL HUB FOR METALLOMICSRESEARCH

Understanding the function of biometals forhuman and environmental health23Top Research Program
MUCOSAL IMMUNOLOGY AND THERAPEUTICSFighting Pathogens at Their Point of Entry

INTERNATIONAL CENTER FOR HADRON ASTROPHYSICS

Revealing Hidden Messages From the Cosmos

CHIRAL MATERIALS SCIENCE

Using Light to Establish a New Field of Chiral Materials© iStock.com/gremlin

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MUCOSAL IMMUNOLOGY AND THERAPEUTICS

FIGHTING PATHOGENSAT THEIR POINT OF ENTRY-Vaccines that induce immune responses at mucosal

membranes of the intestines, lungs and other organs could
help prevent deadly infections.

Research Keywords: Immunology, Mucosal Immunity, Allergy

The mucous membranes that line manyof the tracts and structures in the body are
the first lines of defense against foreign
invaders. Equipped with a powerful andhighly specialized immune system, thesemucosal sentinels protect the surfaces and,by extension, the body interior, against thethreat of gastrointestinal, respiratory andsexually transmitted infections, as well ascancer, allergies and more.
If these immune cells let their guard
down, pathogens such as bacteria andviruses can invade. On the other hand,
if they are overly vigilant, hyper-reactive
conditions like asthma or autoimmune
inflammatory bowel disease can take hold.
Getting the balance right is the goal of
the International Center of Excellencein Mucosal Immunology and Innovative
Allergy Therapeutics.
Launched as a joint initiative between
Chiba University and the University ofCalifornia, San Diego, in 2016, the center
aims to harness the power of the mucosal immune system to develop the next
generation of preventive vaccines against
infectious, allergic and inflammatory
diseases.
Most vaccines in use today are administered by injection. But since most infectious agents enter the body at mucosal
surfaces, vaccinating through the nose,
mouth, or some other mucosal route
could provide more protection. Sincetransmission often occurs at these sites,
boosting the body’s ability to block thattransmission could stop an infection or
autoimmune reaction at its source.
“While existing injectable vaccines areable to prevent serious conditions fromdeveloping, they are not effective enoughto defend against infection,” notes program director, Toshinori Nakayama.

FROM BASIC RESEARCH TO
CLINICAL APPLICATIONSBefore new treatments can be developed,
however, much more needs to be learned
about the molecular architecture of themucosal immune system. That is why theInternational Center of Excellence is focusing on basic research while simultaneously advancing clinical applications. It isalso strengthening ties between researchers and industry in the hope of translating
its discoveries into therapies for patients.
To this end, Nakayama is building a robust
pipeline of talented scientists who canmove research findings seamlessly fromthe lab bench to the hospital bedside.
“The research system we are creating isunprecedented,” says Nakayama, who isalso vice president of Chiba Universityand dean of the Graduate School of Medicine and the Faculty of Medicine.
Projects at the International Center of
Excellence fall into three categories:
Hiroshi Kiyono is studying the basic
mechanisms of mucosal immunology inresponse to microbial infections and assorted diseases; Nakayama and colleagues,
including Atsushi Onodera, Motoko
Kimura and Osamu Ohara, are focusing
on allergic reactions and novel treatmentsthat target the mucosa; and Hiroshi
Nakajima and colleagues belong to theclinical research team that is developing
new vaccines and adjuvants for pathogens
endemic to Japan and around the world.
Chiba has initially committed US$2
million over five years to this alliance.
Together with a matching contribution
from UC San Diego, the project will facilitate joint research and exchanges between
investigators and students on both sidesof the Pacific.

MUCOUS MEMBRANE
IN THE AIRWAY

Mucous coat layered
with tiny hairlike cila.

Immune cells in the
mucous membraneprotect the bodyagainst invasion bypathogens such asbacteria and viruses.
However, if they are
too vigilant, they cancause diseases.

Vaccines that directly
target the mucosal surface
could provide more protection
than a typical injection.

Members
Toshinori NAKAYAMA
Professor, Graduate School of Medicine

Hiroshi NAKAJIMA

Hiroshi KIYONO

Osamu OHARA

Motoko KIMURA

Atsushi ONODERA

Akira SUTO

Yosuke KURASHIMA		© Science Photo Library / Alamy Stock Photo

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INTERNATIONAL CENTER FOR HADRON ASTROPHYSICSREVEALING
HIDDEN MESSAGESFROM THE COSMOS

Two towers receive informationfrom 5,160 light-detecting
sensors buried 2,500 metersbeneath the South Pole.

The IceCube Neutrino Observatory, at theSouth Pole's Amundsen-Scott station. The International
Center for Hadron Astrophysics is part of the
global collaboration constructing IceCube.

Research Keywords:
Neutrino Astronomy, Cosmic Rays, South Pole, Elementary Particle Experiment-From a remarkable observatory buried deepin the south polar ice, Chiba University astrophysicists
are helping to explore the origins of the Universe.

Humans have been observing the stars
for tens of thousands of years, first with
our eyes, then with optical telescopes,
and more recently using devices that can
detect light at the extremes of the electromagnetic spectrum far beyond the visible
range. Yet despite phenomenal progressin astronomy over the past half century,
much of the Universe remains completely hidden from view, obscured by othermatter, other radiation sources, and light’sinteraction with the interstellar medium.
Now, scientists are on the verge of being
able to peer into some of the most mysterious corners of the cosmos using not lightbut neutrinos — near-massless subatomic
particles that travel close to the speed oflight across the Universe without being
deflected by magnetic fields or absorbed
by matter.
The International Center for Hadron
Astrophysics (ICEHAP) led by Shigeru
Yoshida is part of the global collaboration
responsible for managing the IceCube
Neutrino Observatory deep in the ice at
the South Pole’s Amundsen–Scott station.
“One of the longest standing puzzles inastrophysics is the origin of high-energy
cosmic rays and neutrinos,” says Yoshida. “The new windows to our Universe
opened by neutrino observations, combined with powerful computer simulations

8of cosmic plasma, have great potential to
finally resolve this mystery.”THE ICECUBE COLLABORATION

Neutrinos are the most abundant particles
in the Universe after photons (light particles). They originate in some of the mostviolent and least understood cosmologicalphenomena like supernovas, galactic coresand black holes. After their birth, they
travel in straight lines from their sourcewith almost no deflection or absorption,
making them ideal messengers from theheart of these mysterious astronomical
objects. But these same properties also
make them exceedingly difficult to detect.
The IceCube collaboration, involving 300
physicists from 53 institutions in 12 countries, has gone to extreme lengths to detect
these ghost-like, high-energy particles.
The IceCube observatory is a cubic
kilometer of crystal-clear ice, deep below
South Pole Station — the only place on
Earth where such large volumes of clear,pure and stable ice can be found alongwith the infrastructure needed to supportscientific research. By suspending thousands of delicate photodetectors on strings
in a network of vertical holes drilled
through the ice, physicists can capture
the rare explosion of energy that occurs
when a neutrino collides with an oxygenor hydrogen nucleus. Of the trillion, trillion
neutrinos that pass through IceCube every
day, the facility records just a few hundred
collisions from high-energy neutrinos— a minute fraction of the neutrino flux
but more than enough to stimulate somevery exciting research. “We are proud of
having been key players in the discoveryof high-energy cosmic neutrinos, which
astrophysicists have been dreaming
about for more than 30 years,” says
Yoshida talking about his team members in ICEHAP.
Another important contribution of ICEHAP to understanding the high-energy
Universe is its supercomputer-based massive numerical simulation program for deep
investigation of the physical mechanisms
behind high neutrino production. “Throughour simulations we are helping to uncover
the hidden messages carried by these neutrinos and to reveal the physical mechanism
by which high-energy cosmic rays areaccelerated at their source,” says Yoshida. In
2018, the IceCube collaboration has finallydiscovered that a special type of galaxy,
TXS 0506+056, is a birthplace of cosmic
neutrinos. This achievement was selected
as one of the top breakthroughs by Science.
In 2022, the team’s new detectors called“D-Egg” will be used at the South Pole. It
clearly shows the steps being taken forward.

Neutrinos are subatomic
particles that typicallypass freely through matter.
Other particles cannot
penetrate the Earth, so
below the 'Dark Sector'
near the South Pole,
free from every otherinterference, it is quiet
enough for the neutrinos
to be detected.

Members
Shigeru YOSHIDA
Professor, Graduate School of Science

Aya ISHIHARA

Ryo NAGAI

Lu LU

Kenichi KIN

Colton HILL

Maximilian MEIER

Ryoji MATSUMOTO

Yosuke MATSUMOTO

Tomoyuki HANAWA

Tomoaki ISHIYAMA

Hideyuki HOTTA

9CHIRAL MATERIALS SCIENCE

USING LIGHT TO ESTABLISH
A NEW FIELD OF
CHIRAL MATERIALS
Research Keywords: Applied Optics, Optical Vortex, Chirality-Understanding theuniversal property of chirality
could lead to new materials
and technologies for photonics
and other applications.

Members
Takashige OMATSU
Professor, Graduate School of Engineering

Hisao ISHII

Masami SAKAMOTO

Takeshi MURATA

Peter KRÜGER

Kazuyuki SAKAMOTO

Hiroyuki YOSHIDA

Kenichi OTO

Toyokazu YAMADA

Nobuyuki AOKIKazuki NAKAMURA

Takayoshi ARAI

Atsushi NISHIDA

Akira YANAGISAWA

Midori ARAI

Shiki YAGAI

Kazuhiro YOSHIDA

Tetsuhiro NEMOTO

Motohiro AKAZOME

Akira MATSUURA

Yoshihiro NISHIDA

Kohji ITO

Hiroki TAKAHASHI

Daisuke UMENO

Naohiko ANZAI

Keisuke IIDA

Satoshi OGASAWARA

10

Of the many mysteries still to be unraveled in the natural sciences, one of themost compelling is the origin and powerof chirality — the property of a moleculeor object that has two mirror-image forms— like our left and right hands.
Chirality is universal in biology, chemistry
and physics. It critically affects the biochemical processes underpinning life, is avital aspect of drug discovery, and crops up
in particle physics. Light can have chiralproperties that affect how it interacts withmatter. But how can the power of chirality
be harnessed and controlled? And what
new discoveries and technologies might
this give rise to? These are some of thequestions Takashige Omatsu and his teamare asking.
Light beams can be chiral when they are
imparted with so-called helical wavefronts, that is, polarity that rotates either
left or right. “We can use ‘optical vortices’to twist the physical properties of metals,
semiconductors and organic materials on
the nanoscale to create chiral nanostructures with unique features,” says Omatsu.
“Our goal is to establish chiral photonic
materials as an original research field andto pioneer new technologies such as chiralplasmonics and metasurfaces for nanoscalechiral chemical reactors, chiral-selective
imagers and chiral sensors,” he explains.
LIGHT CORKSCREWS

Omatsu’s team focuses on the interaction
between helical light and materials, andthe physical properties and potential usesof such modified materials. The electromagnetic field of helical light rotates as
the light moves through space. When thisfield interacts with conductive materials
like metals, nanoscale corkscrew-likevariations in physical properties can be

inscribed on the material’s surface. The
modified surface can then react differently
to left- and right-handed chiral molecules
or helical light, giving rise to a range ofinteresting possibilities for chemical sensing, synthesis and imaging.
“We can use helical light to create nanostructures such as twisted needles, twisted
reliefs and twisted fibers,” says Omatsu.
“We have also found that the same process
can polymerize fullerene — a well-known
functional organic molecule that is normally not conductive. This causes fullerene
to form a novel conductive metallic phase,
which could be used as the basis for fabricating electronic devices without metals
and semiconductors.”
Omatsu believes ‘nanovortices’ will one
day be used for nanoscale precisioncontrol of light polarization, electron
orbital motion and the aggregation ofchiral molecules. “Our research will leadto materials for next-generation photonics
and electronics, and new applications inchemical synthesis, pharmacy, biology andmedicine,” he says. “It might also allow us
one day to answer the scientific mystery:‘Why does handedness exist in nature?’”Omatsu has collaborated with many
Japanese and international researchers,
and is always looking for students andearly career researchers. “Our research
center brings together physicists, chemists,biologists and even medical doctors, andwe frequently have brainstorming meetings to think up ideas for new projects,”
he says. “Several international researchers
work here. There is a wonderful diversityof backgrounds and expertise.”© iStock.com/loops7

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Humanities andSocial Sciences
CHIBA STUDIES ON GLOBAL FAIR SOCIETY

Forging a Fairer WorldSMALL AREA ESTIMATION AND
ITS APPLICATION

Improving Datasets Using
Small Area Estimation
TRANSLATIONAL RESEARCH PROGRAM
OF PSYCHIATRY AND PSYCHOLOGY

Cognitive Behavioural Theraphy
Comes of Age in JapanMIGRATION AND REFUGEE STUDIES

Living with People with Foreign
Backgrounds

12© piick/Shutterstock.com

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CHIBA STUDIES ON GLOBAL FAIR SOCIETY

SMALL AREA ESTIMATION AND ITS APPLICATIONFORGING A
FAIRER WORLD

IMPROVING DATASETSUSING SMALL AREA
ESTIMATION

Research Keywords: Global Welfare Society, Multidisciplinary Social Science, Fairness

Research Keywords: Economic Statistics, Baysian Statistics, Small Area Estimation-A multidisciplinary team of researchers looks at
how to create a fair society — on a global scale.

With globalization comes the need toensure that people from all cultures,countries and backgrounds are treatedfairly and equally. The drive to create a justglobal society requires solid foundations in
all countries, backed by informed government policies and strong support networks
at local, regional and national levels.
Much previous research into justice andsocial change has been dominated bystudies of Western societies, but the rapidchanges experienced by Asian countries inrecent decades have spawned a growing
field of research focused on building fairsocieties in Asia.
Researchers in law, politics, economics andsocial sciences have recently established
the Chiba Studies on Global Fair Society
project, with the aim of creating an interdisciplinary research base to inform future
local, national and international policies.
Lead researcher on the project, Jiro
Mizushima, says the key concept is fairness.
“We define fairness as the basic element ofjustice,” he explains. “In fact, we argue thatit exceeds justice in most cases. At the sametime, we embrace values such as equality
and liberty.”
Mizushima, whose research interests lie
in welfare state reform in Europe, says the
project aims to go beyond the traditional
discussion of equality — it seeks to construct new principles that value diversity
among people in a global society.

14-Statistical techniques can improve the accuracy andscope of limited information, saving time and money.

HOW DO WE ACHIEVEA FAIR SOCIETY?
The project consists of four interrelated
research groups and a further six teams
working to publicize the findings to a wide
audience. Their focus is on challenging andovercoming unfair practices on all scales, investigating issues such as gender inequality,
widening income gaps, migration, and thecollapse of regional and marginal communities, both in Japan and around the world.
In particular, the researchers believe that
proposals and practices aimed at closing the
gap between large cities and local cities andresolving gender gaps are essential to overcoming the divides.
The key aims of the project are to investigate
the development, transformation and limitations of existing welfare state models andto provide empirical evidence for how a fairsociety can be achieved in the 21st century.
Mizushima has spent considerable time
researching aspects of the welfare state in the
Netherlands, including how it has responded
to social challenges such as global economic
fluctuations and an aging population.
“Fairness has been the core of legal andpolitical philosophy since ancient times, andso one of our teams is examining equality
and fairness from a historical perspective,
comparing political, economic and legal
standpoints over time,” he says. “Anothergroup will analyze the meaning of fairness
in the 21st century, providing us with fundamental guidelines to underpin our program.”
The team plans to form networks of academics across the globe. To this end, they havehosted five highly successful international

symposiums. “Many of our members are
involved in local and national policymaking
committees, and they are key to informing
policy makers of our work,” says Mizushima.
The project has published books and papers
both in Japanese and English based on theirresearch outcomes, and welcomes those interested in all aspects of social science, fromlaw and politics to sociology and economics.

Collecting comprehensive data on populations is not always possible, or even the bestuse of resources. Surveys can be expensive
and time-consuming, so improving theaccuracy of data with “small area problems”
can stretch data resources further.
“Small area problems happen when an
estimator, such as sample mean for a smallarea, becomes very unstable because of small
sample sizes,” explains Associate Professor
Genya Kobayashi, who is part of a new Chiba project called Small Area Estimation and
Its Application to the Analyses of Poverty,
Public Health and Disaster.
His group is focused on overcoming such
issues by developing small area estimation(SAE) techniques that borrow statisticalstrength from supplementary data.
OVERCOMING INEQUITY AND
PUBLIC HEALTH INSIGHTS

Members
Jiro MIZUSHIMA
Professor, Graduate School of Social Science

Masaya KOBAYASHI

Akiko OISHI

Hikari ISHIDO

Masahiro OGIYAMA

Hiroyuki MINAGAWA

Seiichi IGARASHI

Iwao FUJISAWA

Kentaro SATO

Takayuki KAWASE

Chiyo YONEMURA

Reiko OGAWA

Li XIANG

While the applications of SAE are broad,“small area problems arise particularly within
official statistics on which governments makeimportant political decisions. Hence, small
area estimation techniques could lead to more
effective policy making,” notes Kobayashi.
An example crops up in the monthly Family
Income and Expenditure Survey (FIES)
conducted by Japan’s Statistics Bureau.
Although FIES provides the latest information on household income and expenditure,
at a small area level, such as a city level, thesample size of FIES becomes so small that
direct estimators are unstable and can’t grasp
detailed trends.
But FIES, says Kobayashi, can borrow
statistical strength from data in the National

Survey of Family Income and Expenditure(NSFIE). The sample sizes in the NSFIE
are much larger than in the FIES and thus
more reliable, but because the survey is time
consuming and costly, it’s only carried out
every five years.
The FIES and the NSFIE collect area-level
aggregated data, so Kobayashi’s group used
the Fay-Herriot, a mixed regression model
routinely used in SAE.
However, when data is in other formats
more appropriate SAE models must be developed. Recently, for example, Kobayashi’sgroup has been working to improve an
income map of Japan based on the Statistic
Bureau’s Housing and Land Survey (HLS).
Using a new statistical model that accounts
for the grouped data format of the HLS andadditional data from the Population Census,
they measurably reduced the uncertainty of
the HLS’s income estimates.
SAE’s scope isn’t limited to stabilizing data,
adds Kobayashi. SAE techniques can add
information. For example, the HLS model could also infer income in areas wheredata is missing. Using a mixture modelingapproach, the team recently estimated the
distribution of land prices around train
stations in and around Tokyo by making
inferences across areas.
Contributing to public health discussions, in2018 Kobayashi collaborated on a paper thatused a spatial Poisson regression model tolook the links between access to clean waterand dropping mortality rates in the early
1900s. Kobayashi and collaborators at theTokyo Institute of Technology and Duke
University in the United States looked
at death rates in Tokyo in 1930 against a

Members
Genya KOBAYASHI
Associate Professor, Graduate School of Social Science

Yuki KAWAKUBO

Eisaku SATO

Shouto YONEKURA

Hiromi SAITO

Tsubasa ITO

Yuta YAMAUCHI

Ryota YUASA

Syonosuke SUGASAWA

Yukiko OMATA

dataset of taps. The group found that accessto clean water accounted for 41.3 percent of
the improvement in Tokyo’s crude death rate
between 1921 and 1937. This paper adds
to discussions on the relative importanceof nutrition and clean water on mortality.
Kobayashi hopes that everyone from policy
makers to businesses will soon come to
the group to add a finer resolution to theirdatasets.

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TRANSLATIONAL RESEARCH PROGRAM OF PSYCHIATRY AND PSYCHOLOGYMIGRATION AND REFUGEE STUDIESCOGNITIVE
BEHAVIOURAL THERAPHYCOMES OF AGE IN JAPANLIVING WITH PEOPLE WITH
FOREIGN BACKGROUNDS-Better access to mental health care in schools, at workand online could help people of all age groups sufferingfrom anxiety, depression and other related conditions.
THOUGHTS
What we think affects
how we feel and act

What we feel affects
how we think and act

CBT
CHANGING PERCEPTIONSBEHAVIOURS
What we do affects
how we think and feel© www.betterhelp.com

Major efforts are underway to help treat andprevent anxiety-related disorders in Japan—where as many as one in four people
experience mental health problems during
their lifetime.
Social Anxiety Disorder (social phobia), oneof the most prevalent, is characterised byan intense fear of social situations. In somecases, social phobia can lead to addiction,
depression or suicidal behaviour.
Many doctors, legislators and patients now
recognise cognitive behavioural therapy(CBT) as an effective treatment for social
phobia. By changing negative patternsof thinking and behavior, CBT can help
children overcome anxiety and the fear of
uncertainty, adolescents better manage depression and irritability, and adults deal witha host of stressful life experiences.
A LEADING CENTRE FOR CBTRESEARCH AND EDUCATION
We are now actively trying to increase thenumber of CBT experts in Japan,” says Eiji

16

Eiji SHIMIZU
Director and Professor, Research Center forChild Mental Development

Research Keywords: Psychiatry, Psychology, Cognitive Behavioral Therapy

EMOTIONS

Members

Shimizu of Chiba University’s ResearchCenter for Child Mental Development
and Chiba University Hospital’s Cognitive
Behavioral Therapy Center. “However, CBT
resources in Japan are still relatively scarce.”
Chiba University and its affiliated hospitalare spearheading efforts to address this.
The Chiba Improving Access to Psychological Therapies (Chiba-IAPT) program,
adapted from a UK model, became the firstpost-qualification training course of its
kind in 2010.
“It’s important to tailor treatments toreflect not only cultural differences, but also
personal differences,” Shimizu adds. His
team are developing new tailored interventions, such as internet-based CBT (iCBT),
which are low-cost, easy to use, and provide
optional anonymity.
In 2017, his group released a study protocol
for iCBT on patients with persistent insomnia. They have also produced a simplified,
five-minute program that can be used tohelp reduce depressive symptoms.
As part of his wider research, Shimizu

Research Keywords: Globalization, Migration and Refugee Studies, Multicultural Coexistence

Eiji KIMURA

Makoto ICHIKAWA

Chikae ISOBE

Miho IWATA

Fumiko SUNAGAMI

Keito NAKAMICHITomihisa NIITSU

Aika TOMOTO

Yoshiyuki HIRANO

Toshiyuki OTANIKenichiro SHIMAI

Kensuke YOSHIMURA

contributed to the first study that visualised changes in brain activity during
psychotherapy in 2015. Using functional
magnetic resonance imaging (fMRI), theresults indicated that the left posteriorparietal cortex plays a vital role in cognitive restructuring — a process used in
CBT that enables people to challenge
existing beliefs.
In 2016, Shimizu and his colleagues showedthat CBT can help reduce social anxiety for patients ineffectively treated with antidepressants.
In recognition of the growing need for
professional CBT care, at the end of 2018
the Japanese government began to certify
licensed psychologists. The national healthinsurance system has been updated to cover
doctor-administered CBT for patients withdepressive disorders, anxiety disorders andbulimia nervosa.
There are also moves to introduce CBTbased anxiety prevention programs inJapanese elementary schools.
A 2018 study, designed by Yuko Urao andsupervised by Shimizu, examined the effectiveness of an anxiety prevention program
named Journey of the Brave, targeted atchildren aged 10–12 years. Consisting often 45-minute sessions held during school
hours, the program involved deepening understandings of anxiety, monitoring feelings,
and developing assertiveness skills to reducesocial stress.
While further follow-up studies are planned,
preliminary results indicate that the program
can help children manage their anxiety levels.
“Our hope is that in ten years’ time, allchildren in Japan will have access to thisprogram,” Shimizu says.

-The Global-Local Nexus
THE INCREASED TRANSNATIONAL
MOVEMENT OF PEOPLE
Until countries started closing their borders
due to COVID-19, the cross-border mobilityof people was part and parcel of everyday life
in a globalized world. Some crossed borders
for study or work, while others had no choice
but to flee across boundaries to escape conflictand persecution. Globalization has increased
the number of migrants and refugees, creating
numerous impacts worldwide that lead to theburgeoning of research in the field of humanities and social sciences on migration andtransnational mobility of people.
As witnessed in the 2015 Syrian refugee crisis
in Europe, Britain’s withdrawal from theEU, the massive flow of Rohingya refugees
from Myanmar to neighboring countries, themovement of people has significantly influenced and altered the society.
As of late 2019, approximately three million
registered foreign residents are living in Japan,
led by several policy initiatives including theamended Immigration Control and Refugee
Recognition Act and the “300,000 International Students Plan”, which aimed to increase
the number of international students.
Migrants are engaged in different types ofwork that sustain our daily lives and contribute to the economy. However, their contribution is not always visible. Migrants include
people of various backgrounds and Japanesesociety is in fact quite diverse; however, sharpboundaries are often drawn between “Japan/
Japanese” and “foreign countries/ foreigners”.
There is also a tendency to perceive people interms of prejudice and stereotypes based on
the intersections of race, class, and genderedhierarchies that exists in Japan.
Led by Reiko Ogawa, this research groupaims to integrate the transnational mobilityof people with practical initiatives in the local
area. It comprehensively studies the background for this global mobility, networks thatenable it, policies and institutions, educationand employment of migrants in Japan to
identifying the challenges affecting multicultural coexistence in Chiba.
First, we study the migration trajectories through multidisciplinary approach.
Backgrounds, global norms and networks
provide the context in which mobility has
been shaped, facilitated or hindered. Second,
we focus on education and employment of
migrants and children with foreign roots in
Chiba.
Taking a multidisciplinary approach encompassing international relations, history, sociology, economics, management, educational
studies, law and area studies, we present the
research findings, facilitate networking andpolicy advocacy.

impact and results in severe losses for society.
Instead of marginalizing and excludingchildren with international backgrounds, wemust provide an environment in which they
can apply their latent skills. “As the Japanese
population shrinks at an accelerating rate, it
has become urgent to create a positive cyclethat integrates the education and employmentof migrants. This is a significant undertaking, both academically and policy wise,” says
Ogawa.
A society that recognizes diversity and where
different cultures coexist would be a betterone not only for migrants, but also for theJapanese, who are themselves diverse in termsof class, gender, ethnicity, social position, andphysical and mental challenges.

INTERGRATING EDUCATION AND
EMPLOYMENTThe keyword of this research is multicultural
coexistence. “The term ‘multicultural coexistence’ is often used to mean the integrationof migrants into society. In contemporary
Japan, the critical issue is to ensure the rightsof migrants and integrate education andemployment,” says Ogawa. Japan has ratified
many international treaties, but the failure ofinternational norms to penetrate domestic
affairs has caused many challenges. One ofthese challenges is education for children withforeign roots. Thus far, education policies inJapan have not given a clear place to thesechildren. Therefore, low education levels, dropout and unemployment have become pressing
issues. Many studies have shown that a lackof educational opportunities causes a lifelong

Members
Reiko OGAWA
Professor, Graduate School of Social Sciences

Ayako SASAKI

Tomoko FUKUDA

Chihiro NAKAMURA

Kaoru SHIMIZU

Harumichi YOKOO

Yuichi TSUCHIDA

Satoko KOBAYASHI

Naoki SAKIYAMA

Yoshie TAKAMITSU

Ai SAITO

Keiko SAKAI

Hiroko GOTO

Ken ISHIDA

17

Science andEngineering
NEXT-GENERATION THREE-DIMENSIONALDISPLAY AND MEASUREMENT

Future Images —More than Meets the Eye
MULTIMODAL MEDICAL ENGINEERING

Toward Image-Based Disease Diagnostics
CENTER FOR INNOVATIVE MICROWAVEREMOTE SENSING

The Next Wave in Remote Sensing
IMAGING SCIENCE AND TECHNOLOGYFOR MATERIAL APPEARANCE AND AFFECT

Affect and Realness in Digital Images
INSECTS-INSPIRED BIG INNOVATION

Looking to Nature to Revolutionize Flight
SOFT MOLECULAR ACTIVATIONFOR INTELLIGENT MATERIALS

Catalyzing the Future of Smart Materials
ADVANCED BONE-CONDUCTION COMMUNICATION

Bone-conductionTechnology beyond Hearing Aid
LYMPHEDEMA MONITOR

Making Invisible Lymphedema Visible© iStock.com/Nongkran_ch18

19

NEXT-GENERATION THREE-DIMENSIONAL DISPLAY AND MEASUREMENTMULTIMODAL MEDICAL ENGINEERING

FUTURE IMAGES
MORE THAN MEETS THE EYETOWARD IMAGE-BASEDDISEASE DIAGNOSTICS

Research Keywords: Computer Holography, Volumetric Display, High Performance Computing

Research Keywords: Medical Engineering, Physical Measurement, Multimodality-Advances in three-dimensional image display andmeasurement techniques have applications in multiple fields,from medicine to communication and entertainment.

Members
Tomoyoshi SHIMOBABA
Professor, Graduate School of Engineering

Takashi KAKUETakashi OKAMOTO

Atsushi SHIRAKI

Tomoyoshi ITO

Seiichi KOAKUTSU

Michiko TAKAGAKI

Shigeo SHIODA

Yota YAMAMOTO

Technologies based on three-dimensional(3D) image displays and holography may
conjure up visions of science fiction, but the
Next-generation Three-dimensional Display
and Measurement program aims to makethese advanced tools part of everyday life.
Holograms create true three-dimensional
images, which allow the viewer to see an
object from all angles. They are created using
coherent light sources such as lasers, which
can store the complex light interference patterns required to accurately recreate an entire
3D object in full color. However, the maindrawback of holography is the immense computational burden of producing high-quality
holograms, not to mention creating moving
3D video images in real time.
Leader of the 3D program, Tomoyoshi Shimobaba says his team is developing ultrafast
algorithms and dedicated computers for holography to create the world’s first real-time
holographic 3D display system.
“These dedicated computers will have a computational speed three or four orders of magnitude higher than the household computersof today,” adds Tomoyoshi Ito, advisor on the
project. “Based on this dedicated technology,
we will investigate holographic projection,

20

digital holographic microscopy and ultrarapid
holographic imaging techniques.”
Among the team’s recent successes is a small,
inexpensive, zoomable holographic projection system, suitable for use in classrooms,
medical applications and entertainment
products. Shimobaba’s team refined mathematical image manipulation techniques toensure a high-resolution, non-grainy holographic image even when zooming in andout. The researchers are further developing
algorithms that can reduce ‘speckle noise’ inreconstructed images to avoid degradationin image quality.
ONE IMAGE, MULTIPLE VIEWS
Another aim is to reconstruct large 3D
images with a large viewing angle —something that is difficult to realize using
current technologies.
“We are also developing accurate holographic
measurement systems, which will be invaluable in medical science because they allow
researchers to image and measure samples in
3D alongside visualizing moving phenomena
in real time,” explains Shimobaba.
In another exciting field of research, theteam is exploring a form of 3D image
creation called volumetric displays — thedifference being that, while holograms canonly be seen clearly by a few people at atime, volumetric displays can be viewed bymultiple people from different viewpoints.
And, in an even more challenging concept,
they are trying to create multi-viewpoint
images with plural information appearing
in specific directions. In other words, one
person standing at one place will see one-Novel, high-precision imaging techniques are being
used to provide non-invasive disease diagnosis and guide
future treatments.

piece of information, while another standing
somewhere else will see completely different
information.
“Our volumetric display simultaneously
provides several observers with different
information,” explains Shimobaba. “Thisvery exciting feature is quite new, and weare considering new applications for using
it, such as developing multi-language
signage for the Tokyo Olympics in 2020,”
he says. Such 3D displays may benefit fromadvanced aerial projection techniques, also
under development by Shimobaba’s team.
“Networking is the key to our success,”says Shimobaba. “Many students who have
graduated from our laboratory move on to
conduct research in academia or in privatecompanies, and we continue to work withthem. In this way, we expand our project andbuild fruitful working relationships acrossacademia and industry.”

Non-invasive, precise diagnosis of diseases
using advanced medical imaging technologies could one day replace traditional
techniques based on biopsy and dissection.
With this prospect in mind, researchers at
the Multimodal Medical Engineering program are combining medical and engineering expertise to create novel, noninvasive
imaging-based methods for diagnosing andtreating disease.
The program uses various scanning techniques, or ‘modalities’, including computerized tomography, magnetic resonanceimaging (MRI) and ultrasound, to analyze
cellular and organ variations caused bydifferent diseases.
The program’s goal is to develop highly
precise, non-invasive imaging methods,
while boosting existing imaging techniques
to improve resolution and enable more-detailed tissue analysis, says program leader
Hideaki Haneishi.
“Many current disease diagnostics, particularly for cancer, involve highly invasive,
unpleasant procedures to clarify the type andstage of the disease,” explains Haneishi. “We
are investigating, for example, the development of a system to diagnose breast cancer
using very-high-frequency ultrasound.”Rather than physically sampling and dissecting lymph nodes from potentially cancerous
tissue, his team has shown that it is possible
to analyse cell characteristics of lymph nodes
using ultrasound. Their technique highlights
metastasis positive and negative cells in lymph
nodes, enabling rapid, painless diagnosis.
Haneishi and his team are also devising ways
to combine data from two or more modalities.
For example, in 2016 they developed an image

registration method that transforms two data
sets into one coordinated system using MRI
and pathological images of brain tumors.
“If we can establish the technology forregistering two kinds of images, then MRI
features that are strongly related to the pathological features of tumors can be highlighted.
This may eventually allow us to diagnose using only MRI,” says Haneishi. “Determining
the relationships between different data setshelps us build up detailed pictures of what isgoing on inside the body, not only for diagnosis but also to improve our understandingof disease development,” he adds.

Members
Hideaki HANEISHI
Professor, Center for Frontier Medical Engineer

Tadashi YAMAGUCHI

Hideki HAYASHI

Kenji YOSHIDA

Kazuyuki SAITO

Kazuya KAWAMURA

Takashi UNO

Toshiya NAKAGUCHI

Mikio SUGA

Takashi ONISHI

Yuzuru IKEHARA

Yasuo IWADATE

Koichi HAYANO

Hao LIU

Ken-ichi TSUBOTA

WenWei YU

Hiroki SUYARI

standing of different diseases,” says Haneishi.
The Multimodal Medical Engineering
program has access to highly specialized
equipment and technologies that can help
realize researchers’ ideas.
“We welcome engineers and medical
researchers who wish to work at the cutting-edge of research and development withdirect clinical applications,” says Haneishi.

NOVEL OPTICAL PROBES
Alongside conventional imaging techniques,
the researchers are also exploring novel optical probes. One example involves a method
for monitoring microcirculation — the flowof red blood cells — in the body. The probe
comprises multicolored light-emitting diodes (LEDs). As the LED light is scatteredthrough the tissue, it is partly absorbed bymolecules in the red blood cells, generating
a clear, detailed picture of the cells and theirmicrocirculatory network.
Building on previous work, the team hopes
to use this probe to estimate features such as
the oxygen saturation of each blood vesselin areas around suspected tumors in realtime. This could aid diagnosis and further our
understanding of vascular behavior in andaround tumors. “Ultimately, we would like tobuild on these imaging techniques and use
machine learning and artificial intelligence
technologies to relate measured signals anddiagnoses, to develop a comprehensive under21

CENTER FOR INNOVATIVE MICROWAVE REMOTE SENSINGIMAGING SCIENCE AND TECHNOLOGY FOR MATERIAL APPEARANCE AND AFFECT

THE NEXT WAVEIN REMOTE SENSING

Research Keywords: Microwave Remote Sensing, Synthetic Aperture Radar,
Environment and Disaster Monitoring-Microsatellites and remote imaging technology are
revolutionizing the way we predict earthquakes andmonitor disaster zones.

© iStock.com/Sirintra_Pumsopa

The Microwave Remote Sensing Laboratory is far more than a laboratory. It is anexperimental aerospace workshop whereworld experts in remote sensing collaborate
with mechanical and aerospace engineers
to construct state-of-the-art microsatellites,
unnammed aerial vehicle (UAV), and airborne sensors. The research team specializes
in microwave-radar technology for detecting
ground movements and earthquake predictors as part of a new generation of remotesensing technologies.
“Microwave radiation is particularly useful for
remote sensing because it penetrates cloud,haze and fog, allowing us to observe the Earth’s
surface from space,” explains Josaphat Tetuko
Sri Sumantyo who leads this research project.
The core area in this research project is the development of synthetic aperture radars (SARs)
for microwave remote sensing to monitor land
deformation. SAR emits a microwave signal
in the direction of the target and then detects
microwaves scattered from the target. By comparing SAR images obtained before and after

22

a change such as an earthquake or a landslide,researchers can determine how much the land
has moved.
The research team has a well-developed
research-and-development program with
15 researchers, 25 students and facilities fordesigning, manufacturing, calibrating andoperating SAR for UAV, aircraft, and microsatellite applications.
ADVANCED AEROSPACE FACILITIES“Our facilities include an anechoic chamber forcalibrating sensors, a satellite–ground communication system, and microsatellite calibrationand measurement systems. We also have asimulator for designing microwave circuits andantennas, along with a suite of manufacturing
equipment,” says Sri Sumantyo. “We even have
our own 6-meter experimental UAV, the JX,
which we developed in this laboratory.”
They have already developed SAR sensors forcircularly polarized (CP) microwave radiationin the L, C and X bands, which have been de-

AFFECT AND REALNESSIN DIGITAL IMAGES

Research Keywords: Engineering for Material Appearance, Image Sensing, Visual Psychology

Members
Jasaphat Tetuko SRI SUMANTYO
Professor, Center for Environmental Remote Sensing

Kazuteru NAMBA

Wen LIU

Katsumi HATTORI

Hiroyuki NAKATA

Chiharu HONGO

Akira KATO

ployed on both large and small aircraft, as wellas on the JX UAV. The CP-SAR sensor is thefirst of its kind, utilizing interference between
left- and right-handed circularly polarized
light to obtain precise information about the
Earth’s surface in a compact, lightweight andinexpensive sensor.
We have developed several techniques basedon SAR imaging to monitor infrastructure andareas affected by disasters such as forest fires,
landslides, subsidence and volcanic eruptions,”
says Sri Sumantyo.
Engineers in this team are developing two novel microsatellites. One is equipped with radio
occultation and electron density temperatureprobe sensors for measuring the atmosphericsignatures thought to precede earthquakes,
while the other is a CP-SAR satellite withlightweight gold-coated mesh antenna. Thesesatellites are poised to take the lab’s researchbeyond the stratosphere.
“Our microsatellite program is very exciting for
future SAR sensor applications and planetary
exploration,” says Sri Sumantyo. “We eventually aim to have five microsatellites in orbit,
which will provide real-time monitoring for
global disaster mitigation and research.”
The team has strong collaborations with Japanese and overseas research institutions and industry — it has more than 50 agreements withresearch and industry partners throughout theworld. The group also encourages short- andlong-stay programs, and Double Degree Program for Master and Doctoral Courses undervarious government programs, through whichmore than 500 students and researchers
from many different countries have worked
at the lab.

-Understanding how the human brain interprets images
could underpin the future of internet shopping, virtual
communication, digital fabrication and even non-invasive
medicine.
When internet purchases arrive and seemnothing like their picture, it can be a disappointing experience for shoppers. So, while
big e-commerce players are increasingly
investing in technologies to help personalize
products or shop via phone or virtual reality
headset, a significant stumbling block is rendering realistic, digitally produced images.
“To achieve a realistic rendering of something, we also need to deeply consider
human perception,” explains Keita Hirai,
a member of the “Creation of Material
Appearance and Affective Imaging” groupat Chiba University’s Graduate School ofEngineering. How we perceive a material,
he says, can also be linked to cognition, notjust physical phenomena.
To examine the complex effect of the mind’seye, Chiba University have drawn froma diverse range of researchers, including
engineers, psychologists, and medical andcognitive scientists.
Recently, Hirai’s team developed a new
system for texture evaluation, and throughparticipant feedback have devised a set ofalgorithms that can produce more realistic
digital representations of patinas and colours
overlaid onto textured fabrics in digital
images. The aim, he says, is to one day digitally simulate photo-real fabric appearance via
a smart device. Hirai points out that this will
not only be helpful to internet shoppers, butthat these algorithms could also find applications in rapidly advancing digital fabrication
techniques, such as printing digital patinas
onto fabrics or objects, and manufacturing
representative digitally-designed 3D products.
In fact, the group aims to contribute to industries as diverse as cosmetics and medicine.

© iStock.com/wacomka

UNDERSTANDING THE MECHANISM
OF MATERIAL APPEARANCE AND
AFFECT
Among the work done by the diverse groupis a study analyzing affects and emotions. A
research team led by Norimichi Tsumura, who
is also the leader of this research project, hasdeveloped a technology to visualize the amountof hemoglobin, which carries oxygen in the
blood, on the images taken with a smartphone
camera. If you take a video of your face using
this technology, you can also measure yourheart rate based on the increase or decreasein the amount of hemoglobin. Furthermore,by capturing a slight change in the interval
between heartbeats, it is possible to grasp the
respiratory rate and the balance between thesympathetic nerve and the parasympathetic
nerve. It is expected as a technology for measuring human affects and emotions.
Another group found that our perception ofcolour is affected by our understanding of its
dimensionality. The same viewer looking at thesame image saw colours differently dependingon whether they interpreted the image as twodimensional or three dimensional. Viewing
images with one eye or both, and whether theimage or the viewer’s head was moving, also
affected how natural the image seemed. Thiswork, says Hirai, is important for better smart
device production. “A more informed colour
management system, for example, may help
realize more accurate colour reproduction
between different devices: displays, cameras
and printers,” he explains.
Hirai says the group’s work will influence themost cutting-edge imaging technology, such as
the omni-directional 3D camera systems andvirtual reality headsets coming from technology giants such as Sony, Panasonic, Canon and
Nikon. While he also mentions cosmetics andautomotive painting, one team have alreadyhad some remarkable success in one crucial,
but quite unique area — medical diagnostics.
The pulse measurement technology developed by the research team of Tsumura has
already produced remarkable results in medical
diagnosis via the internet communication. It
is expected to be applied to a wide range ofuse, from non-invasive medical diagnosis toimproving understanding of physical exercise
using a simple smartphone app. Furthermore,this research project connects the expertise ofvarious researchers in order to establish newimaging technologies that integrate material
appearance and affective engineering, whichmonitors human emotional states and provides
images with high quality material appearance.

Members
Norimichi TSUMURA
Associate Professor, Graduate School of Engineering

Takahiko HORIUCHI

Keita HIRAI

Yoko MIZOKAMI

Shoko IMAIZUMIMichinari KOHRI

Noriko YATA

Toshihiko MATSUKA

Kensuke YOSHIMURA

Rumi TOKUNARA

Ayumi AMEMIYA

Eriko KOBAYASHI

Kazuki NAKAMURA

Shunji KOTSUKI

Shinichi INOUE

23

INSECTS-INSPIRED BIG INNOVATIONSOFT MOLECULAR ACTIVATION FOR INTELLIGENT MATERIALSLOOKING TO NATURE TO
REVOLUTIONIZE FLIGHT

CATALYZING THE FUTURE OF
SMART MATERIALSMembers
Hao LIU

Members

Professor, Graduate School of Engineering

Research Keywords: Bioinspired Engineering, Biological flight, Drone-The beating wings of insects hold the secrets
to controlled low-speed flight and Micro Aerial Vehicles.

Akio NAMIKI

Kazuya OKAWA

Toshiyuki NAKATA

Michinari KOHRI

Toshihiko MATSUKA

Tomokazu USHITANI

Arii WATANABE

Yuma TAKAHASHI

Hiroyuki ISHIKAWA

Akira KATO

Research Keywords: Synthetic Chemistry, Catalytic Reaction, Iodine Bond

-Catalysts developed from soft iodine, graphene
and metal complexes could transform smart material
technologies.

Takayoshi ARAI
Professor, Graduate School of Science

Hirofumi KANOH

Shoji MATSUMOTO

Katsuhiko MORIYAMA

Yasushi YOSHIDA

Nobuyuki ICHIKUNITomonori OHBA

Yasuhiro YAMADA

Shoichi KATSUTA

Takeshi MORITA

Hyuma MASU

Fumio SAKANE

Takeshi MURATA

Takuya HASHIMOTO

Shigeru ARAI

Kazuhiro YOSHIDA

Takashi MINO

Hideaki SHIROTA

Masaya NAKAJIMA

Shinji HARADA

Shingo HARADA

Tomoya UEHARA

Mamoru TAKADA

Keisuke IIDA

Yasuhiro YAMADAManabu TSUKADA		Inspired by the fascinating flying ability of
insects and humming birds, Chiba University’s Biomechanical Engineering Laboratory
has been conducting pioneering research on
beating-wing flight for more than 20 years.
Headed by Professor Hao Liu, the lab is on
the verge of revolutionizing the very conceptof flight itself.
“Insects have this amazing ability to hoverand execute highly controlled flight in bothstill air and turbulent wind gusts,” says Liu.
“Scientists once knew very little about how
insects generate aerodynamic force in turbulent environments, and even less about
how they are able to maintain such agile
control in flight.”
BIOLOGY INSPIRES MICROAIR VEHICLESConventional flight is based on the uninterrupted flow of air over the curved upperand lower surfaces of a wing, which causes a‘suction’ effect that lifts the wing upward.
“Fixed wings need smooth airflow to generate lift,” explains Liu. “Turbulence over thewing can lead to disaster. Our first major
breakthrough in unravelling the mysteryof insect flight was that most flying insects
in fact generate most of their lift force by
creating a vortex on the leading edge of the
flapping wing. It’s a completely different
principle of flight to conventional flight.”
It all started in 1996 with Liu’s developmentof the first computational fluid dynamics
simulation for insect flight, which led tothe discovery of the universal leading-edge
vortex mechanism in insect and bird flight.
To delve deeper, the laboratory installed an

24

ultra-low-speed wind tunnel capable of airflow as slow as half a metre a second. Theyuse it to observe and analyse the flight oflive birds and insects such as moths, beetles
and dragonflies, as well as micro air vehicles(MAVs), very small drones with potential
uses in disaster relief and covert operations.
“Using high-speed imaging and particle
image velocimetry data, we were able tocreate a computer model of an insect andits flight mechanism, and from there we
made an experimental robot insect that
actually flew. That was another pioneering
breakthrough,” says Liu.
“Our research brings together biology, engineering, computational physics, biorobotics
and neuroscience, and we collaborate withthe likes of Cambridge and the University of London on some really interesting
international, cooperative projects. Chiba
is definitely a world leader in this area witha strong interdisciplinary team and worldclass facilities.”
The lab’s research now focuses on developing insect-inspired flight systems, which heexpects to lead to big developments in thedesign of insect- and bird-size MAVs.
“For example, we think it’s wing flexibility
that gives insects much of their resilience
to wind gusts, but we are also seeing that
insects use their body much more than wethought to control direction and movement,
both actively and passively. This is completely different to the conventional wingbased control used by planes today and has
the potential to revolutionize flight control
strategies in general,” says Liu.
“Ultimately we want to develop an insect-inspired autonomous drone that is far

more reliable and agile than anything based
on today’s rotor-based technology. In 2019,
we established the Center for Aerial Intelligent Vehicles, aiming at creating innovationfrom a new mechanism of flight. In themeantime, we continue to collaborate on thedevelopment of advanced, flapping MAVs,
as well as help improve the reliability ofrotor-based drones by introducing flexible
wing technology.”

The very idea of materials that change theirshape or function as required sparks theimagination. Smart materials are impressive artificial molecules, often inspired bynaturally occurring chemicals, which have thepotential to revolutionize design. They undergo changes that are reversible and repeatable,
meaning they can function as molecularswitches, valves and sensors. Other smart
materials include shape-memory alloys that
return to their original shape after bending,metal-bearing polymers that can switch frominsulator to conductor and drug-delivery
systems that slowly release pharmaceuticals
where and when they are needed.
Researchers at the Soft Molecular Activation for Intelligent Materials program areleading investigations into catalysts madefrom soft molecules that could one day
transform smart material design.
Lead researcher Takayoshi Arai says the
program is focused on developing powerful
catalysts to create novel smart materials using three catalyst types. “Firstly, soft halogen

catalysts, predominantly using iodine, canbe used to develop highly targeted medications,” he explains. “A second type is ‘soft
Π-electron’ using carbon nanotubes andgraphene, which would provide a uniquereaction sphere for catalysis. The third type,‘soft metal’ catalysts allow us to introduce
soft elements such as gold and copper into
target molecules.”NEW CATALYST DESIGN
Arai says one of the main goals of the program is to create new asymmetric catalysts,
which are used to generate large numbersof very specific molecules. Most biologicalmolecules are chiral, meaning they exist in
one of two mirror-image forms called enantiomers. Many drugs and smart materials use
just one specific enantiomer, and so catalysts
are needed to direct the chemical reactions
toward forming the correct enantiomer.
For example, iodine has been used to help
synthesize specific enantiomers of cyclic

and ring-shaped molecules. “We are luckythat Chiba prefecture in Japan is one of theworld’s leading producers of iodine,” says
Arai. “In fact, the Chiba Iodine Resource
Innovation Center (CIRIC) has opened at
Chiba University in July, 2018. A key goal of
our program is to perfect iodine-based soft
molecular activation.”
Recent success for Arai’s team includes
the development of an aminoiminophenoxy-copper carboxylate catalyst that can
trigger high yields of O-cyclized molecules.
These can, in turn, be used to generate aparticular chiral compound that is invaluable
for use in antimicrobial and antiosteoporotic
compounds.
“A crucial part of our research is designing
catalysts that can be reused multiple times,
thereby creating cost-effective, sustainable
methods for generating useful compounds,”
says Arai. His team recently designed arecyclable catalyst made from a zinc-polymeric ligand complex. The polymeric ligand
allows the catalyst to be separated from thefinal product by a simple filtration process,meaning it can be reused — indeed, poly-Zn
remained a stable and active catalyst for
creating iodine-based ring-shaped molecules
more than five times.
“By introducing soft elements to target molecules, our research will facilitate the development of smart materials with smooth andrapid responses,” says Arai. “We welcome
anyone interested in research at the forefrontof iodine-related soft molecular activation
chemistry to come and work in this diverseand challenging field at Chiba.”© Akiko Sato

25

ADVANCED BONE-CONDUCTION COMMUNICATION

BONE-CONDUCTIONTECHNOLOGY BEYONDHEARING AID
Research Keywords: Bone Conduction, Hearing Aid, Biomedical Engineering

LYMPHEDEMA MONITOR

Members
Seiji NAKAGAWA
Professor, Center for Frontier Medical Engineering

26

cartilage conduction, and try to apply them tohearing aids and smartphones.
PERCEPTUAL MECHANISMS AND
DEVICE DEVELOPMENT
Bone-conducted ultrasonic waves canbe perceived as a sound even by severely
hearing-impaired people who cannot heareven with the use of a conventional hearing
aid. Prototype testing of an ultrasonic bone
conduction hearing device showed that, withthe use of this device, about half of severely hearing-impaired persons were able toperceive verbal sounds, and around 30% wereable to identify the words being spoken. The
cartilage conduction is technology in which
the vibrator is attached to the pinna cartilage,
and now it is applied to hearing aids forpatients with atresia of the ear canal and also
to speakerless smartphones.
The cartilage conduction and the ultrasonicbone conduction are both ground-breaking
approaches. There are still some challenges
before applying them to practical products
for widespread use: improvement of soundtransmission performance, wearability andcomfort of use, and development of industry

Members
Masahiro TAKEI
Professor, Graduate School of Engineering

Shingo KUROIWA

Yoshihiro SHIMOMURA

Shinsuke AKITA

Ryoji YAGI

Yasuo HORIUCHI

Keita ISHIBASHI

Yoshihiro SHIMOMURAMichiko SUGAWARA

Sho OTSUKA

Satoki ZENBUTSU

Nobuyuki MITSUKAWA

Akira MITSUHASHI

Takafumi SANGAITakuro HORIKOSHI

Tadashi YAMAGUCHI

Ichiro MANABE-A low-cost and easy-to-use tomography device can ensure early
detection and proper understanding of lymphedema.

Mikio SUGA

Kenji YOSHIDA“Lymphedema,” or stagnant lymph flow andabnormal swelling of the arms and legs that
may occur following the removal of lymph
nodes by surgery or radiotherapy, occurs inabout 30% of patients who had surgery for
gynecological cancers such as breast cancer
and uterine cancer. “It has been considered
as an abandoned sequela for a long time andhas only recently garnered the attention ofresearchers,” says Masahiro Takei. “The riskof lymphedema onset lasts for a lifetime,
and the condition cannot be fully cured if
detected late, so the patients are forced tohave a significant psychological burden. Fora good prognosis, early detection of stages
0 and 1 of lymphedema is critical, but there
is still no effective detection device for thispurpose.”Takei is now forming a research team ofengineering, medical, pharmaceutical, andscientific experts from Chiba University,
aiming to improve the accuracy of detection
by developing IoT lymphedema tomographic monitor with artificial intelligence (AI)system that can be used at home.

using machine learning and big data analysisof the lymphedema images. With this device, patients can check their edema stage bythemselves at home.
To elucidate the mechanism of development
and progression of lymphedema, not only
engineering and medical knowledge but also
pharmaceutical and scientific considerations
are crucial. By implementing the knowledge
gained from such integrated research to theprototype, Takei’s team aim to improve theaccuracy and convenience of the machine.
“Ultimately, we want to visualize the medical condition in real-time on a mobile device
and to reduce the pain of patients.”

Masashi SEKINE-Elucidating the perceptual mechanisms of ultrasonic bone conduction
and cartilage conduction with a view to new device development.
Against the background of the aging society
and diversifying lifestyles, there is a growing need for a broader range of options inhearing aids and audio devices. Among thevarious technologies used for hearing aids,bone conduction has mainly been used forcompensating conductive hearing loss causedby middle or outer ear disorders. In recent
years, the incidental benefits of bone conduction technology, such as benefits in speech
perception under noisy conditions, less soundleakage, and usability in water, have come toattract attention. However, the perceptual
mechanism of bone conduction is complicated and has yet to be fully understood.
“The sound we usually hear through ourearholes is called air conduction. While there
is only one pathway for air conduction,
there are at least four pathways available forbone conduction,” says Seiji Nakagawa. “Theperceptions of bone-conducted sound largely
changes according to frequency and location,
and at times differ largely from the soundperceptions by air conduction.” Nakagawa
and his team are working to elucidate auditory perceptual mechanisms with a focus on
ground-breaking bone conduction phenomena, including ultrasonic bone conduction and

MAKING INVISIBLE
LYMPHEDEMA VISIBLE

standards and hearing-related safety standards. Fundamental understanding of theperceptual mechanisms is essential to solving
these challenges.
“Research on ultrasonic bone conduction
and cartilage conduction have just begun,and most of their perceptual mechanisms
are still unknown. For example, the mechanisms of how the bone-conducted ultrasonicwaves are propagated and easily perceived areunclear when the vibrator is attached to theneck, chest, or even the upper arm. Most of
the technical challenges of bone conduction
cannot be solved without understanding theperceptual characteristics and propagation
process of bone conduction.”
Nakagawa believes that if he advances bone
conduction technology based on a deep
understanding of such mechanisms, it opens
up possibilities for new applications.
“For example, we are now going to develop
bone conduction headphones and microphones that can be used even under severely
noisy conditions, and an earphone for infants
who often resist the use of conventional
earphones or headphones. Furthermore, bone
conduction is also suitable as an interface forsmart glasses, which people think to be thenext-generation information terminal.”“Chiba University has many faculty memberswith expertise and knowledge in humaninterface technology and acoustic signal
processing. We can develop new devices bybringing those strengths together for projects
centered on bone conduction technology.
We also have collaborative partnerships withbusinesses in Japan and abroad and hope toachieve innovation by pursuing fundamental
research for mechanism elucidation as wellas the development of practical applications,”
says Nakagawa.

Research Keywords: Electrical Impedance Tomography (EIT), lymphedema, Cloud Computing

A SMALL ELECTRIC TOMOGRAPHY
As a mechanical engineer, Takei’s belief is“to make invisible things visible by using amachine.” So far, he has been working on
developing hardware and software related
to electrical tomography. Tomography refers
to cross-section visualization measurement,
as in computed tomography (CT). Medical
CT is a large machine that costs hundredsof millions of yen, and it is impossible forpatients themselves to use it easily at home.
This challenge has been recognized aroundthe world. In the 1990s, the theoreticalconstruction of a new electric tomographybegan at the University of Manchester, UK.
Takei had also participated in this projectcalled “European Action.” Several challenges
occurred during this project, and the member researchers tried to solve these problems
one by one. They developed the sensors, theelectrical circuits to reduce noise and speeding up, the image reconstruction softwarewith mathematical inverse problem-solving
capability, and proceeded with developing
the appropriate procedures for industrial
and biological use. However, the prototype
equipment had cost millions of yen, and theaccuracy was not sufficient for practical use.
“At that time, I thought it would be innovative if we could easily see our inside of
the body with a machine that costs aroundtens of thousands of yen,” says Takei. Thus
emerged the breakthrough technology—asmall electric tomography with diagnostic
function. The new system works as follows:
several electrodes are placed on the body, anda weak electric current is passed through the
body. The system produces images showing
the distribution of conductivity and dielectric constant in the body at each frequency
using a wearable sensor to measure thepotential, small hardware, and mathematicalalgorithms.
Currently, Takei’s research team is working
on developing an easy-to-use IoT lymphedema tomographic monitor. First, withthe monitor, impedance data measured by asmall unit from the multi-electrode winded
sensors are sent to the cloud computing
unit. Next, 4D images of limb cross-sections
are reconstructed at high speed on the cloudusing specialized software. Finally, edema(including early-stage edema) is diagnosed

27

Medical andPharmaceutical
Sciences
PHYTOCHEMICAL PLANT MOLECULAR SCIENCES

Unlocking the Potential of Phytochemicals

CANCER EPIGENOME CENTER

A Different Approach to Fighting Cancer

MEDICAL MYCOLOGY RESEARCH CENTER

Manipulating Microbes for Human Health

MEDICINE FOR RARE DISEASES

Innovative Approach Offers Hopefor Intractable Problems

GLYCOMEDICINE RESEARCH CENTER

Sugar Science’s Immunotheraphy PlayLABORATORY OF DDS DESIGN AND
DRUG DISPOSITION

Big Hopes for Nanotechnology Based
Drug Delivery Systems
INTERNATIONAL HUB FOR METALLOMICS RESEARCH

Understanding the function of biometals forhuman and environmental health© iStock.com/BlackJack3D

PHYTOCHEMICAL PLANT MOLECULAR SCIENCES

CANCER EPIGENOME CENTERUNLOCKING THE POTENTIAL
OF PHYTOCHEMICALSA DIFFERENT APPROACH
TO FIGHTING CANCER

Research Keywords: Plant Molecular Science, Phytochemical, Gene

Research Keywords: Cancer, Epigenome, Inhibitor

Members
Atsushi KANEDA
Professor, Graduate School of Medicine-Advanced genetic and genomic techniques
are transforming our understanding of how
phytochemicals can improve human health.

-A new center aims to combat cancer by rewriting
the epigenetic modifications harbored by tumor cells.

Ichiro MANABE

Tomoaki TANAKA

Tetsuhiro NEMOTO

Kiyoe URA

Hisahiro MATSUBARA

Ichiro YOSHINO

Hideki HANAOKA

Tomohiko ICHIKAWA

Hiroyuki MATSUE

Emiko SAKAIDA

Toyoyuki HANAZAWA

Yoko SHINAGAWA© iStock.com/mashuk

ENLISTING PHYTOCHEMICALSTO FIGHT DISEASE

Members
Kazuki SAITO
Director, Plant Molecular Science Center

Mami YAMAZAKI

Naoko YOSHIMOTO

Amit RAI

Hiroki TAKAHASHI

Daisuke UMENO

Takashi TSUCHIMATSU

Hajime SATO

Kohji ITO

Masami ISHIBASHI

Mariko KITAJIMA

Akiko TAKAYANoriyuki KOGURE

Tomoko IGAWA

Mitsumasa HANAOKA

Eiji GOTO

Natsuko KAGAWA

Takashi SHIMADA

Hidenori SASSA

Yasumasa HARA

Shinji KIKUCHI

Taira MIYAHARA

Takanori SAITO

Since ancient times, people have used thenatural compounds in plants, known as phytochemicals, for medicinal and nutritional use.
Now, scientists at Chiba University are using
advanced genetic and genomic techniques
to verify how phytochemicals are generated
in plants, how they can be manipulated to
optimize certain plant groups, and how they
may help tackle lifestyle- and aging-relateddiseases.
Plants naturally generate chemicals for various
purposes, including for attracting pollinatorsand defending themselves. These specialized
metabolites allow plants to colonize specific niches in the food chain, adapt to newenvironments and evolve to survive potential
stressors. Crucially, phytochemicals also exhibit
properties that can help treat human diseases.
Examples in modern medicine include morphine, the antimalarial drug artemisinin andchemotherapy agents derived from taxanes.

30

Kazuki Saito, who leads the Phytochemical
Plant Molecular Sciences program, says that
because phytochemicals display considerable
natural diversity, they have huge potential
to fight disease. “Although phytochemicals
have been used in pharmaceuticals andancient remedies for many years, it is only
now, with the advent of next-generation
DNA sequencing, that we can really begin
to understand how they work and unlock
their full potential,” says Saito.
The program consists of three collaborative research groups, each working on a
specific theme.
One group is focusing on the genomics of
medicinal plants and food crops with the
key aim of revealing the genomic principles
of phytochemical production. Employing
state-of-the-art technologies, the researchers
identify and clarify the roles of unknown
genes, as well as investigate plant metabolism.
In 2016, Saito’s team assembled a draft
genome for licorice (Glycyrrhiza uralensis),which is used worldwide as a natural sweetener and a medicinal component.
They identified several components known
to play a positive role in human healthwithin the plant, while pinpointing key
genes, the manipulation of which could leadto crop improvements.
The second team is identifying novel phytochemicals and active products in a wide
variety of plants, searching for drug components to tackle diseases such as cancer,
dementia and diabetes. As well as isolating
and analyzing promising molecules, thegroup conducts animal trials to assess thepharmaceutical potential of molecules. In
particular, they have extensively investigatedLycopodium alkaloids (LAs), molecules
found in the vascular plant Lycopodiaceae,
which may help to treat Alzheimer’s disease
and schizophrenia.
The third group is investigating how
plants respond to different environmental
stresses by growing plants in different artificial environments and monitoring their
responses to change.
“Our aim is to optimize plants so that they
produce high-quality phytochemicals that we
can harvest for use in medicines and functional foods,” explains Saito. “Our insights
will enable us to grow rare plants more
successfully and will also inform agricultural
practices for commercial crops in the future.”
While the group is focusing on phytochemicals, it also conducts wide-ranging interdisciplinary studies and hence welcomes
researchers and students with backgrounds
in chemistry, horticulture, genetics andpharmacy who are interested in this exciting
and rapidly developing area of research.

Cancer is thought of as a genetic disease,with mutations to a cell’s DNA causing
a normal cell to give birth to a malignant
tumor. Yet epigenetic alterations, whichleave the DNA sequence intact, can be justas important in a cell’s transformation tocancer. Even though epigenetic regulation
through mechanisms such as methyl tags
and histone modifications does not alter the
DNA sequence, it can chemically modify
the genome to signal which genes should beturned on and off. When tumor-suppressor
genes are silenced or oncogenes are activatedin this way, many different forms of cancer
can result.
Fortunately for medicine, epigenetic
alterations are not permanent. They can beundone to prevent or reverse cancer, leaving
a cell with its entire complement of normal
DNA intact.
This is exactly what researchers at theCancer Epigenome Center are striving to
do. Led by Atsushi Kaneda, the center isseeking to understand the various epigenetic
drivers that contribute to different typesof cancer and then develop new drugs that
overturn these effects.
“We will explain key epigenomic aberrations
and their molecular causes,” says Kaneda.
“And then, taking advantage of small molecules that bind to DNA in a sequence-specific manner, we will develop drugs thatcan rewrite the accumulated epigenomic
aberrations or prevent them accumulating intargeted genomic regions.”

UNRAVELING MOLECULARMECHANISMS
Kaneda points to ongoing investigations ofgastric cancer as an example of this strategy
in action. Patients with this cancer exhibit
different levels of DNA methylation in theirtumor cells, depending on the pathogen
responsible for the disease. The cancer-causing
bacterium Helicobacter pylori is one sourceof irregular methylation. Epstein-Barr virus
is another pathogen of gastric cancer, which
not only inactivates tumor suppressor genes by
inducing extreme DNA hypermethylation, butalso activates proto-oncogenes via an epigenetic mechanism the research group has named“enhancer infestation” (Nat Genet 2020).
Kaneda and his colleagues are using clinicalsamples and cell experiments to unravel themolecular mechanisms that induce hyperactive
methylation patterns following infection withthese pathogenic agents. They ultimately hopeto stop the process in its tracks. Similar projects are ongoing to combat colorectal cancers— which Chiba researchers have shown canbe categorized into three types, depending on
methylation levels — as well as blood cancers
and other types of tumor.
With an eye to developing novel therapeutics,
chemists at the Cancer Epigenome Center
are working on new methods to efficiently
synthesize molecules that can act on epigenetic aberrations. One such group of molecules isthe pyrroleimidazole polyamides. These molecules can bind to DNA at specific sites in the
genome, and when coupled to an epigenetic
inhibitor they can prevent methylation-based
gene silencing. Kaneda hopes to deploy themolecules to edit the epigenome at targeted
regions to regulate tumor formation.

The Cancer Epigenome Center includes
researchers from a wide range of backgrounds
and specialties. This multidisciplinary teamapproach, says Kaneda, is essential for turning
the center’s discoveries into clinically meaningful treatments and diagnostic tools. “Wewill help determine the mechanisms ofcancers and develop new cancer drugs throughcollaborating with experts in medicine, physics
and pharmacy,” he says.

© iStock.com/vitanovski

31

MEDICAL MYCOLOGY RESEARCH CENTER

MEDICINE FOR RARE DISEASESMANIPULATING MICROBESFOR HUMAN HEALTHINNOVATIVE APPROACH
OFFERS HOPE FORINTRACTABLE PROBLEMS

Research Keywords: Infection and Immunity, Microbiota, Superorganism

Members
Mitsutoshi YONEYAMA
Professor, Medical Mycology Research Center-Detailed investigations of host–microbe interactions
could yield new therapies against infectious agentsand
autoimmune diseases.

The human body is made up of a staggering
30 trillion cells or so. But just as numerous, if
not more so, are the several hundred trillionsof microbial co-inhabitants that teem in andon us. These microbiotas are essential to ourwell-being, and a distortion in its balance cantrigger a wide range of disorders.
Only recently, however, have scientists cometo appreciate just how critical this collectionof microbiota is for determining humanhealth and disease. They are also becoming
excited about the prospect of how manipulating this microbial ecosystem could form thebasis for the next generation of life-saving
therapeutics. Led by Mitsutoshi Yoneyama,
researchers at the Medical Mycology Research Center have launched a comprehensive research effort to dissect the intricacies
of host-microbe interactions in the skin, lung,intestines, and bone marrow.
“Dysregulation of host-microbe interactions
can give rise to a wide variety of humandisorders, including opportunistic infections,allergies, and autoimmune disease,” explains
Yoneyama. “It is hence crucial to understand32

how hosts and commensal microbes communicate as a superorganism.”
Creating a superorganism is an apt metaphor for what Yoneyama is trying to achieve
because, through the melding of minds fromacross Chiba and around the world, thecenter can make a far greater impact than any
individual scientist working independently.
At Chiba University, the investigators comefrom the Medical Mycology Research Center,
the Graduate School of Medicine, and the
Graduate School of Pharmaceutical Sciences,while external collaborators are based in the
United States, Germany, and elsewhere in Japan. These scholars, together with others fromaround the world, convene each November
at the Medical Mycology Research Centerfor the annual Global Network Forum on
Infection and Immunity.
EXPLORING HOST–MICROBE
INTERACTIONS
The team that Yoneyama has put together
is roughly divided into four groups, each

Shinobu SAIJO

Koichi HIROSE

Tomohiro TAMACHI

Akiko TAKAYA

Yoshiyuki GOTO

Hiroshi ASHIDA

Kinnosuke YAHIRO

Arifumi IWATA

Koji ONOMOTO

studying molecular interactions in different
host-microbial systems. One, led by
Shinobu Saijo, is focused on fungal andbacterial infections in the skin of mice andhumans; another, led by Koichi Hirose,
Tomohiro Tamachi, and Arifumi Iwata isinvestigating the microbes — both goodand bad — that reside in the respiratory tract. A third group, which includes
Yoshiyuki Goto, Hiroshi Ashida, andKinnosuke Yahiro, is concentrating on thegut microbiome and how opportunistic
intestinal infections gain a foothold; while
the fourth, led by Akiko Takaya, isworking on more basic mechanisms of
immunological memory in response to
microbial invaders.
“Results obtained from our projects will
help efforts to create innovative newtherapeutics against infectious diseases andwill eventually lead to improvements inhuman health,” says Yoneyama, whose own
research focuses on the mechanisms ofinnate antiviral immunity with Koji
Onomoto.
To assist all these research projects,
investigators from each group have accessto the Japanese government’s networkof core facilities — a resource known as
the Joint Usage/Research Center, whichis staffed by specialized researchers andtechnicians who can run state-of-theart experiments, including with fungi andother microbes. A bioinformatics unit at
Chiba led by Hiroki Takahashi helps withcomputational analyses.

Research Keywords: Rare Disease, Intractable Cancer, iPS Cell

-The ReDenim network is developing therapies totreat rare and intractable diseases.

TWO-PRONGED APPROACH

Members
Shinichiro MOTOHASHI
Professor, Graduate School of Medicine

Hideki HANAOKA

Koji ETO

Itsuko ISHII

Masayuki KURODA

Kiyoshi HIRAHARA

Kotaro SUZUKI

Sonoko MISAWA

Katsunori FUJII

Scientists at Chiba University have along track record of excellence in clinicalresearch, particularly for investigations inpatients with immune-related diseases.
And Chiba University researchers havemade a number of important breakthroughs
in basic immunology and disease biology.
However, connecting these two areas, afield known as translational research, hasoften been less successful.
That is a problem that Shinichiro Motohashi wants to fix. Motohashi leads Chiba’s
Research and Development Network of
Innovative Medicine for Rare and Intractable Diseases — ReDenim. The network isaiming to provide the clinical support andresources needed to take discoveries fromthe lab to the clinic.
In particular, ReDenim has singled out two
disease areas for which there are currently
no good treatment options — deadly formsof cancer, such as head and neck tumors;and rare diseases that each afflict fewer than
50,000 people in Japan, but collectively
affect about 10 percent of the population.

Motohashi belongs to the tumor immunity
team, which intends to capitalize on Chiba
University’s expertise in developing cellbased immunotherapies. Their approach
uses tumor-destroying natural killer T-cells
to search for combination therapies thatcan further modulate the tumor immune
microenvironment in a favorable way. They
also intend to identify biomarkers that can
predict how individual patients will respondto these treatments.
Led by Sonoko Misawa, the rare-diseaseteam, including Masayuki Kuroda and
Katsunori Fujii, is using immune-modulating drugs and gene therapies to address
immune-related peripheral nerve disease
and hereditary disease. Kotaro Suzuki andKiyoshi Hirahara are aiming to develop newtreatments based on the analysis of pathological conditions using animal models of
autoimmune diseases and tissue fibrosis. Koji
Eto and his collaborators of orthopedics andplastic surgery, Seiji Ohtori, Sumihisa Orita,
Yasuhiro Shiga, and Nobuyuki Mitsukawa,are developing a new method of woundhealing using platelet-rich plasma derived
from iPS cells. Kuroda is also working
with the tumor immunity team to developtransgenic adipocyte technology that canbe applied to cancer treatments, in addition
to his research target, hereditary metabolic
diseases.
Importantly, both teams will share researchexperiences, technology platforms and manufacturing facilities. “Sharing the know-how
to treat each disease within the network will
accelerate drug development,” says

Motohashi. And the two teams will also
have access to support units at the university’s Core Clinical Research Hospital, a designation granted to Chiba University underJapan’s Medical Care Act. Hideki Hanaoka
and Itsuko Ishii develop the support units
to apply basic science toward therapeutic
applications.
This support includes consultation services
on issues such as intellectual property,
project management, clinical trial designand other steps needed to fulfill the promiseof translational medicine. “Our ultimate goal
is to form a therapeutic cluster that can beapplied to a wide variety of rare and intractable diseases,” Motohashi says. He can evenforesee a day when the infrastructure createdthrough ReDenim could be used to develop
new therapies for common diseases, such as
diabetes or lung cancer.
Judging by the progress they have made sofar, Motohashi and his coworkers are well on
their way to fulfilling their dream, and theirpotential is widely recognized. ReDenim has
already forged collaborations with some of
the world’s leading experts in cancer immunotherapy and rare diseases, and is working
with Japanese drug companies to partner on
additional research projects.

33

GLYCOMEDICINE RESEARCH CENTERLABORATORY OF DDS DESIGN AND DRUG DISPOSITION

SUGAR SCIENCE'S
IMMUNOTHERAPHY PLAY
-By bridging the gap between glycoscience and medicine,major advances in immunology and drug development
are imminent.

Motoyuki ITOH

Noritaka NISHIDA

Hirofumi DOHI

Noritaka YAMAGUCHI

Research Keywords: Drug Delivery, Nanobio, Vaccine

Yasunori MATSUMOTO

glycans produced by two enzymes —N-acetylglucosamine-6-O-sulfotransferase
1 (GlcNAc6ST-1) and GlcNAc6ST-2 —are essential for the binding of lymphocytes,
and consequently play a vital role in controlling lymphocyte homing in mice.
After working on this study at California’s
Burnham Institute, Kawashima returned
to Japan in 2005, bringing with him the‘knockout’ mice (deficient in the two key
enzymes) he had developed. At Chiba hehas used these to continue hunting for new
antibodies that target glycans.
GLYCOMEDICINE TAKES OFF
Today, the expanding fields of glycoscience(the study of glycans) and glycomedicine(combining glycoscience and medicine) areleading to breakthroughs in drug development and diagnostics for autoimmune
diseases.
Chiba University’s Glycomedicine ResearchCenter, which opened in August 2017, marksa shift towards accelerating such breakthroughs in Japan.
“Many researchers here at Chiba University have been working independently on© Akiko Sato

34

Hiroto KAWASHIMA
Professor, Graduate School of Pharmaceutical Sciences

Research Keywords: Immunology, Biochemistry, Glycobiology

Lymphocytes are the body’s warrior cells.
They circulate through the bloodstream
and arrive at sites in the body such as thespleen and lymph nodes, where they combat
harmful bacteria, viruses and even cancer
cells. Sugars, or glycans, are integral to thismigratory process called lymphocyte
homing, which is of intense interest to
researchers. These scientists hope to target
glycans to find new immunotherapies anddrugs for autoimmune diseases.
“We now know that glycans — chains ofsugar molecules that have diverse functions in our bodies — play an essential
role in lymphocyte homing,” says Hiroto
Kawashima, a professor at Chiba University’s Graduate School of Pharmaceutical
Sciences, Laboratory of Microbiology and
Immunology.
“These glycans are found on the surfaceof endothelial cells in lymph nodes,” heexplains. “Thanks to glycans, lymphocytes
recognize and bind to the surface of thosecells.” Lymph nodes activate lymphocytes
to fight disease.
In a study published in Nature Immunology
in 2005, Kawashima and his colleagues inJapan and the United States showed that

Members

BIG HOPES FOR
NANOTECHNOLOGY BASEDDRUG DELIVERY SYSYEMS

glycans,” Kawashima says. “Some specialize
in biological functions, while others focus onsynthesis or analyze glycan structures. The
idea is to bring all of these researchers together, build new collaborations and understandthe function of glycans across many
biological phenomena.”
The new centre has plans to collaborate
with teams both nationally, for example, at
the Glycomedicine Technology ResearchCenter and the National Institute of Advanced Industrial Science and Technology(AIST), and internationally.
Already, Kawashima has developed antibodies that will specifically bind to the building
blocks of glycans and disable them in studies
published in The Journal of Biological
Chemistry in 2010 and 2015. This could halt
the dysfunctions involved in autoimmune
disease, in which the immune system isoverreacting.
“Usually, it’s very difficult to generate monoclonal antibodies against carbohydrates,”says Kawashima. This difficulty in producing
clones of these antibodies is because carbohydrate antigens are not generally very antigenic. “To get around this problem, we immunized knockout mice with cells expressing themissing sugar chains, which are highly prone
to stimulating the production of antibodies.”
The next step will be to further investigate andidentify new ideas for drug development andto collaborate with pharmaceutical companies
to bring them to market.
“Right now, there are lots of antibody drugs,”
says Kawashima. These immunotherapies
target issues such as rheumatoid arthritis andcancer, but, he says, new advances are limited
by a shortage of molecules to target. “Glycans
have unexplored potential, so this is an exciting time to be looking into developing new
candidate drugs based on glycoscience.”-Drug delivery systems that nanocarriers could enhance theeffectiveness of therapies ranging from genetics-based cancer
treatments Alzheimer's medicines.

© iStock.com/Dr_Microbe

Drug delivery systems that nanocarriers could
enhance the effectiveness of therapies ranging
from genetics-based cancer treatments to
Alzheimer’s medicines.
Personalised medicine — tailoring medical
treatments to individual needs — may nolonger be far-off.
Developments in nanocarriers have progressed
rapidly, promising targeted delivery andrelease of nucleic acid-based drugs (NABDs),an emerging class of therapeutics designed totarget diseases at the genetic level.
A BREAKTHROUGH MOLECULE
In 2013, Akita’s group reported on SS-cleavable Proton-Activated Lipid-like Material(ssPalm), a molecule designed and tested
over five years that showed promise fordrug delivery.
The molecule itself consists of two main
components: One, tertiary amines, are activated in response to an acidic environment,such as the endosome compartment inside
the cells of plants and animals. These activat-

ed amines enable membrane destabilisation.
The other, a disulfide bond (SS) that can becleaved in a reducing environment such as in
the cytoplasmic material inside cells, triggers
the release of NABDs in specific cells.
In proof-of-concept studies in mice in 2016,
the researchers showed that lipid-based
nanoparticles, formed using ssPalm, enabled
efficient delivery to the liver of a genetic
treatment that uses small interfering RNA.
They have since gone on to develop second-generation ssPalm, which uses Vitamin
E as a waterproofing scaffold (ssPalmE).
One of the biggest challenges for cancer
therapeutics researchers, Akita explains,
will be “to develop DNA- and RNA-based
vaccines that could target unique genetic
changes in individual cancers.”
The hope is that the versatility of ssPalm
could help maximise drug efficacy while
reducing side effects. For example, in mousestudies performed in 2018, Akita’s groupdemonstrated that a plasmid DNAencapsulating lipid nanoparticle (ssPalmE-LNP) induced anti-tumour effects. They

Members
Hidetaka AKITA
Professor, Graduate School of Pharmaceutical Sciences

Akihiro HISAKA

Naohiko ANZAI

Kousei ITO

Takeshi MURATA

Kunikazu MORIBE

Satoshi OGASAWARA

Hiroki TANAKA

Kenjirou HIGASHI

Keisuke UEDA

Shigeki AOKI

Hiroto HATAKEYAMA

Hiromi SATO

Yu SAKURAI

also showed that ssPalmE-LNP enhanced
the therapeutic effect of an antibody used
to combat immune system supressing
programmed cell death protein 1 (PD-1),
raising hopes for combination therapies tocombat cancer.
Brain disorder treatments also stand tobenefit from nanocarriers. Recent studies
suggest that using ssPalm as an alternative
to viruses that deliver genetic material
could improve treatments.
In experiments with Hokkaido University
in 2018, Akita’s team used ssPalm in thedelivery of messenger RNA (mRNA) toneurons and astrocytes — star-shaped cells
found in the brain and spinal cord increasingly implicated in neurodevelopment anddisease.
By surpassing the limitations of other forms
of delivery (such as DNA-based artificial
gene carriers), mRNA therapeutics could
be used to treat many conditions, including Alzheimer’s, Parkinson’s, Huntington’sdisease and other neurological disorders.
“Our strengths at the Faculty of Pharmaceutical Science include our expertise incharacterizing physicochemical properties,
and evaluation of pharmacokinetics andpharmacodynamics, as well as safety,” Akita
explains. These skills could potentiallycontribute to a wide range of fields he says,
including immunology and cancer research.
“We need to keep our eyes open to societal
needs,” Akita adds. “Until now, we havebeen concentrating on materials science.
We have only just begun to enter the arenaof nucleic acid-based therapeutics. I believe
innovations arise when you can look beyond
your own particular filed, and apply originaltechnologies in unexpected ways.”35

INTERNATIONAL HUB FOR METALLOMICS RESEARCH

Research Keywords: biometal science, metallomics, theranostics

INSTITUTE FOR
GLOBAL PROMINENT RESEARCH
To accelerate innovative research beyond the borders of academic disciplines, theMembers

IGPR was founded at Chiba University in 2016 as a core institution for world-lead-

Yasumitsu OGRA
Professor, Graduate School of Pharmaceutical Sciences

Tomoya UEHARA

Noriyuki SUZUKI

Yasunori FUKUMOTO

Yuki TANAKA

Biological phenomena are recognized as a collection of organic chemical reactions consistingof carbon, hydrogen, oxygen, and nitrogen.
A trace amount of metals, such as iron, zinc,copper, and selenium, play an important rolein controlling these reactions. These metals
specifically required for physiological reactions
are called “essential metals.” Contrary to theessential metals, some metals disturb the physiological reactions. Since there are many industrially useful “non-essential metals” in our daily
life, some non-essential metals are the risk inhuman and environmental health. In addition,
excess amounts of essential metals also disturb
the physiological reactions. Hence, organisms
have the mechanisms underlying the distinctionof essential and non-essential metals, and thehomeostasis of essential metals. The disturbanceof the mechanisms results in critical problems
in human and environmental health.
Metallomics is a study of metallome whichmeans metal-containing biomolecules. Metals
can induce various physiological and toxicological effects in a very small amount, in otherwords, the metal concentrations are very low inorganisms. Thus, analytical techniques for a trace
amount of metals are crucial to understand thebiological and toxicological functions of metals.
36

RESEARCH IN METALLOMICS IS
UNDERPINNED BY UNIQUE ANALYTICAL TECHNIQUESThe research group made discoveries based ona unique biometal analytical technique. “Ourmethod is the only analytical technique formeasuring biometals. We aim to expand applications by refining existing methods to enablebiometal analysis at a single cell level, whereas
prior biometal analysis was performed at thelevel of tissues or organs,” says Yasumitsu
Ogra, the leader of this project.
One of these single cell-level analyses specified the function of metal nanoparticles, orbiogenic nanoparticles, which are produced
by organisms. It has been generally understood that organisms take in, use, and secrete
metals as ions, and they do not replace metal
ions with metal elements. However, certain
micro-organisms, higher-order plants, andanimals show an exception.
“Our analytical technique revealed that higher
plants and animals exhibit a common mechanism to convert metal ions into elements
which involves detoxification of the ions of
non-essential metals and excess amount ofessential metals. In other words, they detoxify

impact as a global hub for world-class research.
The institute is also focused on the capacity development of young researchers-Metallomics opens new frontiers in eco-toxicology, disease
prevention, drug discovery, and medical diagnosis and therapy.

© Akiko Satoing research. IGPR has been actively supporting research projects with potential

who will lead new research fields in the next generation. Currently, IGPR is supporting more than 20 research projects in diverse areas.
metal ions to elemental nanoparticles.” Investigating this mechanism requires a techniquethat can measure metal nanoparticles inhigh-matrix biological samples. Ogra andothers are confident that they can establish
this technique and are looking ahead to apply
it for bioremediation, resource recovery (biomining) and in the field of medicine. Previous
technologies have used plants to eliminate
toxic metals and recover useful metals fromthe environment. Recovering these metals as
elements instead of ions will be significantly
more efficient than existing techniques.
“The technique that we are trying to establish to measure metal nanoparticles can be
developed for the accurate measurement ofelements in individual cells.” If a techniquethat quantifies the metal concentrations inindividual cells can be established, we can havea more detailed understanding of pathologies involving metals. It is anticipated that in
the future, applications will prevent diseases
through AI using big data obtained fromperipheral cells on elements in individual cells.
This research project also entails research on
the production of metal-containing drugs
using the unique physicochemical properties of elements in the bottom half of theperiodic table, which have been seldom used
as medication. They will conduct researchon practical application of theranostics that
employs radioactive metals to develop a novel
medical technology for simultaneous diagnosis
and treatment. Furthermore, the group led by
Tomoya Uehara will continue their researchin the field of diagnostics and treatment withradioactive metals, using a SPECT/CT device
for small animals. This research project willserve as a comprehensive research hub thatunravels the relationship between organisms
and metals.

TEL : +81-43-290-2916
Mail : gp-office@chiba-u.jp
URL : igpr.chiba-u.jp/global

ACADEMIC RESEARCH &INNOVATION MANAGEMENTORGANIZATION (IMO)
IMO was established in 2020 at Chiba University as a hub to enhance academic research and collaboration between industry, academia and government. IMO fosters
innovation by strengthening fundamental and advanced research, cross-sectoralcollaboration, and venture support system.
URL: imo.chiba-u.jp

Research Promotion Division
Tel: +81-43-290-3833
Mail: ccrcu@faculty.chiba-u.jp
Intellectual Property Strategy Division
Tel: +81-43-290-3831
Mail: beo3566@office.chiba-u.jp
Venture Support Division
Tel: +81-43-290-3519
Mail: bex4680@chiba-u.jp© iStock.com/farakos

UNDERSTANDING THE
FUNCTION OF BIOMETALSFOR HUMAN ANDENVIRONMENTAL HEALTH

37

RELATED RESEARCH CENTERSMESSAGE FROM
THE DIRECTOR OF IGPR

· Center for Environmental Remote Sensing· Medical Mycology Research Center· Soft Molecular Activation Research Center,
Chiba Iodine Resource Innovation Center· Molecular Chirality Research Center· Center for Frontier Medical Engineering· Center for Environment, Health and Field Science· Research Center for Child Mental Development· Plant Molecular Science Center· International Center for Hadron Astrophysics· Center for Aerial Intelligent Vehicles· International Center of Excellence in the Mucosal Immunology
and Innovative Allergy Therapeutics· Center for Artificial Intelligence Research in Therapeutics· Shanghai Jiao Tong University and Chiba University
International Cooperative Research Center

Takeshi Tokuhisa

and walls by sensing airflow fluctuations

the projects. Associate Professor Genya

generated by mosquitoes. This study

Kobayashi, who is leading the project

was published in Science and widelyon small area estimation and its applica-featured in national newspapers.

tion, has analyzed the data of coronavi-

Professor Takayoshi Arai, who is leading

rus infection using statistical models tothe project on soft molecular activation,

estimate the effects of behavior change

has succeeded in catalytic asymmetric

before and after the state of emergency

iodoesterification from simple alkene

declared by the Japanese government

substrates and carboxylic acids. Pub-

and to predict infection outbreaks.

lished in Angewandte Chemie Interna-

Starting in October 2020, the bioin-

President of Chiba University

tional Edition, this new research wasspired engineering research project led

accomplished by precisely controlling

by Prof. Hao Liu held a VR exhibition on

multiple interactions in a single catalytic

drones where you could learn the tech-reaction and is expected to contributenology developed by the project as wellto the development and improvement

as the history of aviation and the de-of medicines.

velopment of robotics technology. This

Professor Hidetaka Akita and Assistantunique and interactive virtual exhibition

Professor Hiroki Tanaka have been re-

has attracted many visitors. In addition,

searching nanotechnology-based drug

IGPR held a symposium in November

delivery systems. They have successfully

2020 as part of IGPR’s initiative to foster

developed a lipid-like material thatthe development of next-generation

self-degrades after being taken into

researchers. The symposium served as acells. This study published in Advanced

platform for young researchers engaged

Functional Materials is expected to be

in IGPR research projects to brush up

applied in systems that deliver various

their skills and effectively communicate

drugs to target cells. The cancer epig-

their findings to people outside of theirenome research team led by Professor

specialization.

Atsushi Kaneda has studied the mech-

Through promoting world prominentanism of how Epstein-Barr virus (EBV)

research at IGPR, Chiba University

infection causes gastric cancer. Pub-continues to make vital contributions tolished in Nature Genetics, this researchsociety. I strongly hope that this issue ofwill contribute to elucidation of the

CHIBA RESEARCH will help you gain acauses and establishment of treatment

deeper appreciation of the University’s

methods for cancers involving the virus.

cutting edge research activities.

you that the 2021 edition of CHIBARESEARCH is now available. All of theresearch projects introduced in thisissue have been carried out with thesupport of the Institute for Global Prominent Research (IGPR), a university-wideorganization of Chiba University. IGPR
was established in 2016 with the goal
to enhance prominent international research projects of Chiba University andfoster the development of young scientists who will lead the next-generation
research. This is an original attempt tobring together research resources fromall sources throughout the university,and support and promote high-quality
research in a wide range of disciplines.
© iStock.com/farakos

to take different measures to implement

Director, IGPR and

It gives me great pleasure to inform38

a new mechanism for detecting floors

The projects have produced many innovative research outputs and findings.
Assistant Professor Toshiyuki Nakata,
who is working on the bioinspired engineering research project, has proposed

Due to the worldwide spread of the newcoronavirus in 2020, we were required

39

HOKKAIDOWHERE ISCHIBA UNIVERSITY?

ABOUT
THIS MAGAZINETOHOKUCHIBA Prefecture is located at the east edge of the South

Copyright © 2021 Chiba University.

Kanto region. It has a population of approximately 6 mil-

All rights reserved.

lion, the 6th largest among the 47 prefectures in Japan.

Chiba is the center of Keiyo Industrial Area and has the

KANTO

well-developed industry. The three sides of the prefecture

Design and layout:

CHUBU

are surrounded by the sea, which helps Chiba's growth inIkjoon Chang, Takumi Satothe seafood industry as well.

Editing and coordination:

CHUGOKU

Chiba University has 4 campuses in Chiba Prefecture.

Midori Ishii, Ayako Shimura

KANSAISHIKOKU
KYUSHU

Nishichiba Campus (Main Campus) is located between Na-rita International Airport and Tokyo Station. It takes about

Narita Airport

30 to 40 minutes by train to Tokyo Station and also Narita

The information in this publication

Tokyo

International Airport.

was correct at the time of going

Chiba
University

to press in January 2021. The views
expressed by contributors in thispublication are not necessarily

PUBLIC TRANSPORTTO CHIBA

those of Chiba University.

1. KASHIWA-NO-HA CAMPUS

Fuchuhonmachi

5-min walk from the Tsukuba Express Kashiwanoha-campus

Kashiwanoha Campus
Minami-Nagareyama
Kita-SenjuA Matsudo

biko

KASHIWA-NO-HACAMPUS

Tsukuba

Suido

MATSUDOCAMPUS

Nippori

Station.

Take the Tobu bus bound for National Cancer Center or

Kashiwanoha Park from bus stop No2 at JR Kashiwa Station or near the east exit of Tobu Kashiwa Station.

2. MATSUDO CAMPUS
Ueno
MitakaShinjuku

10-min walk from Matsudo Station

Ichikawa

Akihabara
Tokyo
Hamamatsu Cho
Minami-Funabashi
Shinagawa(JR Joban line, Tokyo Metro Chiyoda Line, Shin-Keisei Line)

Shin Kamagawa
Nishi-Funabashi
Narita Airport

Funabashi
NaritaHaneda Airport

2-min walk from JR Nishi-Chiba Station to the South Gateof Nishi-Chiba Campus

Tsudanuma

Kurihama
Keisei Tsudanuma
Inage

1-33 Yayoi-cho, Inage-ku,
Chiba-shi, Chiba,263-8522 Japan

7-min walk from Keisei Midoridai Station to the Main Gate

SakuraMidoridai
Nishi-chiba

Keisei Chiba

of Nishi-Chiba Campus

NISHI-CHIBACAMPUS

Chiba

INOHANACAMPUS

North Gate

After arriving at JR Chiba Station or Keisei Chiba Station,a bus stop can be found in front of JR Chiba Station east

exit 7. Take the bus bound for Chiba University Hospital or

Chiharadai

Kimitsu

10-min walk from Chiba Monorail Tendai Station to the

4. INOHANA CAMPUS

Chibawww.chiba-u.jp/e

3. NISHI-CHIBA CAMPUS

Minami-Yahagi and get off at the School of Medicine EnKazusa-Ichinomiya

trance bus stop. To get to the university hospital, get off at
the Chiba University Hospital stop.