RESEARCH HIGHLIGHTS 2021
www.naist.jp/en‒ Outgrow your limits ‒NANOMACHINE

Moving Molecular Machines
ROBOTICS

Creating Highly Intelligent Robots p.14
CANCER RESEARCHInterview on PD-1 Discovery p.19

p.46

Outgrow
your limits

NAIST was founded in 1991 as a Japanese national university withthe aim of conducting advanced research and educating scientists
and technologists to support the development of society. NAIST iscomprised of the Graduate School of Science and Technology,
which focuses on the areas of information, biological and materials
sciences and the development of their interdisciplinary fields. At
present, over 1,000 students—roughly 25% from overseas—aresupervised by roughly 200 NAIST faculty.
With its cutting-edge facilities and a 5 to 1 student-to-faculty ratio,
NAIST’s world-leading research and education are a direct result of
its rich, global environment and supportive infrastructure. The
outstanding achievements of NAIST’s faculty and students areshared worldwide through publications, patents, licenses and active
exchange with overseas partners.

WebsitePromotional Videowww.naist.jp/enwww.naist.jp/en/about_naist/
facts_history/videos.html

Twitter

Facebook

www.twitter.com/naist_main_en

www.facebook.com/naist.jp.en

NAIST Research Highlights
ISSN 2189-714X

For further information on the research
published in NAIST Research Highlights
or to arrange an interview with a faculty,
please contact:

NAURA (NAIST URA Team)
Institute for Research Initiatives
Nara Institute of Science and Technology
8916-5 Takayama-cho, Ikoma, Nara 630-0192, JAPANE-mail: naura@rsc.naist.jp©2021 NAIST All rights reserved

Aims & Scope

NAURA

NAIST Research Highlights showcases
promising and important researchachievements at NAIST and presents
their current research and coretechnologies to the public. The
publication distills highly technicalresearch papers into short,easy-to-understand articles that appeal
to a global audience of both specialists
and non-specialists. NAIST ResearchHighlights aims to inform readers of
the latest developments in NAIST’s
pioneering research and to stimulate
new and existing international
collaborations.

NAURA (NAIST URA team)publishes NAIST Research Highlights
under the auspices of the “Program for
Promoting the Enhancement ofResearch Universities”, which isfunded by Japan’s Ministry of
Education, Culture, Sports, Scienceand Technology (MEXT). Throughthis program, NAIST further supports
its cutting-edge research while
expanding into new interdisciplinary
fields in science and technology toward
becoming a globally recognizededucation and research center.

NAIST Divisions and Laboratories
NAIST conducts advanced research in the core study areas of information, biological and materials sciences and engages ininterdisciplinary studies to explore and seek solutions in the most challenging areas. NAIST actively addresses important social issues bygenerating international-level research products that will help to build a better society.

Division of Information Science
Computer Science

Media Informatics

Applied Informatics●Computing Architecture●Computational Linguistics●Robotics●Dependable System●Augmented Human Communication  p.10

●Intelligent System Control●Ubiquitous Computing Systems

 p.8●Social Computing●Large-Scale Systems Management●Software Engineering●Network Systems●Mathematical Informatics●Software Design and Analysis●Interactive Media Design●Imaging-based Computational●Cyber Resilience●Information Security Engineering●Optical Media Interface
 p.6

 p.12

 p.11●Cybernetics and Reality Engineering p.16

Biomedicine●Computational Systems Biology●Internet Architecture and Systems●Robot Learning p.14

Division of Biological Science
Plant Biology

Biomedical Science

Systems Biology●Plant Cell Function●Molecular Signal Transduction●Microbial Molecular Genetics●Plant Developmental Signaling●Functional Genomics and Medicine  p.19

●Systems Microbiology●Cell Signaling●Plant Metabolic Regulation

 p.29●Tumor Cell Biology●Plant Growth Regulation

 p.30,32●Molecular Immunobiology

 p.22●Applied Stress Microbiology

 p.24●Plant Stem Cell Regulation and p.33

 p.26●Molecular Medicine and Cell Biology  p.23

●Environmental Microbiology

Floral Patterning●RNA Molecular Medicine●Structural Biology●Plant Physiology●Stem Cell Technology●Structural Life Science●Plant Immunity●Developmental Biomedical Science●Gene Regulation Research●Plant Symbiosis●Organ Developmental Engineering●Systems Neurobiology and Medicine  p.28

●Bioengineering●Cell Proliferation and Differentiation●Computational Biology●Plant Secondary Metabolism●Gene Function in Animals●Cellular Function Systems●Molecular and Cell Genetics

Division of Materials Science
Core Laboratories

Collaborative Laboratories●Quantum Materials Science p.36●Synthetic Organic Chemistry●Bio-Process Engineering p.35●Photonic Molecular Science●Surface and Materials Physics●Nanostructure Magnetism●Photonic Device Science p.40●Information Device Science●Organic Electronics

 p.42,44●Sensory Materials and Devices●Photofunctional Organic Chemistry  p.41

●Functional Polymer Science●Supramolecular Science●Ecomaterial Science p.45●Complex Molecular Systems●Biomimetic and Technomimetic●Sensing Device●Mesoscopic Materials Science●Advanced Functional Materials
 p.46,48

Molecular Science p.38●Nanomaterials and Polymer Chemistry●Data-driven Chemistry

As of February 1, 2021
NAIST Research Highlights

1

Contents
1

NAIST Divisions and Laboratories

4 Editorial

Information Science

6

ImpactInformation Security Engineering

Information system security with hardwareas the root of trust

8

ImpactDependable System

Improving the reliability of a system throughteamwork using devices connected to a network

10 Research Highlight

Augmented Human Communication

One class in all languages

11 Research Highlight
Optical Media Interface

Reconstructing histological slices into
3D images

12 Impact

Social Computing

Automatically reading internet information
to track viral infection trends

14 Impact

Robot Learning

Creating highly intelligent robots using skillfulmachine learning

16 Research Highlight

Imaging-based Computational Biomedicine

Artificial intelligence learns muscle anatomy
in CT images

17 Research Highlight
Mobile Computing

All Bitcoin mining should beenvironmentally friendly

Biological Science

19 Impact

Functional Genomics and Medicine

Interview with Associate Professor
Yasumasa Ishida, who discovered the protein
PD-1, the basis for the research on drugs
for cancer immunotherapy developedby Dr. Tasuku Honjo, a Nobel laureatein physiology or medicine

22 Research Highlight
Tumor Cell Biology

Stressing cancer with spice

23 Research Highlight

Molecular Medicine and Cell Biology

GAS7 protein allows cells to eat

2

NAIST Research Highlights

24 Impact

Applied Stress Microbiology

29 Research Highlight

Plant Metabolic Regulation

Revealing the mechanism of stress tolerance
by cells to create stress-resistant yeast

26 Impact

Environmental Microbiology

Discovering PET-eating bacteria and elucidating
the underlying mechanism to employ themfor environmental improvement

28 Research Highlight

Plant polymers do not always act together
to make beautiful shapes

30 Impact

Plant Growth Regulation

Revealing astute strategies employed
by stress-tolerant, long-lived plants

32 Research Highlight
Plant Growth Regulation

Systems Neurobiology and Medicine

Axons grip and slip their way around the brain

Plants grow less in hotter temperatures

33 Research Highlight

Plant Stem Cell Regulation and Floral Patterning

Turning off growth to make flowers growMaterials Science

35 Research Highlight
Bio-Process Engineering

Measuring metabolites in algae one cell at a time

36 Impact
Quantum Materials Science

Light is created with quanta; quanta aremanipulated by light

38 Impact
Organic Electronics

Developing a new field of electronics withflexible organic semiconductors

40 Research Highlight
Photonic Device Science

Miniaturized infrared cameras take coloredphotos of the eye

41 Research Highlight

45 Research Highlight
Supramolecular Science

Photofunctional Organic Chemistry

Microorganisms build the best fuel efficienthydrogen cells

World's widest graphene nanoribbon promises
the next generation of miniaturized electronics

42 Impact

46 Impact

Biomimetic and Technomimetic Molecular Science

Photonic Molecular Science

Skillfully utilizing the power of light and heatto actualize next-generation high-performancemolecules

44 Research Highlight

Synthesizing moving molecular machines andgoing beyond the boundaries of nanoworld

48 Research Highlight

Photonic Molecular Science

Light burns with new acids

Biomimetic and Technomimetic Molecular Science

A 2 nm sized nanomachine able to spin andtransfer its rotational energy

49 Innovative Research and Education Programs
50 The Graduate School of Science and Technology
NAIST Research Highlights

3

NARA INSTITUTE of SCIENCE and TECHNOLOGYRESEARCH HIGHLIGHTS 2021

Nurturing
discoveryW

elcome to NAIST Research Highlights 2021. Thispublication provides an overview of the work and peopleof one of Japan’s leading research bodies, the Nara
Institute of Science and Technology. In these pages we present a view of
the institute’s achievements in two different formats.
Research Highlights are short features that cover recent extraordinary
advances and breakthroughs, including 16 topics from 16 laboratories.
Twelve longer Impact profiles explore some of our research achieving
significant outcomes in the three divisions.
Of course, at the heart of such outcomes are our researchers. Each year
NAIST attracts more leaders in scientific fields. We look forward tonurturing their important work and the careers of all our researchers in
the atmosphere of cutting-edge discovery that will continue to befostered at NAIST.

On the cover
NAIST
RESEARCHHIGHLIGHTSRESEARCH HIGHLIGHTS 2021
www.naist.jp/en‒ Outgrow your limits ‒http://www.naist.jp/en/

NANOMACHINE

Moving Molecular Machines

p.46

ROBITICS

Creating Highly Intelligent Robots p.14
2021

CANCER RESEARCHInterview on PD-1 Discovery p.19

By synthesizing moving molecular machines, NAIST researchers
are one step closer to their goalof going beyond the boundaries
of nanoworld.
Page 46

4

NAIST Research Highlights

INFORMATIONSCIENCEInformation Science

IMPACT
Information Security Engineering
Prof. Yuichi Hayashi

Information system security
with hardware as the root of trust

Rapidly increasing physical attacks on
hardwareWith computer information networks spreading to every corner ofthe Earth, and enormous amounts of information flow, building
security to counter system interference and information leaks due
to cyberattacks is now critical. While strong defenses have beendeveloped against the intense threats faced by software, including
networks and applications, countermeasures have also become
essential to protect hardware such as PCs and mobile information
devices that operate over the Internet as well as storage devices. For
example, if a malicious integrated circuit (IC) chip is input into asystem, the IC can cause serious damage that adversely affects theentire system; addressing such damage would be highly expensive.
As the Internet of Things (IoT) spreads, various Internet-connected
devices are under direct attack. Thus, hardware security has become
crucial.
The Information Security Engineering Laboratory is studying
the security of entire systems, focusing on the hardware. Professor
Yuichi Hayashi says, “Hardware is essential for operating systems
and applications to work. Therefore, if there is vulnerability in the

6

NAIST Research Highlights

hardware, the security of the entire system is compromised. Ensuring the security of the hardware, which is key to trust, becomes animportant challenge that must be examined in the same way as thatfor applications and networks.” The devices that attackers use are
rapidly evolving, and their price is decreasing with improving
performance. This is the backdrop to the increasing damage thatcyberattacks are causing.

Developing sensors for detecting attacks
Hayashi’s group has developed a sensor to detect information leaks
occurring via electromagnetic waves from the hardware. In thiscase, the attacker does not target the regular input and output of
information to attack the hardware. Rather, using a physicalmethod such as an electromagnetic field probe, the attacker surveys
the operations of the encryption device to acquire highly confidential information such as the privacy key. However, it is difficult to
conduct this survey without disturbing the electromagnetic waves
around the hardware according to the laws of physics; hence, a
disturbance occurs in the electromagnetic field. The developed
sensor can detect this disturbance with a high level of accuracy overa wide range, and detect probing by attackers. Thus, in this case,Information Sciencegroup has shown that by installing a hardware-version computervirus, composed of cheap circuits costing a few dozen yen, on a
device during a manufacturing process, it enables an attacker toaccess the device from areas that would have been difficult to
operate without the virus. They are developing a sensor to detect themalicious circuits that attackers install on devices by visualizing
such circuits using a principle similar to that of SONAR.
Hayashi has established a technical subcommittee to discuss theinformation security of electromagnetic waves on consumer
devices at the Institute of Electrical and Electronics Engineers(IEEE), the world’s largest technical professional organization for
the advancement of technology. In the subcommittee, he exchanges
opinions with foreign researchers.
Hayashi studied computer networks, information security, andelectromagnetism in graduate school, leading him to the advanced
subject of hardware security. “When I look at issues in a different
field from the perspective of the field in which I am conducting
research, I am able to find new solutions and open a new path ofresearch,” he says.

Circuit design with security
Assistant Professor Daisuke Fujimoto is conducting research on thedesign of semiconductor electronic circuits. When he was astudent, he discovered that information leakage occurred not only
through electromagnetic waves but also through the silicon
substrates of IC chips. This inculcated in him an attitude of “gettingat the root of the problem rather than covering it up” by designingsafe circuits and installing encryption circuits for protection. The
range of his research has broadened to include measuring information leakage from the attacker’s perspective, the design of circuitry
for a sensor that detects the installation of malicious IC, and amethod to prevent the manipulation of analytics data of vehicle
location information, which has become a problem in automateddriving technology.
“We can have new realizations in scientific research, when welearn about both hardware and software, and see the whole
picture,” he says.
Interviewed by Yoshinori Sakaguchi
damage can be prevented by blocking the attack at the beginning.
Furthermore, when information is touch-input on the screen of
a portable device such as a smartphone, the attacker can get theoperation information from a distance using the leaking electromagnetic waves. To counteract this, they have developed technology that can prevent information leakage, both electromagneticallyand optically, by combining a polarizing filter and transparent
shield sheet with a metal mesh that blocks the electromagnetic
waves. When attached to a smartphone’s screen, this technology
can limit the extent of electromagnetic information leakage towithin a 50-cm range.

Changing perspective
In addition, attacks known as “fault injections” are being continually researched. This attack causes a temporary breakdown in some ofthe processes performed in the hardware. The resulting error
output information is analyzed to acquire confidential informationsuch as the privacy key used for encryption.
Moreover, from viewpoint of offensive security, Hayashi’s

Visualization of information leakage paths based on large-scale EM field
simulation techniques.

More information about the group’s research can be found at https://isw3.naist.jp/Contents/Research/cs-09-en.html

NAIST Research Highlights

7

Information Science

IMPACT
Dependable System
Prof. Michiko Inoue

Improving the reliabilityof a system through teamwork
using devices connected
to a network
Toward distributed processing from centralized management

group has proposed an algorithm that can effectively divide numerous low-performance individuals (molecular robots) into twogroups with the same number of individuals exhibiting similar
performances, and assign separate tasks to the groups. Theydeveloped this efficient algorithm minimizing the number ofindividual states used for the computation. When the algorithm isused, molecular robots rearrange groups so that they can work
efficiently according to internal environmental changes, enabling
the creation of a flexible and effective system.

With the widespread of Internet of Things (IoT) where information
devices that perform various tasks connect to the Internet, and thedevelopment of complex and large-scale information networks,
considerable attention has been directed toward distributed
algorithms (algorithms for distributed systems) to realize dependable and efficient information systems. The concept of dependability encompasses several desired properties such as
Introducing deep learningfault-tolerance, reliability, availability, safety, andsecurity.
Inoue’s group is also conducting research on quality
The Dependable System Laboratory iscontrol of VLSI devices, including topics such as
studying distributed algorithms based on
circuit design to facilitate production test. Despitemathematical theories of computation andcomprehensive test of circuits at the time ofalso addressing the issue of quality forshipment, one test escape can occur within several
highly densified very large-scale integratens of millions, which leads to problems undertion (VLSI), considering “what is a dependspecial conditions during operation. Thus, they
able system for users?” Professor Michikodeveloped a quality test that adopted the deep
Inoue emphasizes, “For example, evenlearning of AI, with satisfactory results. In this test,
though each device connected to the IoT
AI learns the pattern of a perfectly-made VLSI in
detects an abnormality only in the range ofadvance and shows predicted values of defective
its own view, problems such as system
devices that do not match the perfect pattern.
failures can be solved appropriately andMobile robot.
Inoue has excelled at mathematics and science
quickly based on collective intelligencesince her time in primary and middle school. She is
obtained through communication between
an advisor to the President for Gender Equality at NAIST. Fivethe related devices. We aim to develop algorithms that are more
years ago, she started hosting an annual symposium for supporting
suitable for distributed processing rather than centralized managefemale researchers. “I want to increase the opportunity for brilliant
ment.”
women to succeed in the scientific field, as the number of researchHer research topics also include a near-future system thaters is decreasing owing to the declining birthrate,” Inoue says.
comprises nanometer sized machines, i.e., nanomachines, despite
being based on the current system. Concerning this topic, Inoue’s
8

NAIST Research Highlights

Information Science

Clarifying essence of cooperative problems
Associate Professor Fukuhito Ooshita has continued studying the
distributed algorithm to allow many computers to operate cooperatively. In addition to the molecular robots mentioned above, he hasdeveloped an algorithm for low-performance mobile robots thatcan move in spaces autonomously and can detect only nearby
robots; this algorithm allows them to patrol environments cooperatively or gather together in one place for further cooperation.
“I am keen on elucidating essence ofthe cooperative problems for future
practical use by clarifying minimum
equipment of individual robots andsimple algorithms to solve the problems
with a theoretical model,” Ooshita says.

Elucidating the deterioration mechanism
Assistant Professor Michihiro Shintani
is conducting research on circuitdesigns that detect the degradation of
VLSI systems overtime early on. Afterclarifying the mechanism of actual
degradation, he postulated a theory
based on the collected degradation data
and developed a method to be reflectedin the design. He found that the degradation of the threshold voltage occurredbecause defects are preexisting in thegate electrode, which was incorporated into a model. Consequently,
he succeeded in mathematically formulating the degree of degradation predicted via temperature and an elapsed time at the time ofoperation.
In addition, Shintani has built a circuit simulation model for
operating the power semiconductors used for power converter,
which is receiving considerable attention from related companies.
Recently, he has been also working on a highly reliable design ofneuromorphic-type circuits that imitate the neural circuits of thehuman brain.
Shintani transitioned into academia after
conducting research on the design ofintegrated circuits in a company for nine
years. “While in a company, I sought
short-term success; however, at a university,
I can start with fundamental studies andlook ten years into the future. I would like toconduct research from scratch while notbuying into the common wisdom and takethe technology in the direction of much
improved performance,” Shintani says.
Interviewed by Yoshinori Sakaguchi

Evaluation circuit of semiconductor device reliability.

More information about the group’s research can be found at https://isw3.naist.jp/Contents/Research/cs-02-en.html

NAIST Research Highlights

9Information Science

RESEARCH HIGHLIGHT

Augmented Human Communication
Prof. Satoshi Nakamura

One class in all languages

Aand developed a deep learning-based system to transcribe Japanese
lecture speech and to translate it into English. While watching thevideos, users would see subtitles in Japanese and English that matched
the lecturer’s speaking.
One might expect the ideal output would be simultaneous translations that could be done with live presentations. However, live translations limit the processing time and thus the accuracy.
“Because we are putting videos with subtitles in the archives, wefound better translations by creating subtitles with a longer processing
time,” he says.
The archived footage used for the evaluation consisted of lecturesfrom robotics, speech processing and software engineering. Interestingly, the word error rate in speech recognition correlated to disfluency
in the lecturers’ speech. Another factor from the different error rates
was the length of time speaking without pause. The corpus used for the
training was still insufficient and should be developed more for further
improvements.
“Japan wants to increase its international students and NAIST has agreat opportunity to be a leader in this endeavor. Our project will not
only improve machine translation, it will also bring bright minds to thecountry,” he continues.

© 2019 Information Processing Society of Japandvances in communication technology have had a major
impact in all sorts of industries, but perhaps none bigger thanin education. Now anyone from around the world can listen
live to a Nobel Prize Laureate lecture or earn credits from the most
reputable universities with nothing more than internet access. However, the possible information to be gained from watching and listening
online is lost if the audience cannot understand the language of thelecturer. To solve this problem, scientists at NAIST, presented asolution with new machine learning at the 240th meeting of theSpecial Interest Group of Natural Language Processing, Information
Processing Society of Japan (IPSJ SIG-NL).
Machine translation systems have made it remarkably simple forsomeone to ask for directions to their hotel in a language they havenever heard or seen before. Sometimes the systems can make amusing
and innocent errors, but overall achieve coherent communication, atleast for short exchanges usually only a sentence or two long. In thecase of a presentation that can extend past an hour, for example, anacademic lecture, they are far less robust.
“NAIST has 20% foreign students and, while the number of English
classes is expanding, the options these students have are limited bytheir Japanese ability,” explains NAIST Professor Satoshi Nakamura,
who led the study.
Nakamura’s research group acquired 46.5 hours of archived lecture
videos from NAIST with their transcriptions and English translations,

A deep learning-based system to transcribe Japanese lecture speech and to translate it into English.

More information about the group’s research can be found at http://isw3.naist.jp/Contents/Research/mi-02-en.html

10

NAIST Research Highlights

Optical Media Interface
Prof. Yasuhiro Mukaigawa

Reconstructing histological slices
into 3D images

Information Science

RESEARCH HIGHLIGHT

J

apanese scientists report in Pattern
Recognition a new method to construct
3D models from 2D images. The
approach, which involves non-rigid registration with a blending of rigid transforms,
overcomes several of the limitations incurrent methods. The researchers validate
their method by applying it to the Kyoto
Collection of Human Embryos and Fetuses,
the largest collection of human embryos in
the world, with over 45,000 specimens.
MRI and CT scans are standard
techniques for acquiring 3D images of the
body. These modalities can trace with
unprecedented precision the location of an
injury or stroke. They can even reveal the
microscopic protein deposits seen in brain
A set of histological serial sections of a human embryo with organ annotations (left) and 3D
pathologies like Alzheimer’s disease. Howevreconstruction (right).
er, for the best resolution, scientists still
depend on slices of the specimen, which isthat minimizes all three factors using less computational cost than
why cancer and other biopsies are taken. Once the information desired
standard methods.
is acquired, scientists use algorithms that can put together the 2D slices“First, we represent non-rigid deformation using a small number ofto recreate a simulated 3D image. In this way, they can reconstruct ancontrol points by blending rigid transforms,” says Funatomi. The small
entire organ or even organism.
number of control points can be estimated robustly against the
Stacking slices together to create a 3D image is akin to putting a
staining variation.
cake together after it has been cut. Yes, the general shape is there, but“Then we select the target images according to the non-rigid
the knife will cause certain slices to break so that the reconstructed
registration results and apply scale adjustment,” he continues.
cake never looks as beautiful as the original. While this might not
The new method mainly focuses on a number of serial section
upset the party of five-year olds who want to indulge, the party ofimages of human embryos from the Kyoto Collection of Human
surgeons looking for the precise location of a tumor are harder to
Embryos and Fetuses and could reconstruct 3D embryos with extraorappease.
dinary success.
In fact, the specimen can undergo a series of changes when
Notably, there are no MRI or CT scans of the samples, meaning no
prepared for sectioning.
3D models could be used as a reference for the 3D reconstruction.
“The sectioning process stretches, bends and tears the tissue. The
Further, wide variability in tissue damage and staining complicated thestaining process varies between samples. And the fixation process
reconstruction.
causes tissue destruction,” explains NAIST Associate Professor Takuya“Our method could describe complex deformation with a smaller
Funatomi, who led the project.
number of control points and was robust to a variation of staining,”
Fundamentally, there are three challenges that emerge with the 3D
says Funatomi.
reconstruction. First is non-rigid deformation, in which the positionand orientation of various points in the original specimen havechanged. Second is tissue discontinuity, where gaps may appear in thereconstruction if the registration fails. Finally, there is a scale change,
Reference
where portions of the reconstruction are disproportional to their real
Kajihara, T., Funatomi, T., Makishima, H., Aoto, T., Kubo, H., Yamada, S. &size due to non-rigid registration.
Mukaigawa, Y. 2019. Non-rigid registration of serial section images by
For each of these problems, Funatomi and his research teamblending transforms for 3D reconstruction. Pattern Recognition, 96,
proposed a solution that when combined resulted in a reconstruction
106956.
More information about the group’s research can be found at http://isw3.naist.jp/Contents/Research/mi-06-en.html

NAIST Research Highlights

11

Information Science

IMPACT
Social Computing
Prof. Eiji Aramaki

Automatically readinginternet information
to track viral infection trends

12

Analyzing language data

Twitter is a powerful source of information

Conversations on social media on the Web, such as Twitter,
represent trends of phenomena influencing social life, e.g., influenza epidemics, at a certain point in time. The Social Computing
Laboratory, led by Professor Eiji Aramaki, is conducting research todevelop technologies for investigating various social phenomena
based on language data that manifest according to communication
patterns on social media. Aramaki’s group is also conducting
research that can be utilized in less-explored areas of information
science, e.g., the applications of natural language processing inmedical care.

Aramaki is supporting efforts to understand the infection status of
the novel coronavirus that has broken out worldwide. “Regarding
the infection-related information posted on the internet throughTwitter, we are investigating whether locally concentrated cases are
clusters (small outbreaks) and analyzing information that could beviewed as wild rumors and fake news,” Aramaki explains. Aramaki’s group provides their research data to national research
institutes for reference. The amount of retrieved information in
English, Chinese, and Japanese, with the words “novel coronavirus”
and related terms as a clue, reaches about 10,000 per day.

NAIST Research Highlights

Improving accuracy byremoving noise
Furthermore, Associate Professor
Shoko Wakamiya has proposed a
calculation model that considers
the gap between the estimatednumber of patients with tweets andthe real number of patients toimprove the accuracy of thedeveloped method. The research
paper describing this model wasawarded best paper by the International Medical Informatics Association (IMIA) in 2018. “Whenexamining a particular area, thenumber of tweets decreases once
the information is posted because
the people’s interest fades, whereas a temporary surge of tweets isobserved after a news report. Therefore, we compensated for themby additionally considering information about the infection posted
from other areas and also considering components that become
noise in the count,” Wakamiya explains. The subjects of the surveys
conducted so far are wide-ranging, including infectious foodpoisoning due to norovirus and hay fever. Recently, studies are also
conducted based on symptoms such as fever, chills, diarrhea, andrunny nose, attempting to narrow down the characteristics of evenunknown viruses based on symptoms and aiming to investigate theconditions of infection at an early stage.
“We are exploring the possibility of acquiring effective data by
expanding our methods, such as selecting frequently searchedwords on internet search engines, detecting the location history ofpeople who have installed specific applications on their smartphones and examining applications that allow the patient to report
actively,” Aramaki says.

characteristics when an individual speaks freely. Based on examination data collected at hospitals, certain speech characteristics signify
dementia, such as “a reduced amount of vocabulary (the total
number of words) and nouns” and “delayed utterance.” Based onthese data, a dementia-screening system called KOTOBAKARI has
been developed. The simplified version of this examination method
automatically calculates the number of words in a response to aquestion; e.g., “Have you had any fun lately?” If the calculated value
is significantly lower than the reference, it implies a decline incognitive function.
“A decline in cognitive function is thought to be related not only
to dementia but also to depression in elderly people and to the side
effects of anticancer drug treatment.
Thus, through the proposed system, weare additionally examining therelationship between diseases such as
cancer and decline in cognitive
function,” Aramaki explains.

Information Science

Aramaki has proven that social media can become an influential
source of information for creating countermeasures for andpreventing infectious diseases, including influenza. First, theproposed method automatically infers the meaning of a sentence
using a natural language processing technique that converts vague
expressions from everyday conversation into language that can beunderstood by computers. Then, keywords such as “influenza” andsecondary terms such as “feverish” and “coughing” are searched,and extracted data are classified using artificial intelligence (AI).
Based on location information obtained from Twitter, the areas
showing more tweets are identified, enabling the prediction ofincreased infections. When the results based on the tweet data werecompared with data on thenumbers of patients released by the
National Institute of Infectious
Diseases, the correlation was sohigh as to almost match perfectly,
thereby receiving global attention.

Studying ethical issues
Research is also underway for cases
requiring long-term treatment, such asbreast cancer. A website called
EPISODE BANK has been established,
wherein patients are encouraged topost their experiences of fighting
illnesses to share and ease theirconcerns. Furthermore, the nation’s
first large-scale analysis technology is
being developed that analyzes large
quantities of clinical data, including
specialized medical terms, through anatural language processing technique,extracts accurate information andturns them into text using AI.
As research on medical treatment such as the handling of
medical examinations and clinical data is being undertaken with
doctors as well as other medical personnel, it is expected that thefield of information science will expand into the medical field in the
future. Therefore, collaborative research is also being conductedwith biotechnology research institutes regarding the ethical issues
related to handling personal medical information.
“Going forward, ethical issues pertaining to handling a variety
of information will become important. Furthermore, I want tocontinue to explore undeveloped fields, such as the connection
between information technology and creative concepts like art,
which AI cannot create,” Aramaki says.
Interviewed by Yoshinori Sakaguchi

Determining decline in cognitive function
Using techniques of speech recognition and natural language
processing, a study is currently underway on using medical care to
predict the difficult-to-detect signs of dementia by analyzing speechMore information about the group’s research can be found at https://isw3.naist.jp/Contents/Research/mi-08-en.html

NAIST Research Highlights

13

Information Science

IMPACT
Robot Learning
Associate Prof. Takamitsu Matsubara

Creating highly intelligent robots
using skillful machine learning
Effective learning using small-scale data
For a robot to be integrated into and act as a capable companion in
an environment where people work and live, the robot must haveadvanced perception and flexible judgment. The Robot Learning
Laboratory is developing artificial intelligence (AI) using machinelearning algorithms in which data from the neighboring environment and objects are automatically input and analyzed to infer rules
14

NAIST Research Highlights

regarding optimal action. Further, studies are being conducted to
explore the future of robotics in fields where automation has beenchallenging; e.g., providing the robot operational skills to work withflexible and amorphous cloth and providing an automated driving
functionality to small vessels that are susceptible to the effects ofwind, waves, and tides.
This laboratory was established in January 2019 via a

Learning complicated cloth-handling skills
Matsubara’s group has achieved a significant success using theabove
technology.
Theydeveloped robots that canefficiently learn the task offlipping a handkerchief andfolding children’s clothes. While
such amorphous and flexible
objects are a challenge for robots
to handle, the learning processthat took at least 10 h or more in
the past was significantly
shortened to 4 h.
“We accumulated experience
data while viewing images of therobots picking up and droppinga cloth. Since the amount of data
was limited, we designed thealgorithms where they provided
a stable answer that was roughly
presumed to be the best,” explains Matsubara.
In this study, he employed the stochastic control theory toestimate errors in experimental data and compensate for them. The
challenge concerning the insufficiency and unevenness of data was
successfully addressed by applying this theory.
In 2013, Matsubara studied at Radboud University in the
Netherlands for the Project for International Brain Circulation of
NAIST for one year. He avoided studying modern robotics andfocused on learning the underlying fundamental mathematical andphysical theories instead. “There were theories I learned there that
had been developed independently without being linked to AI, andthen, I tied one of them to robot learning, paving a new path,” heemphasizes.

Automated driving of small vessels
Matsubara’s group is currently working on more than 10 project
topics. A collaborative research with a maritime business company
aims to provide an automated driving function for small-sized

vessels, which are susceptible to the effects of weather and tides.
After collecting data on weather and sea areas by randomly navigating for 1 h, the algorithm learns the data and infers the vessel’s
movement to derive action rules to manage the given operations. If
the vessel arrives at a specified destination on the sea for fishing, thealgorithm operates the steering wheel to stop there.
“Similar to the study on the cloth-handling robots, this technology utilizes a small amount of data but uses another theory. Asvarious fundamental theories are available, it is our policy to design
AI algorithms that meet specific purposes,” says Matsubara.
In collaboration with a major restaurant chain, they are also
developing a robot that can arrange Japanese food on platters. For
Japanese food, the robot must show delicacy on par with a professional chef; e.g., the robot must be able to place the food properly,
taking into account various requirements. Thus, they employed apioneering AI technology called generative adversarial imitation
learning, a type of deep learning. After converting chef’s demonstration into data, they are mixed with an enormous amount ofpractice data obtained from the robot, from which point it isdetermined whether the data sufficiently resemble the demonstration. Studies are being conducted to learn delicacy by repeating thisprocess such that the robot
outputs food arrangements
closely
resembling
those
prepared by a Japanese chef.
Furthermore, contributions
are being made to the introduction of AI technology in several
fields, such as automating fineadjustments in chemical plants
with reinforcement learning tosignificantly shorten the timespent on such adjustments.

Information Sciencetenure-track system, with an outstanding young researcher as
principal investigator. The leader, Associate Professor Takamitsu
Matsubara says, “We are developing algorithms that can makestable calculations with the efficiency required for practical use
from the autonomous collection of necessary data to machinelearning and deep learning that infer optimal action rules based on
the collected data, in accordance with the robot’s particularpurpose.”Within machine learning, significant advancements have been
made in reinforcement learning, in which the robot selects the
optimal action through repeated trial-and-error, and deep learning,in which the robot automatically extracts feature points based on aneural network, resembling nerve cells of a human brain. However,these types of learning require substantial data and are unsuitablefor practical use when considering the effort and failures the robot
encountered during data collection. Thus, a technology is being
developed that can perform deep reinforcement learning withsmall-scale data within a range that robots can collect.

Aiming to increasingly automate
the machineryaround us
After entering the Graduate
School of Information Science of NAIST in 2003, Matsubarainterned at the Advanced Telecommunications Research Institute(ATR), in which one of NAIST’s collaborative laboratories islocated. Here, Matsubara encountered the ongoing robot study andwas instantly absorbed in it. “I worked on a study of biped locomotion with reinforcement learning, but there was no GPU or deeplearning in those days. Compared with the current situation where
there are many social demands, the atmosphere was such that I
could conduct research calmly,” he says.
Concerning future studies, Matsubara says, “There still are moremachines that can be automated with current technology. I want tocontinue to make breakthroughs in the research. I found that theissue of ensuring safety without making a dangerous mistake when
AI performs trial-and-error and learning is also critical, and I am
addressing the issue by going back to fundamental studies.”
Interviewed by Yoshinori Sakaguchi

More information about the group’s research can be found at https://isw3.naist.jp/Contents/Research/ai-08-en.html

NAIST Research Highlights

15

Information Science

RESEARCH HIGHLIGHT

Imaging-based Computational Biomedicine
Prof. Yoshinobu Sato

Muscle segmentation from CT volume using Bayesian U-net. Skin mask is obtained using conventional U-net during thefirst stage, and then Bayesian U-net is utilized to assign a muscle label as well as uncertainty to each pixel.

Artificial intelligence learns
muscle anatomy in CT images

Personalized medicine has stirred the imagination of drugs andtherapies that are individually tailored to patients. In the future,
there will no longer be a need to worry about side effects, andpatients will be screened to identify which treatment will be mosteffective for them, instead of for the average population. Deep learning
is one tool that will be key to realizing personalized medicine. A new
study by Japanese researchers describes a new deep learning tool thatwill advance personalized medicine for musculoskeletal diseases. The
tool can segment individual muscles for a comprehensive model of themusculoskeletal system, which is expected to advance personalized
biomechanics.
Accurate measurements of the musculoskeletal system can have atremendous impact for the extremely ill, like those suffering from ALS
or other severe forms of atrophy, to influence the design of rehabilitation devices, and for the extraordinarily gifted, like high-performanceathletes who want to take their game to the next level. These measurements come from computed tomography or other imaging modality
with which researchers build computer models to study the forces andstresses on muscles and bones.
“Once we have the CT images, we need to segment the individual
muscles for building our model,” explains Professor Yoshinobu Sato of
NAIST, who led the study.
“However, this segmentation was time consuming and depended
on expert-knowledge. The figure shows an overview of our system. We
used deep learning to automate the segmentation of individual
muscles to generate a musculoskeletal model that is personalized tothe patient,” he continues.
While it is normal to expect a physician to evaluate the images, thisadds a level of subjectivity to the diagnosis. The system is especiallybeneficial for patients in remote areas with limited access to expert

orthopedic surgeons, for decisions based on a more quantitativeinterpretation should improve outcomes.
The method depends on Bayesian U-net architecture.
“U-Net is a deep learning framework based on a fully convolutional neural network for the precise segmentation of images. Ourcolleague, Dr. Yuta Hiasa, extended U-net by combining Bayesianinference to formulate Bayesian U-net, in which uncertainty is associated with segmentation results,” says Sato.
The challenge in segmenting individual muscles is the low contrastof the imaging at border regions of neighboring muscles. To test theirsystem, the researchers examined 19 muscles in the thigh and hips.
Bayesian U-Net had better segmentation accuracy than other methods
including the hierarchical multi-atlas method, which is viewed asstate-of-the-art, and did so while reducing the time to train andvalidate the system by a surgeon.
“Some pixels in the images had high uncertainty. It was these pixels
that especially need confirmation by surgeons,” notes Sato.
The researchers thus defined an uncertainty threshold to identify
which pixels required human verification.
“Bayesian U-Net learned the musculoskeletal anatomy to create
segmentations that would have been created by experts with highfidelity and our collaborator orthopedic surgeon, Prof. Nobuhiko
Sugano of Osaka University Hospital, is quite satisfied with thisachievement,” says Sato.
Reference
Hiasa, Y., Otake, Y., Takao, M., Ogawa, T., Sugano, N. & Sato, Y. 2020.
Automated muscle segmentation from clinical CT using Bayesian U-net
for personalized musculoskeletal modeling. IEEE Transactions on Medical
Imaging, 39, 1030‒1040.

More information about the group’s research can be found at http://isw3.naist.jp/Contents/Research/ai-05-en.html

16

NAIST Research Highlights

Information Science

RESEARCH HIGHLIGHT

Mobile Computing
Associate Prof. Naoki Shibata

All Bitcoin mining should
be environmentally friendly
but neither is it wasted.
PoS is the newest of more than a dozen alternative algorithms to
PoW that all aim to reduce energy cost. PoW has remained thestandard algorithm through which cryptocurrencies operate, because
it is extremely decentralized and democratic, which prevents any one
user from having an outstanding influence on the currency value.
“The problem with the alternatives is that they lose their democracy or are more vulnerable to outside attacks,” notes Shibata.
By adding the feature of an approximate solution, PoS also invites
possible corruption to which PoW is immune. Therefore, as adeterrent, PoS demands that the user who submits the problem be theone who pays the user who proposes the solution. This prevents users
from colluding together to submit problems for which they alreadyknow the solution.
Another appeal of PoW is its robustness. PoS preserves this robustness by introducing miniblocks each time an optimization problem issubmitted.
Shibata envisions the optimization problems that can be solved byredirecting the wasted energy with PoS will include diverse problems
from medicine to the beginnings of the universe.
“PoS could help solve problems in protein folding, the dynamics ofinterstellar formations and finance,” he says.
Reference
Shibata, N. 2019. Proof-of-Search: Combining blockchain consensus
formation with solving optimization problems. IEEE Access, 7,
172994‒173006.

© Ravil Sayfullin/shutterstock.com

T

he rise in popularity of cryptocurrencies such as Bitcoin has thepotential to change how we view money. At the same time,governments and societies are worried that the anonymity ofthese cashless transactions could allow criminal activities to flourish.
Another less remarked issue is the energy demands needed to mint
new coins for these cryptocurrencies. A new report by Associate
Professor Naoki Shibata of NAIST presents a blockchain algorithm,
which he calls “proof-of-search” (PoS), that retains the attractive
features of most cryptocurrencies at a lower cost to the environment.
While the economics of cryptocurrencies gets most of theattention, it is becoming readily apparent that cryptocurrencies have amassive environmental cost. The energy used in the world to mine for
Bitcoins alone equals almost that of the energy consumption of all of
Ireland, while in Iceland, Bitcoin mining consumes more energy thanhouseholds. In the end, it could be environmental implications, noteconomic ones, that halt the mainstream adoption of cryptocurrencies.
The basis of all major cryptocurrencies is the blockchain. Ironically,
while the blockchain provides pure anonymity to the human user, it isremarkably transparent in all its transactions, meaning the digitalowner of the digital coins is clear, even the actual person represented
by the digital owner is not.
“Bitcoin uses a proof-of-work [PoW] system to decide the chronological order of transactions. PoW works anonymously because theorder is identified by IP addresses,” explains Shibata.
When a transaction in the Bitcoin blockchain is made, a user makesa request. PoW makes a series of calculations to confirm the validity ofthe transaction, calculations that consume
energy. In PoS, users in the blockchain are
invited to use this energy to request a job forfinding a solution to an optimization
problem.
“There are three kinds of users in the
PoS blockchain. The first two are those whowant to use the blockchain as a payment
system or mine for e-coins, which is thesame as PoW. The third group wants to use
the PoS blockchain as grid computing
infrastructure,” says Shibata.
The energy lost in the PoW is redirected
to finding an approximate solution to thesubmitted problem. Thus, energy can be
devoted to adding new blocks to theblockchain or to another problem, namely,
the optimization proposed by a user, so thatthe amount of energy used is not reduced,

More information about the group’s research can be found at https://shibata.naist.jp/~n-sibata/

NAIST Research Highlights

17BIOLOGICALSCIENCEBiological Science

IMPACT
Functional Genomics and Medicine
Associate Prof. Yasumasa Ishida© iStock/selvanegra

Interview with
Associate Professor Yasumasa Ishida,
who discovered the protein PD-1,
the basis for the research on drugs
for cancer immunotherapy developedby Dr. Tasuku Honjo, a Nobel laureatein physiology or medicine

After the Nobel lecture of Dr. Honjo (right), thephoto was taken during the reception at Karolinska
Institutet in Stockholm.

NAIST Research Highlights

19

Biological ScienceD

r. Tasuku Honjo, a Distinguished Professor of Kyoto University, received the Nobel Prize in Medicine or Physiology in2018 for his achievement in developing a breakthrough drug for cancer immunotherapy (therapeutic anti-PD-1
antibody) based on the receptor protein PD-1 that mediates immunosuppression. PD-1 was discovered and named by
Dr. Yasumasa Ishida, an associate professor in the Division of Biological Science at NAIST, who is conducting basic medical
studies, including research on the detailed mechanisms that enable specific targeting of cancer cells. Associate Professor Ishida
shared with us about the relationship he has had with Dr. Honjo as his former mentor and the prospects for PD-1 research.

Tenacity of purpose was the key―Professor Tasuku Honjo won a Nobel Prize. How do you feel
about it now?
I simply feel so happy and am thrilled. Since the drug was first
approved for the treatment of malignant melanoma, a type of skincancer, in 2014, it has been used to treat several different types ofcarcinomas in over 60 countries; this is undoubtedly an award-winning achievement. The only question was when Dr. Honjo would
win the award, and I was looking forward to hearing that he won. I
was honored and grateful to attend the Nobel Prize awarding
ceremony in Sweden with him.
―Did you have any contact with Dr. Honjo on the day the award
was announced?
On the day the award was announced, Dr. Honjo was overwhelmedwith press conferences and etcetera, so I did not call him. I simply
sent a congratulatory e-mail to him. Surprisingly, that night, Dr.
Honjo replied briefly from his smartphone that “It was your tenacity of purpose that made everything possible. Thank you!” When I
read it, I felt rewarded for the numerous experiments I havediligently conducted. It still astounds me that he found my e-mailfrom a flood of e-mails.

Interested in self- versus non-selfdiscrimination―When you discovered the gene for this protein in 1991, was thegene named programmed cell death-1 (PD-1) because you weresearching a gene that is turned on when immune competent T
cells (T lymphocytes) spontaneously die, that is, when they
undergo apoptosis?

20

NAIST Research Highlights

We named it PD-1 hoping that it would be a gene involved in selfversus non-self-discrimination at the initial stage of T cell death. A
subsequent study by a graduate student who continued my research
project indicated that the gene was not directly involved in T cell
death. However, because the gene is deeply involved in self- versus
non-self-discrimination, the immune system can detect and begin
attacking cancer cells—which fluctuate between self- andnon-self—when the PD-1 function is weakened via the use of
OPDIVO or a similar antibody. Thus, the role of PD-1 was todelineate and determine between self and non-self.
―Was tenacity of purpose also the key in the experimental
method used to discover this gene?
To identify genes that are expressed only when T cells are dying, I
initially created an experimental plan to subtract genes that are
expressed when T cells are not dying. Dr. Honjo told me, “Morethan 100 candidate genes may be found with that method. That is
not acceptable.” Therefore, we used myeloid progenitor cells, which
are different from T cells, to investigate genes expressed during cell
death in the same manner and select genes common to both cells.
We found only one gene—the PD-1 gene.

Why only cancer cells are targeted―What is your research plan at NAIST?
To date, our knowledge about PD-1 is that it plays the role of abrake, i.e., a negative regulator, in immune responses. Therefore,
when an antibody binds to PD-1 and its function is weakened, thebrake is released; the immune system can then attack cancer cells at
its maximum capacity, and some patients can be cured of cancer.
However, there remains an unsolved question: Why is the immune
response to cancer cells selectively enhanced? If overall immune

Biological Science© iStock/selvanegra

responses are enhanced, it may lead to the development of autoimmune diseases; however, patients receiving the PD-1 antibody
have only experienced minor adverse reactions. This is a researchquestion whose solution requires a basic medicine approach. For
example, knockout mice with no PD-1 gene remained healthy
when they are young, but they required PD-1 to suppress autoimmune disease occurrence withincrease in age. What are the mechanisms involved? I would like toinvestigate the mechanisms in
relation to self- versus non-self-discrimination.

mutations. Cancer cells, being slightly different from normal cells,
are apparently trapped in the gap created by this widened boundary. When the PD-1 antibody is administered, cancer cells are
eliminated as non-self because the antibody restores the boundary.
At that time, some slightly mutated normal cells are also attacked. I
believe that this is the mechanism underlying the occurrence of
certain adverse reactions. Cancer cells
appear to be selectively attacked simply
because they have higher number ofmutations and are thus more readily
discriminated as non-self.

―What are being discovered?

Having a clear goal

―Based on your achievements in basic
We have proposed a hypothesis.
research on PD-1, what advice do you
Gene/DNA mutations gradually
have for young researchers?
accumulate with age, even in normal
It is crucial to “clearly know what you wantsomatic cells. Consequently, mutant
to know.” These are the words of Dr.
proteins are produced in various
Honjo. It is not sufficient to attempt
places in the body. The immune
something owing to a vague thought that it
system quickly detects and begins
seems interesting. If you have a clear goal of
attacking by considering those as
elucidating something, then you would be
non-self, resulting in autoimmune
able to determine what is required todiseases. We believe that the PD-1
Antibody-mediated blockade of inhibitory signaling
achieve it and develop an experimental
gene was acquired in the process ofthrough PD-1.
plan. In my case, I was interested
evolution to prevent the occurrence
inself-/non-self-discrimination even beforeof this phenomenon. There are tens
I joined Dr. Honjo’s laboratory at Kyoto University as a graduateof trillions of cells in the body; and it would be uncontrollable if
student, and I still am interested in that subject. I believe that such
each of them started producing a different set of mutant proteins.
kind of tenacity is necessary.
PD-1 might have widened the boundary between self and non-self
to prevent immune responses to normal cells with slight

Interviewed by Yoshinori Sakaguchi

Application characteristics of PD-1 to develop drugs for cancer immune therapy
PD-1 is a receptor expressed on the surface of immune-competent T cells on activation. When a particular substance (ligand) binds to this receptor, the immune function of
T cells is weakened. Some cancer cells express a similar substance on the surface, which binds to PD-1 on T cells and facilitate cancer cells to escape the attack by T cells.
Therefore, artificial antibodies are used to mask PD-1 to ensure that the ligand-like substance on cancer cells can no longer bind to PD-1, and the therapeutic efficacy isenhanced. Such antibodies have been used to treat numerous types of cancer, such as malignant melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin’s lymphoma, head and neck cancer, bladder cancer, and gastric cancer. However, the treatment is effective in only 20%–30% of patients with lung cancer and 30%–40% of those withmalignant melanoma. Ishida and other researchers are conducting studies to improve these rates.

More information about the group’s research can be found at https://bsw3.naist.jp/eng/courses/courses211.html

NAIST Research Highlights

21

Biological Science

RESEARCH HIGHLIGHT

Tumor Cell Biology
Prof. Jun-ya KatoStressing cancer with spiceA

new study by scientists in Japan and Indonesia reports how anexperimental drug agent stops cancer cells from growing. A
little over a decade ago, Indonesian scientists first reported
pentagamavumon-1 (PGV-1), an analogue of a molecule found inturmeric and that has been since discovered to have anti-cancer effects.
In the new study, tests on cancer cells and animals reveal that theseanti-cancer effects come from PGV-1 inhibiting a series of enzymes
responsible for the metabolism of reactive oxygen species. This finding
is expected to clarify how modifications to PGV-1 will lead to its use
for cancer treatment.
The popular spice turmeric has for centuries been used not just as aflavoring, but also as medicine, with history having shown it to have anumber of anti-inflammatory and even anti-cancer benefits. These
medicinal benefits come from the compound curcumin, which iscommonly sold as an herbal supplement. Several studies haveexamined curcumin’s anti-cancer properties, but the high doses
required and poor understanding of the chemical process throughwhich curcumin acts have limited these efforts.
The team of Professor Jun-ya Kato, at NAIST, had previously
identified that curcumin acts on the same reactive oxygen species
enzymes as its analogue, PGV-1. By suppressing the enzyme activity,
reactive oxygen species are allowed to cause stress on cells, ultimately
leading to cell death. Indeed, many anti-cancer drugs operate similarly,
but sometimes with severe side-effects due to stress on healthy cells.
In the new study, Kato’s team compared the effects of curcumin and
PGV-1 on cancer, finding that they shared many of the same properties, but that PGV-1 did so at higher efficiency and lower dose.

“We found that PGV-1 arrests cells in the cell cycle at M phase” andthat “it inhibits many ROS-metabolic enzymes,” says Kato.
This arrest prevents the cancer cells from dividing, and the enzyme
inhibition causes the cancer cells to die.
Intriguingly, PGV-1 was effective on numerous types of cancers.
Moreover, when administered to mice injected with human cancer
cells, the mice showed no evidence of the cancer and no side-effects.
Furthermore, unlike some other anti-cancer drugs, the anti-cancer
effects persisted even after the cessation of PGV-1 administration.
“Our results suggest that PGV-1 inhibits the enzyme activity more
effectively in cancer cells than in normal cells. This may be the reason
why PGV-1 selectively suppresses tumor cell proliferation with few
effects on normal cells,” notes Kato.
Scientists have long looked at the potential of curcumin to treat
cancer. Kato believes PGV-1 could provide a breakthrough.
“Considering the high drug efficacy and low amount of side effects
in animals, we propose that PGV-1 should be pharmaceuticallydeveloped as an orally administered drug for cancer,” he says.

Reference
Lestari, B., Nakamae, I., Yoneda-Kato, N., Morimoto, T., Kanaya, S.,
Yokoyama, Y., Shionyu, M., Shirai, T., Meiyanto, E. & Kato, J. 2019.
Pentagamavunon-1 (PGV-1) inhibits ROS metabolic enzymes andsuppresses tumor cell growth by inducing M phase (prometaphase) arrest
and cell senescence. Scientific Reports, 9, 14867.

Tumor cells were treated with curcumin (middle) and PGV-1 (right) and subjected to mitotic
spread assay (upper) and Giemsa staining (lower). PGV-1 treatment markedly arrested tumor
cells in the M phase of the cell cycle.

More information about the group’s research can be found at https://bsw3.naist.jp/eng/courses/courses208.html

22

NAIST Research Highlights

Biological Science

RESEARCH HIGHLIGHT

Molecular Medicine and Cell Biology
Prof. Shiro Suetsugu

Phagocytosis and the sheet model of GAS7 assembly in the phagocytotic cup.

GAS7 protein allows cells to eat

Without hands or feet, a single human cell has little to protect
itself from surrounding threats like bacteria or viruses. In
this way, the cell membrane has evolved to be much morethan a wall that keeps cell content inside and everything else outside.
By dynamically changing its shape, the membrane allows the cell topurge itself of waste and also attack nearby threats. Japanese scientists
now report how the assembly of the protein Growth Arrest Specific 7(GAS7) into two-dimensional sheets is crucial for this second process.
Phagocytosis describes a universal mechanism through which cells
consume debris from the outside. The cell membrane will deform intoa curvature known as phagocytic cup that rapidly wraps aroundnearby debris. Once fully engulfed, the debris will be passed into thespecific organelles that will dispose of it. Immune cells such as macrophages use this process to consume and destroy infected or cancerous
cells.
GAS7 is expressed in many cell types, but its function in membrane
deformation is only partially understood.
“GAS7 is expressed in macrophages, and macrophages highly
depend on phagocytosis, but we don’t know the function of GAS7 inthese cells,” explains NAIST Professor Shiro Suetsugu, who led thestudy.
Even though macrophages are only 20 or so microns wide, thephagocytic cup themselves measure in microns. In other words, themembrane deformation required for phagocytosis makes the cell like asnake that dislodges its jaw to eat something as small as a mouse or as
big as a cow.
The study shows that the presence of GAS7 could mark which sites
on the macrophage membrane would deform into phagocytic cups. By
exposing macrophages to zymosan, a type of glucan that scientists use
to model microbes, the researchers found GAS7 along with an assortment of other molecules indicative of the beginnings of phagocytosis
accumulated.

Of particular interest to Suetsugu was a specific region in GAS7,
the Bin-Amphiphysin-Rvs167, or BAR, domain. BAR domains comein several types and are responsible for a protein’s ability to bend thecell membrane. Crystal structures revealed a distinctive morphologyof the GAS7 BAR domain to be the F-BAR domain with small protrusion on its surface.
“These domains formed filamentous oligomers with flat surfaces.
The oligomers had an asymmetry due to two GAS7-specific loops sothat one side is more positively charged than the other. The positively
charged side, we supposed, could be the membrane-binding surface,”says Suetsugu.
Mutants in these loops compromised the macrophage phagocytosis for zymosan.
“Our findings indicate that the oligomerization and membranebinding of GAS7 are essential for phagocytic cup formation,” continues Suetsugu.
GAS7 is just one of many but essential proteins that have evolved tosupport phagocytosis. Elucidating the roles of the many proteins
involved in this universal mechanism will explain not only the dynamics of the membrane, but also insights on how cells could thrive andthus grow into multicellular organisms.
“Further analyses will clarify how GAS7 oligomers cooperate withother proteins to regulate membrane deformation in phagocytosis,”says Suetsugu.
Reference
Hanawa-Suetsugu, K., Itoh, Y., Ab Fatah, M., Nishimura, T., Takemura, K.,
Takeshita, K., Kubota, S., Miyazaki, N., Wan Mohamad Noor, WNI., Inaba,T., Nguyen, NTH., Hamada-Nakahara, S., Oono-Yakura, K., Tachikawa,M., Iwasaki, K., Kohda, D., Yamamoto, M., Kitao, A., Shimada, A. &Suetsugu, S. 2019. Phagocytosis is mediated by two-dimensional
assemblies of the F-BAR protein GAS7. Nature Communications, 10, 4763.

More information about the group’s research can be found at https://bsw3.naist.jp/eng/courses/courses210.html

NAIST Research Highlights

23

Biological Science

IMPACT
Applied Stress Microbiology
Prof. Hiroshi Takagi

Revealing the mechanismof stress tolerance
by cells to create
stress-resistant yeast
Yeast, which is familiar to us as an essential microorganism forproducing fermented foods, such as sake, miso, soy sauce, andbread, is used as a model microorganism to reveal fundamental
mechanisms of life. Professor Hiroshi Takagi and colleagues haveelucidated complicated but sophisticated intracellular mechanisms
underlying adaptation by yeast to various environmental stresses,
such as freezing, ethanol, temperature, osmotic pressure, reactive
oxygen species (ROS) generation, and nutrient starvation. They
applied the findings to construct stress-tolerant yeast strains that
contribute to development of fermentation process and commercial production.
Takagi says, “After working for 13 years as a researcher in a foodcompany (Ajinomoto), I decided to change my carrier to theacademic position in Fukui Prefectural University, and moved to
NAIST. Therefore, I have always been conscious of the balance
between basic science and biotechnological application.” He firstencountered yeast at the company when working on the evaluationof frozen dough for bread making. It was the time he learned about
the need for baker’s yeast which is tolerant to freeze damage.
Numerous bacteria and plant cells protect themselves fromosmotic and salt stresses by accumulating the amino acid proline;
however, yeast cells normally do not induce proline synthesis upon
exposure to stress. This fact captured his attention. He isolated yeast
24

NAIST Research Highlights

mutants capable of intracellular accumulation of proline and foundthat proline protected yeast cells from freezing and various otherstresses, such as desiccation, oxidation, osmotic pressure, andethanol. This achievement is expected to be applied to breeding
industrial yeast strains (e.g., baker’s yeast and sake yeast) with highfermentation ability.

Nitric oxide (NO) transmits information
During the proline research project, Takagi discovered a novel
N-acetyltransferase named Mpr1 in yeast. This enzyme is considered to accelerate the synthesis of arginine related to proline metabolism. Furthermore, it was found that nitric oxide (NO) is
produced by the diflavin reductase Tah18 via proline/arginine
metabolism, and NO protects cells from high-temperature stress.
Regarding NO, scientists in the US found that NO is an essential
signaling molecule in mammals and was awarded a Nobel Prize inPhysiology or Medicine in 1998. However, NO synthase (NOS) inyeast has not been identified, and research conducted on thissubject was limited.
“Because NO is highly reactive, it has two opposed functions—it
is cytoprotective if it is produced in a small amount when needed
but it can be cytotoxic if it is produced in higher quantities. I want
to clarify the detailed mechanism in yeast and molds (filamentous
fungi),” says Takagi.

© Toshi/PIXTA © hafuphoto/PIXTA

Proline protects cells

proteins denatured into an abnormal shape in the endoplasmic
reticulum, an intracellular organelle producing membrane
Another major research theme for Takagi is “functional amino acidproteins. In this system, when a sensory protein (Ire1) in theengineering”—to elucidate mechanisms of metabolic regulation
endoplasmic reticulum membrane detects stress, it is activated andand physiological functions of various amino acids produced intransmits the information to the quality control protein, i.e., molecyeast cells. In terms of application, control of amino acid composiular chaperone. Thereafter, the increased chaperone levels result intion and content contributes to an improvement in productivity
processing of the abnormal molecules.
and add the value of alcoholic beverages. He has established an
Kimata investigates the detailed mechanism underlying theefficient method for isolation of yeast mutants capable of producing
phenomenon that Ire1 certainly detects abnormal proteins anda specific amino acid in a large amount and has successfully
activates itself to induce the remaindeveloped
highlyfunctionaling response using yeast. He
brewery yeast strains. For example,
presented the following mechanism
he isolated some yeast mutants thatfor the first time: when abnormal
accumulate leucine in the cell andmolecules are accumulated, Ire1
overproduces “isoamyl acetate”
releases the bound chaperone andknown as the key flavor for sake andthen aggregates. Furthermore,bread, which is produced from theabnormal molecules bind directly toleucine synthetic pathway. By
the aggregated Ire1. Following
brewing with his yeast, the Okinawa
two-step checking, Ire1 is activatedsprit “awamori” increased a uniqueand increases the amount of chaperfruity flavor and three different
one. Microscopic observation of thetypes of awamori have already been
red fluorescent protein-labeledcommercialized.
endoplasmic reticulum and green
Currently, Takagi serves as thefluorescence-labeled Ire1 revealed
chair of the international academic
that Ire1 aggregates as dots scatteredsociety on yeast (International
across the endoplasmic reticulum in
Novel stress-tolerance mechanisms in yeast.
Commission on Yeasts); he is proud
response to stress.
of introducing Japanese excellent“Similar biological response
yeast technology for fermentation and brewing in the world.
mechanisms are found in animals. While yeast is occasionally used
Regarding NAIST, he says, “There are several researchers andfor manufacturing drugs, I intend to do research that is widely
students from various nations. Our laboratory also has many
useful for human, such as functional enhancement by increasing
graduate students and accepts short-stay researchers from overseas,
the amount of chaperone in yeast,” he says.
such as Southeast Asia, the US and European countries. I reallyInterviewed by Yoshinori Sakaguchi
enjoy to work under this diverse environment.”

Biological Science

Fruity awamori

Getting to the essence of life
Assistant Professor Ryo Nasuno is extensively investigating NO
signaling in yeast. He is searching for enzymes and nitrogen sources
directly involved in NO production, and also trying to identify
enzymes involved in the attachment (modification)/detachment of
NO to/from the relevant amino acid residues on protein when it
serves as a signaling molecule. “I investigate easy-to-handle yeast to
discover the mechanism common to all living organisms,” he says.
Assistant Professor Akira Nishimura discovered NO production during experiments when he was a student at the TakagiLaboratory. He became an assistant professor at Tohoku University, School of Medicine after graduation and then returned to
NAIST. During his research on sulfur (S) at Tohoku University, hediscovered that the antioxidant effect of the amino acid cysteine wasenormously enhanced when its SH group was replaced by the SSH
group. In yeast experiments, he has demonstrated that this type ofmolecule is a possible cellular lifespan regulator. “This moleculeappears to be involved in the energy metabolism of cells, and thisstudy may lead to drug discovery,” he says.

Unraveling the anomaly sensing system
Associate Professor Yukio Kimata is studying a system that
responds to and processes stresses, such as the accumulation ofMore information about the group’s research can be found at https://bsw3.naist.jp/eng/courses/courses305.html

NAIST Research Highlights

25

Biological Science

IMPACT
Environmental Microbiology
Associate Prof. Shosuke Yoshida

Discovering PET-eating bacteria
and elucidating the underlying
mechanism to employ them forenvironmental improvement

Disposal of waste plastics is a global issue
Reducing waste plastics, such as polyethylene terephthalate (PET)
used for drinking water containers, is a major issue worldwide
because they accumulate in and have adverse effects on the naturalenvironment. Although PET produced through chemical synthesis
is disposed via artificial processes, including recycling and incineration, capacity and cost limitations for collecting and disposing
enormous quantities of waste plastics are present.
Therefore, finding and applying a natural system that microorganisms acquired to decompose artificial materials has begun
attracting attention. Associate Professor Shosuke Yoshida and hiscolleagues were the first in the world to discover a bacterium(Ideonella sakaiensis) that possessed the ability to degrade PET.
Furthermore, they demonstrated that this bacterium decomposes
as well as consumes PET by metabolizing it. These research results,
which have the potential of accomplishing dramatic environmental
improvements, have been published in the journal Science.
“We were fortunate to find this bacterium in a PET recycling
plant. This bacterium appears to have special enzymes that canutilize PET to produce the microbial body constituents and energy.
No other bacteria like this one have been reported,” Yoshidaemphasizes.

26

NAIST Research Highlights

Two enzymes work together
This bacterium can grow using PET as a sole carbon source. In theirexperiment, approximately 250 environmental samples were
cultured with a PET film. Various types of microorganisms were
found to gather around the film. Ideonella sakaiensis was isolated
from this population. When the film surface was observed under anelectron microscope, countless dimples were formed, indicatingthat the bacterium was feeding on the PET film.
Further, to determine the mechanism of PET decomposition,
they investigated enzymes possessed by the bacterium. PET is apolymer (multimer) in which ethylene glycol and terephthalic acid
(TPA) are connected alternately together as a chain. Ethylene glycol
is an alcoholic compound, and TPA is an acidic compound witharomatic ring (benzene ring) composed of carbon atoms connected
in a hexagonal shape. The bonds connecting these units are ester
bonds. Typically, ester bonds are readily cleaved by enzymes in an
organism. However, PET is resistant to enzymatic degradation
because the aromatic ring of TPA affects the structure of the entire
PET molecule and renders it difficult to break its ester bonds.
Therefore, they anticipated that enzymes with an unknown
function are present in the PET-eating bacterium.
Yoshida analyzed the entire genome of this bacterium. Using
enzymes that were previously reported to be capable of slight degradation of PET as a suggestion, they explored the bacterial genome

Biological Science© MOHAMED ABDULRAHEEM/shutterstock.com

sequence and found PETase, a PET-specific hydrolase. This enzyme
is powerful and can create cavities in a PET film overnight when thefilm is covered with this enzyme; however, PET decomposition by
this enzyme occurs only until the production of MHET—acompound in which a single molecule ethylene glycol and TPA areconnected. Accordingly, they predicted the existence of another enzyme
capable of cleaving the bond of MHET
into two molecules to facilitate metabolization and found MHETase. These
two enzymes appear to work together.

© iStock/namiroz

For production of useful
substances

Yoshida enrolled in university to study environmental issues
and encountered research exploring PET-degrading bacteria. “Ihave been aiming at research that will produce results that people
find interesting. I want to work on carefully selected and interesting
research subjects with students,” he says. Regarding NAIST, hesays, “NAIST is actively accepting
both domestic and international
students, similar to colleges in Europe
and the United States. The university’s
educational support system forteaching individual students isoutstandingly helpful.”

Research into evolutionof PET-eating bacteria

The overall picture of the PET-eating
mechanism is being elucidated.
Members of his laboratory are“There must be other factors thatworking on the major research subject
assist in the efficient functioning ofof functional characterization and thethis mechanism. We will identify
application of PET-degrading microIdeonella sakaiensis on PET film (Yoshida et al., Science, 2016).
those factors and engineer thisorganisms from various perspectives.
bacterium to produce an industrially useful strain capable of more
They have established a method to knockout specific genes in I.
rapid conversion of PET into useful substances under mild condisakaiensis. They have successfully disrupted the PETase gene,tions,” Yoshida says. “This mechanism is also interesting from therendering it possible to identify the systems that are working andviewpoint of evolution of microorganisms. If the mutation ofdetermine the role of this enzyme. Moreover, they are interested insimply one of the amino acids that constitute an enzyme can impartthe evolution of new bacteria that have acquired the PET-degradinga new function to a microorganism, an environment where PET iscapacity.
the sole available carbon nutritional source can serve as selection
pressure to make the PET-eating bacterium the champion, thereby
Interviewed by Yoshinori Sakaguchi
leading to the selective survival of mutant microorganisms,” hecontinues.
More information about the group’s research can be found at https://bsw3.naist.jp/eng/courses/courses312.html

NAIST Research Highlights

27

Biological Science

RESEARCH HIGHLIGHT

Systems Neurobiology and Medicine
Prof. Naoyuki Inagaki

Mutation in CRASH syndrome leads to dysfunction of the grip & slip mechanism and disrupts laminin-induced axonal haptotaxis.

Axons grip and slip their way
around the brainIn a new study, NAIST scientists, in collaboration with researchers at
the Osaka National Hospital and University of Tokyo, report that
the L1 Cell Adhesion Molecule (L1-CAM) is crucial for directedaxon migration. The study shows that L1-CAM grips and slips on
laminin to steer axons to their final destination. It further explains how
disruption of this L1-CAM system leads to CRASH syndrome, which
describes an assortment of neural disabilities that are all attributed toan underdeveloped brain. The study can be read (open access) in theProceedings of the Natural Academy of Sciences of the United States ofAmerica (PNAS).
Axons sprout from neurons and then migrate to specific parts ofthe developing brain where they interact with other neurons to form
neural networks. The axons move in response to gradients of
attractants with extraordinary sensitivity; the sudden stops and sharp
turns they make during their migration resemble cars stopping andturning at an intersection.
“Laminins function as attractive chemical cues for haptotaxis ofaxonal growth cones,” explains NAIST Professor Naoyuki Inagaki,
whose lab studies how forces are generated in the cellular microenvironment to create directed axonal migration.
Axons migrate in response to laminin on the microenvironment.
The new study by the Inagaki lab showed that neurons will produce
four times more traction force when placed on adhesive substrates
coated with laminin than those without laminin, assuring the axons
reach their final destination.
“The force reduced the F-actin retrograde flow,” says Kouki Abe, adoctoral student in the lab who conducted the experiments. “We
looked at the movement of L1-CAM because it is linked to F1-actin
flow.”

Actin is a crucial molecule for cell motility throughout the body.
However, in axons, it does not directly interact with laminin. Rather,
L1-CAM acts as the intermediary. As expected, additional experiments by Abe showed that the F1-actin flow was dependent on
L1-CAM interactions with laminin.
“We found L1-CAM switches between an immobilized state, or
what we call ‘grip’ state, and a ‘slip’ state. The ratio of grip state increased
with laminin,” says Inagaki. This increased grip state strengthens thetraction force produced by the axon onto the adhesive substrate,
allowing the axon to turn and change its direction on cue. The
scientists further found that disrupting the increased grip ratio
compromised the directional migration, a discovery that could explain
the pathogenesis of several diseases.
“We examined L1-CAM from a patient with CRASH syndrome inwhich L1-CAM was mutated. The different grip ratio seen between
laminin and polylysine was lost, and the directional axon migration
was disturbed,” explains Inagaki.
“L1-CAM controls migration not only in the brain, but also incancer. Grip-and-slip is a new mechanism that could explain otherdiseases,” he says.

Reference
Abe, K., Katsuno, H., Toriyama, M., Baba, K., Mori, T., Hakoshima, T.,
Kanemura, Y., Watanabe, R. & Inagaki, N. 2018. Grip and slip of L1-CAM
on adhesive substrates direct growth cone haptotaxis. Proceedings of the
National Academy of Sciences of the United States of America, 115,2764‒2769.

More information about the group’s research can be found at https://bsw3.naist.jp/eng/courses/courses204.html

28

NAIST Research Highlights

Plant Metabolic Regulation
Prof. Taku Demura

Plant polymers do not always
act together to makebeautiful shapesAnimals and plants are distinguished by many features, one ofwhich is the cell wall. In plants, this structure acts like askeleton, providing support and stability, and also like muscle,passing water from the ground all the way to the highest leaves andbranches. The structure responsible for water transport is the secondary cell wall, which NAIST Professor Taku Demura has been studying
because it is constituted of xylem.
“Xylem is an important resource for land plant biomass. Modifications of xylem cell differentiation are important for strategies toimprove plant biomass resources,” believes Demura.
The secondary cell wall is composed of three types of polymers,
cellulose, hemicellulose, and lignin. In a new study that can be read in
Plant Cell, Demura’s laboratory found that these three polymers inxylem cell mutants contribute to secondary cell wall formation
independently of each other, challenging the contemporary model ofplant growth.
Interaction between cellulose and hemicellulose is critical for giving
cell walls their strength and elasticity to push water upward. Interaction
with lignin adds the hydrophobicity that gives an electrical charge tothe push. Studies in the early 1980s had convinced scientists that theformation of the secondary cell wall occurs in consecutive events,
beginning with the synthesis of cellulose at the cell surface, followed by

Biological Science

RESEARCH HIGHLIGHT

the deposition of hemicellulose that bonds to the cellulose, and finallythe migration and polymerization of lignin.
These interactions result in the three polymers taking an obvious
spatial pattern in xylem cells. However, xylem cells in a mutation of
Arabidopsis thaliana, a small plant commonly used by scientists tostudy plant growth, made by the Demura lab, showed disrupted
cellulose synthesis without disruption of the spatial patterning ofhemicellulose or lignin.
“We made a mutation in the cellulose synthase gene CESA7. Thismutation prevented the formation of cellulose. Despite the lack ofpatterned cellulose deposition, we saw patterned deposition ofhemicellulose and lignin,” explains Dr. Misato Ohtani, who contributed to the project.
Additional study revealed that the sustained patterning could be
attributed to microtubules, molecules seen in just about all life, including humans, and is responsible for transporting materials within cells.
“We were able to disrupt the hemicellulose and lignin patterningwhen we disrupted the microtubules with a drug. This suggests thatduring secondary cell wall formation, the hemicellulose and lignin are
regulated by microtubules and not cellulose,” continues Ohtani.
Considering the increasing efforts to bioengineer plants that can
produce resources at higher efficiencies or withstand extreme changes
in climate, Demura notes that elucidating themechanisms of how fundamental plantstructures like the secondary cell wall develop
will help scientists achieve these goals.
“Identifying the independence of
cellulose, hemicellulose and xylan suggests
we can modify one without modifying theother in plants,” he says.

Reference
Takenaka, Y., Watanabe, Y., Schuetz, M., Unda,
F., Hill, JL. Jr., Phookaew, P., Yoneda, A.,
Mansfield, SD., Samuels, L., Ohtani, M. &Demura, T. 2018. Patterned deposition of xylan
and lignin is independent from the secondary
wall cellulose of Arabidopsis xylem vessels.
Plant Cell, 30, 2663‒2676.
Patterns of different polymers in xylem cells.

More information about the group’s research can be found at https://bsw3.naist.jp/eng/courses/courses104.html

NAIST Research Highlights

29

Biological Science

IMPACT
Plant Growth Regulation
Prof. Masaaki Umeda

Revealing astute strategies employed
by stress-tolerant, long-lived plants
Stem cells underlying vitality
In evolution, plants have developed astute strategies to adapt
themselves to various environmental stresses, such as ultraviolet
rays and high temperatures, for the survival of individuals andprosperity of species. The Plant Growth Regulation Laboratory has
revealed detailed mechanisms underlying ingenious functions ofindividual plant cells at the DNA level and employed this knowledge into applications, such as increased food and biomass production.
Professor Masaaki Umeda says, “Our research subjects include
an extension of plant lifespans and enlargement of plant sizes.

30

NAIST Research Highlights

Regarding lifespan, we are attempting to elucidate the mechanisms
underlying the maintenance of pluripotent stem cells, which undergo differentiation to various organs and support the foundation ofvitality, as well as the mechanisms underlying high-stress tolerance.
Regarding enlargement, we are studying ‘DNA polyploidization,’
which results in volume increases of individual cells.”

Information exchange between cells
Trees continue to grow throughout their lives, and some become
massive trees after more than a thousand years. “Permanently
repeated proliferation and regeneration of stem cells represent theunlimited source of power,” Umeda believes. “Principles of plurip-when chromatin is loosened. Chromatin is a string-like complex,
which comprises DNA wrapping around a protein called histone.
He is also investigating compounds that promote DNA polyploidization.
“The foundation of this research was the cell cycle of plants.
This research subject attracts more attention and more researchers,
although it used to be mundane and unpopular. Rather than goingafter popular research subjects, I choose ones that excite and inspire
me. Discoveries and breakthroughs happen from such research,” heemphasizes.

environmental stresses, Umeda predicts that, conversely, if thegenes can be suppressed to prevent these factors from being
produced, one can create super stress-tolerant plants that continue
to grow regardless of environmental stresses that the plants are
exposed to. Indeed, some rice varieties that are highly tolerant tostresses in the soil reportedly have lost the genes of these factors
during selective breeding.

New functions of phytohormones

Biological Scienceotent stem cells underlying plant vitality,” led by Umeda, waslaunched as Scientific Research on Innovation Areas, a MEXT
Grant-in-Aid Project; it comprises multidirectional collaborative
studies with universities and research institutions across Japan.
At the root tip of Arabidopsis thaliana, stem cells surround cells
called the quiescent center. “The division cycle of stem cells is
controlled by an enzyme called CDK, and the stem cells undergodifferentiation when a CDK-inhibiting factor acts on this enzyme,”
Umeda explains. Investigations in columella stem cells, which
undergo only a single cell division, have shown that a factor called
WOX5 migrated from the quiescent center only to the adjacentstem cells, where it stops the CDK inhibitory action and maintains
the stem cell function.
“WOX5 determines whether stem cells continue to remain asstem cells. A plant cell is encapsulated in a hard cell wall and isunable to move within tissues. Therefore, stem cells are likely to be
kept maintained at a proper
place via cell–cell informationexchange,” Umeda says.

Life and death occur side-by-side

Assistant Professor Naoki Takahashi investigates the mechanism
via which root meristems are maintained to allow for the continuous growth of plants in a stressful environment. In plants, cell death
as a means to eliminate abnormal cells due to DNA damage is aphenomenon observed only instem cells, and the phytohormone auxin inhibits the induction of cell death. FurtherSuper stressmore, when stem cells die,tolerant plants
stress-resistant cells in thequiescent center initiate cell
Plants actively arrest cell
division to regenerate stem
division, thereby suppressing
cells. Takahashi found thatgrowth and saving energy
another
phytohormone—consumption to concentrate on
brassinosteroid—is involved instresses, such as DNA damage.
the process. These findings
Umeda has elucidated theindicate that the life and deathsignal transduction pathwayof stem cells occur in cells
between stress detection andadjacent to each other.
cell division arrest. Specifically,“For a long time, I have
two transcription factors (suchbeen engaged in this field of
as ANAC044) controlling gene
research, such as intracellular
expression are induced andArabidopsis root tip treated with DNA-damaging agents.
monitoring mechanisms, tostabilize different transcription
determine if cell cycle steps arefactors (such as MYB3R3),
normal (e.g., cell division and DNA polyploidization). In the future,
thereby suppressing genes involved in the progression of cell
I intend to extend my research to more application-oriented
division.
subjects, such as stress tolerance,” he says.
Because these factors are induced in response to various

Chromatin loosens
A discovery was made in the research on plant body enlargement.
During the cell cycle, DNA in a cell is replicated and doubled inamount, following which the cell is divided into two with theoriginal amount of DNA. Therefore, duplication of DNA in cells,
called polyploidization, can be induced by blocking and skipping
the division step. Large crops can be produced by applying thismethod to increase the amount of DNA per cell. However, sometrees, such as poplars, do not undergo DNA polyploidization.
Umeda discovered that DNA polyploidization is likely to occur

Assistant Professor Shiori Aki has discovered that Marchantia
polymorpha, a liverwort that is the ancestor of land plants, has asignal transduction pathway responding to the phytohormone
cytokinin, which promotes cell division. The pathway controls
differentiation into various organs, including the gemma cup
required for asexual reproduction.
“I wanted to become a plant researcher because I grew up in arural area, noticing how various plants change their appearance. I
am interested in basic research, and I intend to make discoveries
that are going to be described in textbooks,” she says.
Interviewed by Yoshinori Sakaguchi

More information about the group’s research can be found at https://bsw3.naist.jp/eng/courses/courses105.html

NAIST Research Highlights

31

Biological Science

RESEARCH HIGHLIGHT

Plant Growth Regulation
Prof. Masaaki Umeda

Plants grow lessin hotter temperaturesP

lants have developed a robust system that stops their cell cycle inhostile environments such as abnormally hot temperatures. In
response, they direct their energy to survival rather than growth.
A new study led by scientists at NAIST reports in eLife that twotranscription factors, ANAC044 and ANAC085, are critical for this
response in the flowering plant Arabidopsis. The findings give clues onways to modulate the growth of crops and other agriculture products.
Upon DNA damage, plants and animals halt cell division andexecute DNA repair. This response prevents the damaged cells fromproliferating. NAIST Professor Masaaki Umeda has made a career
studying the molecular biology behind this protective measure.
“We reported that SOG1 is activated by DNA damage and regulates
almost all genes induced by the damage,” he says. Another study fromthe lab showed “Rep-MYBs are stabilized in DNA damage conditions
to suppress cell division,” he adds.
In the laboratory’s newest study, Umeda’s research team shows that
ANAC044 and ANAC085 act as a bridge between SOG1 and
Rep-MYB.
The scientists disrupted DNA in Arabidopsis cells by treating thecells with bleomycin, a compound commonly used to halt the growthof human cancer cells. The Arabidopsis cells failed to proliferate as
expected unless they possessed a mutation in ANAC044 or ANAC085.
In the mutant cases, the cells proliferated as though they were never
exposed to bleomycin.
“We found that ANAC044 and ANAC085 are essential for root
growth retardation and stem cell death, but not for DNA repair,” says
Umeda.
Specifically, ANAC044 and ANAC085 were responsible forpreventing the cell cycle from proceeding from G2 phase to mitosis in
response to the DNA damage.
Rep-MYBs cause the same arrest in the cell cycle. Consistently, innormal cells, bleomycin caused a rise in the accumulation of
Rep-MYBs, but not in cells with ANAC044 and ANAC085 mutations.
These findings suggest ANAC044 and ANAC085 act as a bridge
between SOG1 and Rep-MYBs in the halting of the cell cycle upon
DNA damage.
DNA damage is just one form of stress that can cause the cell cycle
to pause. To investigate whether ANAC044 and ANAC085 act in
response to other forms of external stress, the researchers exposed thecells to different temperatures and osmotic pressure which cause theretardation in G2 and G1 progression, respectively.
Growth arrest was observed in both mutant and normal cells at ahigh osmotic pressure, but higher temperatures only caused pauses in
the cell cycle in normal cells, indicating that ANAC044 and ANAC085
act as gatekeepers in the progression from the G2 phase in the cell cycle
under abiotic stress conditions.

The fact that ANAC044 and ANAC085 operate in response todifferent types of abiotic stress suggests to Umeda that they may be at
the core of new technologies designed to modulate plant growth.
“The research illuminates a new mechanism that optimizes organ
growth under stressful conditions. When trying to increase plant
productivity, scientists should consider ANAC044 and ANAC085,” hesays.

Arabidopsis root tip treated with DNA-damaging agents. Cells (red units) withgreen color, which indicates Rep-MYB stabilized by ANAC044/085, arestopping cell division.

Reference
Takahashi, N., Ogita, N., Takahashi, T., Taniguchi, S., Tanaka, M., Seki, M.
& Umeda, M. 2019. A regulatory module controlling stress-induced cell
cycle arrest in Arabidopsis. eLife, 8, e43944.

More information about the group’s research can be found at https://bsw3.naist.jp/eng/courses/courses105.html

32

NAIST Research Highlights

Biological Science

RESEARCH HIGHLIGHT

Plant Stem Cell Regulation and Floral Patterning
Prof. Toshiro Ito

Proper flower growth depends on the activation and suppression of floral stem cells (left). KNUCKLES and WUSCHEL
expression are seen to colocalize in the nucleus to suppress floral stem cell activation (right).

Turning off growth
to make flowers growThe beautiful colors and smells of flowers serve a much greater
purpose than just decorating one’s home. Flowers are where
the plant’s reproductive organs are found, and those samecolors and smells that make a room beautiful also attract bees andother animals for pollination. Floral stem cells are crucial for thegrowth of the flower and its organs. That growth must eventuallyterminate for the flower to fully develop and set seeds. A new study led
by scientists at NAIST and seen in The Plant Cell shows that thetranscription factor KNUCKLES is a key regulator of this stem cellarrest by initiating a serious of epigenetic events to repress the stem cell
determinant WUSCHEL.
“Floral stem cell activity vanishes when WUSHCEL is suppressedand silenced through changes in its chromatin state. What we did notknow was how this change begins and how it is sustained,” explains
NAIST Professor Toshiro Ito, who led the study.
Ito’s team looked at the activation and suppression of floral stem
cells from Arabidopsis. Stem cell activation was marked by a clear
expression of WUSCHEL, but that changed when the cells also began
to express KNUCKLES, which bound to the WUSCHEL locus and led
to WUSCHEL’s expression almost halving four hours later.
Then at 8-12 hours after the KNUCKLES expression, the group
found that the WUSCHEL locus showed signs of H3K27me3 histone
methylation, a marker of sustained gene suppression.
The question Ito wanted to answer was what were the events thattook place from the KNUCKLES binding to the WUSCHEL locus to
the H3K27me3 histone methylation that could terminate the stem cell
activation.

“H3K27me3 is catalyzed by Polycomb Group complexes, but
nothing is known about how the complexes are recruited to the
WUSCHEL locus,” says Ito.
The researchers discovered that KNUCKLES binding to
WUSCHEL jettisoned SPLAYED, a chromatin remodeling proteinthat activates WUSCHEL. This effect leads to rapid transcriptional
repression of WUSCHEL, followed by the recruitment of Polycomb
Group complex to WUSCHEL, where it formed H3K27me3 marks on
the chromatin to suppress gene expression.
“KNUCKLES binding was essential for the rapid removal of active
H3K4me3 marks and the following deposition of repressive
H3K27me3 marks,” explains Ito.
The recruitment was done by KNUCKLES interacting with a
specific component of the Polycomb Group complex known as
FERTILIZATION-INDEPENDENT ENDOSPERM.
“Our study reveals the temporal steps from KNUCKLES binding to
H3K27me marks that silence the WUSCHEL chromatin. Understanding how stem cell activation is terminated will assist in new foodtechnologies,” says Ito.

Reference
Sun, B., Zhou, Y., Cai, J., Shang, E., Yamaguchi, N., Xiao, J., Looi, LS., Wee,
WY., Gao, X., Wagner, D. & Ito, T. 2019. Integration of transcriptional
repression and Polycomb-mediated silencing of WUSCHEL in floral
meristems. The Plant Cell, 31, 1488‒1505.

More information about the group’s research can be found at https://bsw3.naist.jp/eng/courses/courses112.html

NAIST Research Highlights

33

MATERIALSSCIENCEMaterials Science

RESEARCH HIGHLIGHT

Bio-Process Engineering
Prof. Yoichiroh Hosokawa

Measuring metabolites
in algae one cell at a time
the accumulation of paramylon with time, thus discriminating
efficient cells from their unproductive neighbors.
While the system was only tested on paramylon, Hosokawa statesthat other metabolites will be detectable with appropriate aptamers.
“Our method gives spatial and temporal information about target
intracellular paramylon, but should work for any kinds of metabolites
in future. It will be useful for selecting high-performance cells,” he says.

Reference
Maeno, T., Uzawa, T., Kono, I., Okano, K., Iino, T., Fukita, K., Oshikawa, Y.,
Ogawa, T., Iwata, O., Ito, T., Suzuki, K., Goda, K. & Hosokawa, Y. 2018.
Targeted delivery of fluorogenic peptide aptamers into live microalgae by
femtosecond laser photoporation at single-cell resolution. Scientific
Reports, 8, 8271.

© Lebendkulturen.de/shutterstock.com

In the search for new sources of consumables, scientists have come torealize that life itself could be the solution. Metabolic engineers havealtered the metabolism of living organisms to make new drugs,
biodegradables and biofuels. One of the best examples in modern
times is penicillin. Metabolic engineering bacteria has improved the
production rate of this drug more than 100 times.
A major challenge in this field is identifying which cells are themost productive. It is relatively easy to study bulk populations, which
results in information about the metabolism of the overall cell population. However, it remains extremely difficult to identify which cells inthe bulk population stand above the rest in terms of metabolite
production and are therefore the best to copy and imitate. This identification requires observing inside individual cells in real time while themetabolite is made. Scientists at NAIST report a new system that
achieves this goal in microalgae cells. The system, which can be readabout in Scientific Reports, combines fluorogenic aptamers with femtosecond laser photoporation.
“Algae have a number of attractive qualities formetabolic engineering. First, they are extremely
adaptive, as they have the ability to live in a broad range
of environments, from the equator to the poles and evenin heavily saline or polluted waters,” says Professor
Yoichiroh Hosokawa, who led the study.
Normally, scientists use fluorescence microscopy tolook inside a cell. This strategy involves attaching amolecule that fluoresces to the metabolite of interest.
However, because of cell wall protection, it has beendifficult to introduce fluorescent molecules that detectspecific metabolites in microalgae cells from outside.
Hosokawa’s team has therefore been developing
fluorescent aptamers that emit fluorescence uponbinding to the metabolite paramylon and manufacturingmethods that can introduce them into the cell by laser
pulses.
“We synthesized a peptide aptamer binding toparamylon, and introduced it into Euglena gracilis cellsby single cell laser processing,” says Dr. Takanori Maeno,
who first-authored the study. “Paramylon is produced
only by Euglena and functions like fiber. It can be refined
into biofuels,” he adds.
To get the aptamer inside the cell, the scientists shot
the cells with laser pulses only femtoseconds long. These
pulses created temporary pores big enough for the
aptamers to enter. Once inside, the cells turned green
only in places where the aptamers bound to paramylon.
Euglena
Using this technique, Hosokawa’s group could measure

More information about the group’s research can be found at https://mswebs.naist.jp/english/courses/list/labo_11.html

NAIST Research Highlights

35

Materials Science

IMPACT
Quantum Materials Science
Prof. Hisao Yanagi

Light is created with quanta;
quanta are manipulated by light
Lasers realized using organic materials
A number of photonic network projects are underway to accelerate
information processing and communications by exclusively using
light, with the aim of curbing the rapidly increasing energy
consumption. A significant challenge is to replace the current
situation in normal households, wherein light signals from theoutside are converted into electric ones, to a situation wherein thelight signals are directly utilized by circuits and devices to improvethe energy-saving effect.
36

NAIST Research Highlights

Professor Hisao Yanagi says, “We are developing an organic
laser for light emission, including the light source of opticalcommunication, sufficiently utilizing the characteristic of organic
materials whose molecular design is easy.” He emphasizes, “We
have also been studying the technology that will become the basis
for realizing the super-high-speed quantum computer, which is thepivot of next-generation information processing and communication.”
His group’s study is based on quantum mechanics, a physics
that elucidates phenomena occurring at the atomic or molecularThere was a delayed
response

controlling and reading the quantum state with a time accuracy of
1/1,000,000,000,000,000 of a second or less. If this technique is used
for quantum computers, substantial information could be simultaneously processed in parallel using the superposition of waves.
Furthermore, if a special state called “polariton”, where the lightand molecules in the excited state are mixed at room temperatureusing an organic material, is available, it could enable the application of the quantum coherence control technique under convenientconditions such as on a laboratory table at room temperature.
Furthermore, Katsuki is studying the state known as “vibrational polariton,” wherein molecular vibrational motion and light are
mixed. Using this state, the reaction
path that could not be realized throughconventional chemical reactions can becontrolled and products can beselectively controlled.

Materials Sciencelevel. Light and electrons in a substance are quanta that exhibit
particle properties as well as wave properties. If the position of thepeaks and valleys in multiple waves is aligned, they strengthen eachother; otherwise, they cancel each other out. This characteristic
phenomenon is called “interference.” The electrons in a substanceare enclosed in a molecular box (quantum box), and they behave asa wave on an orbital according to each energy level. The lightemission mechanism is that when an electron is excited to a higher
orbital, subsequently returning to a lower orbital, it releases energy,
which becomes light.

The material studied by Yanagi’s
group is an organic compound called
thiophene phenylene co-oligomer(TPCO) with characteristics of an
Organic crystals for neworganic semiconductor. Various
developments
optical functions from only theorganic material have been elucidat“When the brain is stimulated, nerveed. “When the number or order ofcells quickly and simultaneously
ring structures contained in thisprocess information in parallel throughmolecule is changed, various
quantum interference. In plants,
wavelengths of visible light, from blue
photosynthesis utilizes 100% of theto red, can be emitted. We have alsoavailable sunlight by absorbing the
been able to confirm the effect ofenergy in an aggregate of chlorophyl
confining light in a crystal, which is amolecules and transmitting it throughtype of resonator that amplifies thequantum waves. Organic compounds
light,” Yanagi explains.
that can utilize quanta at room
A molecular crystal-based organic laser.
Using this compound, theytemperature will provide new developsucceeded in optically pumped
ments in the field,” Yanagi expects.
organic laser. After deviating
Assistant Professor Hitoshi Mizuno
electrons to a higher energy orbital (a state called population
says, “As laser oscillation from TPCO crystal shows a specificinversion), photons were generated in a chain reaction through aphenomenon like delayed emission at low excitation energy,
phenomenon called “stimulated emission.” A strong laser beamfurther applications such as devices that temporarily record opticalwith wavelengths of various colors in the visible light region were
information can be expected.”
generated by amplifying photons through phase-matched waves.
Interviewed by Yoshinori Sakaguchi
In a series of such achievements, Yanagi’s group made a significant discovery concerning organic material. When they excited anorganic material via laser irradiation for a short period of time
(1/10,000,000,000,000 of a second), they observed “delayed
luminescence” in which light emission was delayed by~3/10,000,000,000 of a second at a certain range of excitationenergy. “The electron waves in the material interfered with eachother, matched the phase of the waves, and behaved as one
luminous body. This delay constituted the time taken for synchronism,” Yanagi explains. This phenomenon is called “quantum
coherence” and could be related to superfluorescence and used forthe basic technology in quantum computers. “In addition to theorganic laser of the optically pumped type, going forward, we will
advance our studies to that of the electrically pumped type,” Yanagi
says.

Basic technology for quantum computer
Associate Professor Hiroyuki Katsuki has undertaken research on“quantum coherence control” to operate the quantum wave inside
a crystal with ultrashort light irradiation, and has succeeded in

Luminescence from impuritydoped semiconductor nanoparticles.

More information about the group’s research can be found at https://mswebs.naist.jp/english/courses/list/labo_01.html

NAIST Research Highlights

37

Materials Science

IMPACT
Organic Electronics
Prof. Masakazu Nakamura

Developing a new ﬁeldof electronics with
ﬂexible organic semiconductors

Converting exhaust heat into electric energy
Electronics for any surface
Research and development using soft organic compounds asmaterials for next-generation electronics has entered the practicalstage. Bendable high-definition organic electroluminescence
displays have been commercially manufactured, and the practicaluse of organic thin-film solar cells and organic transistors is also
underway. Organic materials exhibit unique characteristics against
their counterparts, such as silicon, including being lightweight,
flexible, and enabling the manufacturing of large-area devices using
low-cost printing techniques. The performance of organic devices
has been markedly improved by the scientists’ efforts to utilize thecharacteristics of organic molecules.
The Organic Electronics Laboratory is researching a range ofthemes, predominantly on organic devices that generate electrical
power from the surrounding environment. Studies are being
conducted from multiple perspectives, such as condensed matterphysics, electronic engineering, surface science, and materials
chemistry. The Laboratory is tackling various themes from thebasics to applications while focusing on the fundamental understanding of the inside of phenomena. Their initiatives include thedevelopment of the world’s only one instrument that can analyze
the nanoscale distribution of electric potential in a material inwhich electric current flows and also the use of theoretical calculations for analyzing unmeasurable parameters of the materials.
Professor Masakazu Nakamura says, “I have continuallyconducted studies to elucidate various interactions in organic
materials and their applications, keeping in mind that we canenrich our lives by adding the functions of electronics to the surfaceof various objects (any surface), such as electronic devices that canbe folded like paper and power-generating clothes.” The current
application research is directed to organic thermoelectric materials,
next-generation plastic solar cells, and super-flexible organic logic
circuits.

38

NAIST Research Highlights

The aim of studying organic thermoelectric materials is to collectexhaust heat from the living environment and the human body andconvert it into electric energy, using a phenomenon called theSeebeck effect, in which a temperature difference in the materials
generates an electromotive force and thus a current in a circuit.
Typically, when the Seebeck coefficient and electrical conductivity
are higher and the thermal conductivity is lower, the efficiency
becomes higher.
Regarding this effect, Nakamura’s group encountered a significant discovery. A fullerene film with sufficiently increased purity
exhibited a giant Seebeck effect, generating a high voltage that is
approximately 100-fold the conventional theoretical value. Later, asimilar phenomenon was found with many other organic
small-molecule semiconductors; however, this is not explainable by
the conventional theory of inorganic materials. When it is practically implemented, a thermoelectric converter with an extremely
simple structure, reminiscent of that of a dry cell, can be realized, inwhich the flexible organic thermoelectric material is sandwiched by
two electrodes. “A unique nature of organic solid such that themolecules are condensed by a weaker interaction than inorganic
materials might be related to the novel phenomenon,” Nakamura
explains.
One of the nanocarbon materials called carbon nanotubes(CNTs) has the issue of extremely high thermal conductivity;
however, Nakamura’s group has also succeeded in developing ananocomposite material that inhibits the thermal conductivity to as
low as 1/1,000 by adding a special protein in between CNTs.
Furthermore, a study on “power-generating clothes” is underway,
in which threads are fabricated with CNTs and sewn into the fabricto make clothes that generate electricity using body heat. “Theorganic thermoelectric materials can exert their strength bydeveloping them such as not to aim at the champion data on
conversion efficiency but rather to prioritize their usability,”
Nakamura says.

Materials Science© iStock/piranka

indistinguishable manner. We use conjugated polymers as anext-generation semiconductor for transistors because of theirunprecedented flexibility and relatively high carrier mobility along
Plastic solar cells are fabricated by mixing two types of organic
orientation direction of the polymer backbone when it is aligned.
semiconductor materials called conjugated polymers that carry“We are developing such fabrication methods that can be print
either a positive or a negative charge and dropping their solution
large-area thin films of oriented conjugated polymers to produce
onto a transparent electrode to form a thin film. By putting anotherhigh-performance super-flexible electronic circuits,” Nakamura
electrode on the other side, they absorb light and generate electricisays.
ty. Plastic solar cells can be fabricated with a low-cost process and“My research started in theare usable even when attached to a
field of inorganic semiconductors
curved wall surface. Furthermore,
based on applied physics. Unlike
they can absorb light of different
such inorganic materials, howevwavelengths depending on the types
er, organic semiconductors showof conjugated polymers used.
a semiconducting property even
Although their practical use hasin one molecular unit. Desired
been promoted due to their superior
functions can be freely tailored bycharacteristics, the quantitative
combining molecules as building
understanding of the photocarrier
blocks to form various structures,
generation/recombination/transpiling up heterologous molecules,
port mechanisms required foror allowing them to be self-orgafurther technological advancement
nized. I was attracted to thesehas not yet been achieved.
functions,” Nakamura says. His
Associate Professor Hiroaki
motto is, “research begins from
Benten says, “The conjugatedanalyzing and measuring materipolymer layer is thin (100 nm), andSchematic illustration explaining the mechanism of the Giant Seebeck
als to understand their propertheinternalstructurethateffect in organic semiconductors which is discovered in the NAIST
ties,” and he has developed many
determines the power-generation
Organic Electronics Laboratory.
unique instruments for characterperformance is even smaller. Thereizations. “Many staff members
fore, we are using original approachfrom different fields work together at my laboratory and proceed
es, such as visualizing various local functions using the cantileverwith multidisciplinary integrated studies, and this is an advantage
tip of a scanning probe microscope (SPM) as a nanoelectrode toof NAIST, which is a research-oriented graduate university thatexamine the factors that determine the performance. The photoenables such a fusion,” he explains.
electric conversion is deeply related to how the polymers are mixed,
and we aim to clarify the concealed nanostructures and mechaInterviewed by Yoshinori Sakaguchi
nisms.”
Transistors are essential for almost all kind of electronic circuits
and this simple device has been blended in our lifestyle in an

Solar cells made of “plastic”

More information about the group’s research can be found at https://mswebs.naist.jp/english/courses/list/labo_10.html

NAIST Research Highlights

39

Materials Science

RESEARCH HIGHLIGHT

Photonic Device Science
Prof. Jun Ohta

Miniaturized infrared
cameras take colored photosof the eyeLook into one’s eye and you might be able to see their soul. Or atleast you can see signs of a stroke or diabetes. By looking at the
blood vessels in the eyes, doctors can tell a lot about a person’shealth. This can be done using fundus photography, which has beenaround for almost two centuries and is the standard imaging tool usedby ophthalmologists. However, for many, especially the poor, travelingto a clinic is not practical. Researchers at NAIST, in partnership with
scientists at the University of Tokyo, have devised a new fundus camera
small enough to fit on a smartphone that could get around thisproblem. The study was described at the 2018 IEEE Symposium on
VLSI Technology this month.
NAIST Professor Jun Ohta is researching the interface of photonic
materials and biomedical treatments for the eye.
“We study photonic devices for biomedical uses. One of our goals is
retinal prosthesis to restore vision. We work on highly sensitive
imaging sensors for diagnostics of the eye,” he says.
When taking a photo of the fundus, the camera must align itself
with the path of light that travels through the retina to the back of theeye. The eye, however, makes regular and rapid movements, constantly

changing this path. To resolve this problem, the new camera describedat the symposium achieves 1000 images/s.
Another challenge when imaging the fundus is the wavelengths oflight detected by the camera. To take a clear fundus image, a strong
flush light must be introduced inside an eye through a pupil because it
is completely dark inside the eye.
For this second problem, the researchers modified CMOS cameras.
The cameras use microelectronics technology to acquire color imagesby using three kinds of invisible light or near infrared light. The newmodule was developed on a miniaturized sensor and incorporates
three near infrared filters. These filters acquire three signals that can begiven a red, green and blue value to generate a color photograph of theeye while using near infrared light that is not sensed.
Importantly, at 2.3 mm2 in size, the module is small enough to be
mounted on a smartphone without compromising the power
necessary for capturing highly detailed images with which a user cantake a fundus image by him/herself. Ohta imagines a future where
patients can be diagnosed with nothing more than the phone in theirpocket.
“People may be able to take a picture of theireye by themselves and know the status of theirhealth from the fundus image. This could open
the door for a personal healthcare system using
fundus images. In addition, they could send it to adoctor over the internet. For people in countries
like Japan perhaps, visiting an ophthalmologist is
not difficult. However, in many countries, it is areal privilege. I want to see our technology
improve people’s health globally,” he says.

Reference

Fundus image taken by portable near-infrared fundus camera.

Sumi, H., Takehara, H., Miyazaki, S.,
Shirahige, D., Sasagawa, K., Tokuda, T.,
Watanabe, Y., Kishi, N., Ohta, J. & Ishikawa,M. 2018. Next-generation fundus camera
with full color image acquisition in 0-lx
visible light by 1.12-micron square pixel, 4K,
30-fps BSI CMOS image sensor withadvanced NIR multi-spectral imaging
system. 2018 IEEE Symposium on VLSITechnology.

More information about the group’s research can be found at https://mswebs.naist.jp/english/courses/list/labo_03.html

40

NAIST Research Highlights

Photofunctional Organic ChemistryProf. Hiroko Yamada

World’s widest graphene nanoribbon
promises the next generationof miniaturized electronics

Materials Science

RESEARCH HIGHLIGHT

W

ith literally the thickness of one carbon atom and electricalproperties that can surpass those of standard semiconductor
technologies, graphene nanoribbons promise a new generation of miniaturized electronic devices. The theory, however, remains far
ahead of reality, with current graphene nanoribbons falling short of theirpotential. A new collaborative study seen in Communications Materials
by a project of CREST, JST Japan including NAIST, Fujitsu Laboratories
Ltd. and Fujitsu Ltd., and the University of Tokyo reports the first ever17-carbon wide graphene nanoribbon and confirms it has the smallest
bandgap seen to date among known graphene nanoribbons prepared by abottom-up manner.
Large-scale integrated circuits (LSIs) that use silicon semiconductors
are used in a wide range of electronic devices, anywhere from computers
to smartphones. They are actually supporting our lives and almost
everything else these days. However, although LSIs have improved device
performance by reducing the size of the devices, LSI miniaturization isapproaching its limit. At the same time, commercial demand continues toput pressure on companies to make higher performing smartphones at
smaller sizes, while industry pressure is demanding large-scale manufacturing with smaller equipment.
“Other methods and/or materials are definitely needed to solve these
problems,” says the group leader Dr. Shintaro Sato, Fujitsu Ltd.
“Silicon semiconductors are giving us better performance at smaller
sizes. However, we are reaching the limit in how small we can makedevices. Thus, we have high expectations for the performance of graphene
nanoribbons, which have semi-conducting properties that are only one
atom thick – a 2D material,” he notes.
Graphene nanoribbons are honeycomb-like structures and, comparedto graphene and carbon nanotubes, are the lesser known carbon-based
semiconductor family member. Graphene nanoribbons exhibit uniqueelectronic and magnetic properties that do not appear in two-dimensionalgraphene.
“Interestingly, the electronic and magnetic properties of graphene
nanoribbons are widely tuned as a function of the width and edge
structure.” says Professor Hiroko Yamada at NAIST.
Armchair-type graphene nanoribbons, which are promising type ofnanoribbon for device application, display width-dependent band gap.
They can be classified into three subfamilies (3p, 3p + 1, 3p + 2), their bandgaps being inversely proportional to the width of those families. Basically,wider armchair-edge graphene nanoribbons belonging to the 3p + 2
subfamily have the smallest bandgaps among different graphene nanoribbons, having considerable potential to be exploited in GNR-based devices.
So far, 13-armchair graphene nanoribbons belonging to the 3p + 1
subfamily with a band gap of more than 1 eV have been reported, but Sato,
Yamada and colleagues show the synthesis of a 17-graphene nanoribbon(a) Bottom-up synthesis scheme of 17-AGNR on Au(111), (b)high-resolution STM image, and (c) nc-AFM image of 17-AGNR.

belonging to the 3p + 2 subfamily, which have even smaller bandgaps.
The graphene nanoribbon synthesis was based on the bottom-up
approach, called “on-surface synthesis,” and a dibromobenzene-based
molecule was used as a precursor for on-surface graphene nanoribbon
synthesis.
“There are many methods to synthesize graphene nanoribbons, but toproduce atomically precise graphene nanoribbons, we decided to use thebottom-up approach. The important point is that the structure of the
precursor can define the ultimate structure of graphene nanoribbons if we
use the bottom-up approach,” explains NAIST’s Dr. Hironobu Hayashi,
who also contributed to the study.
Scanning tunnel microscopy and spectroscopy by Dr. Junichi Yamaguchi at Fujitsu. Ltd. and non-contact atomic force microscopy by Dr.
Akitoshi Shiotari and Professor Yoshiaki Sugimoto at the University ofTokyo confirmed the atomic and electronic structure of the acquired
17-armchair graphene nanoribbons. Additionally, the experimentallyobtained bandgap of 17-armchair graphene nanoribbons was found to be
0.6 eV, and this is the first demonstration of the synthesis of graphene
nanoribbons having a band gap smaller than 1 eV in a controlled manner.
“We expect these 17-carbon wide graphene nanoribbons to pave theway for new GNR-based electronic devices,” says Sato.
Reference
Yamaguchi, J., Hayashi, H., Jippo, H., Shiotari, A., Ohtomo, M., Sakakura,M., Hieda, N., Aratani, N., Ohfuchi, M., Sugimoto, Y., Yamada, H. & Sato,S. 2020. Small bandgap features achieved in atomically precise
17-atom-wide armchair-edged graphene nanoribbons. Communications
Materials, 1, 36.

More information about the group’s research can be found https://mswebs.naist.jp/english/courses/list/labo_08.html

NAIST Research Highlights

41

Materials Science

IMPACT
Photonic Molecular Science
Prof. Tsuyoshi Kawai

Skillfully utilizing the powerof light and heatto actualize next-generation
high-performance molecules
More sensitive than the human eye
With the advancement in sophisticated information systems,
energy-saving, and the use of renewable energy, expectations fordeveloping new high-performance materials are increasing. The
Photonic Molecular Science Laboratory is staying ahead of thecurve and expanding its research themes, such as photochromic
molecules whose molecular structure changes reversibly with lightirradiation and materials that convert exhaust heat into electricity.
Professor Tsuyoshi Kawai talks about photochromic molecules,
which are the basis of his research, saying, “The retina of the humaneye has optical sensor molecules called the retinal, and its efficiency
in reacting to photons (quantum yield) is as high as 65%. This isabout twice higher than reptiles and has been essential for our

42

NAIST Research Highlights

ancestors to survive at the age of dinosaur. We aim to synthesizeorganic molecules with better efficiency.”
Based on the molecular structure and other properties of theretinal, Kawai’s group found that fluctuations in the diverse
structures (referred to as “conformation”) of artificial photochromic molecules result in the low efficiency, and achieved a highefficiency of 100% by fixing them to the planar structure throughthe method of molecular engineering. They claim first “photonquantitative reaction”. By expanding this molecular concept forpractical functionality, they developed a highly sensitive photoacid
generator. For example, semiconductor processing requires areaction between a photosensitive material (resist) and an acid totranscript a circuit pattern. Such an acid could be yielded with lightwith an efficiency of approximately 70%, which is twice as efficientas the conventional materials. “Beyond the classic photoacid gener-

Endless domino reaction“I am interested in chirality and will continue to conduct studies
in this direction. I want to find basic characteristics that can beapplied widely. My principle is to work through a mystery until it isunderstood,” he says.

Light and durable thermoelectric conversion

Materials Scienceators, our latest photoacid generator release no conventional acids
but non-protic Lewis acids. We developed ‘Photo-Lewis Acid Generator, PLAG’ as the state-of-art photoactive material,” Kawai says.

Furthermore, Kawai’s group made a discovery that significantly
sheet
advanced the above study. When addressing the issue that theefficiency to erase color with light conversely decreased to approxiAssistant Professor Yoshiyuki Nonoguchi studies thermoelectricmately 0.5% as the performance of the coloration improved, they
power generation to convert the temperature difference resulting
changed their approach to the idea that “when an electric current isfrom heat energy, such as exhaust heat, into electric energy. As theapplied, and a reaction that extracts an electron from a moleculematerial used for this device requires high durability, he spread aoccurs, the molecular structure changes, and the color disappears.”carbon material called carbon nanotube (CNT), which is light andThey successfully developed an electrochromic molecule that erases
durable, to prepare a sheet of the material. Furthermore, when athe color with electricity with an efficiency ten times or higher thansubstance containing positive sodium ions (Na+), such as salt
the ideal current efficiency (100%). When examining the reaction in(NaCl), was added to a clathrate, negatively-charged electrons weredetail, they discovered that a domino reaction occurred, wherein
effectively injected into the CNT. Consequently, the output properwhen one electron was removed, molecules reacted in succession,ty was improved approximately three-fold compared with thepassing the electron to another. Furthermore, it is believed that thisconventional method, and this performance was maintained at areaction endlessly continues as long as activated molecules are
relatively high temperature of 150 °C for over a month.
available.
“The developed thermoelectric sheet has advanced to the“Approximately 1,000 molecules
demonstration experiment level. I want
react with one-electron transfer
to make a breakthrough in IoT related
now. In other words, the number ofdevices, such as a power supply fortransferred electrons amplifies asensors that automatically measurereaction by 1,000 times or more, andtemperatures and humidity andthe color visibly changes andtransmits data, and in the health carebecomes identifiable. For example,
and environmental power generation
the color fading is triggered by week
fields,” Nonoguchi says.
sky-light and even X-ray radiationof small dosage such as those at
Manipulating emission
aircraft,” Kawai explains. “Although
lifetimestudies on molecular materials
Carbon materials with a ball-like orreacting by light are progressing,bowl-like curved skeleton, such as
they still only used 1% of theThehazardous
radiationssuch
asUltra-Violet
and
X-ray
fullerenes, have a π-conjugated bondmolecules’ potential. I want to takeoxidative
triggers
thecolor-changing
cascade
of
new
dyes
for
where the alternating double and single
on even more challenges for future
1,000 times.
C–C bond share electrons, and their
manufacturing, sensing and energy
π-conjugation is distorted. Therefore,
applications,” Kawai says.
they exhibit characteristics properties such as strong emission andelectrical conductivity, gaining research attention as a next-generaSelectively manufacturing nanoparticles
tion nanomaterial.
Associate Professor Takuya Nakashima’s theme concerns the field
Assistant Professor Mihoko Yamada has researched on awherein metals and semiconductors exhibit superior characteristics
compound called a metal complex by coupling metals to suchby fabricating nanometer-sized crystals (nanoparticles). In the
curved organic molecules, and have been investigating theirnatural world, some minerals form two types of optical isomers, inlight-emitting property that is different from that of planar
which atoms are arranged in a clockwise or counterclockwise
molecules. “A molecule with a curved surface has front and backmanner similar to a mirror image. Nakashima discovered a mechasides owing to dents. The emission lifetime changes, depending on
nism to selectively synthesize a crystal in either direction for thethe side on which the organic substituent group is bonded,”
first time. In a study on the mineral mercury sulfide (HgS, cinnaYamada explains. Currently, she is investigating complexes withbar), he used an amino acid cysteine derivative (N-methyl-L-cysterare metals, including iridium, whose luminosity is large. “If we canine), an optically pure isomer, interacting with HgS. HgS selected
control the fluorescence lifetime, the complex can be used as a
the lattice structure with a counterclockwise arrangement. He wascatalyst that promotes a reaction by light. I intend to pursue thisalso able to prepare a crystal with a clockwise arrangement byresearch with full commitment,” she says.
changing the preparation condition. “Those asymmetric nanopartiInterviewed by Yoshinori Sakaguchi
cles can be used as an asymmetric catalyst stimulating the reaction
with a stereoselectivity,” Nakashima explains. Such a mineral
nanoparticle can also serve as material for new electronics andcould be the key to addressing why more naturally occurring aminoacids are left-handed.
More information about the group’s research can be found at https://mswebs.naist.jp/english/courses/list/labo_07.html

NAIST Research Highlights

43

Materials Science

RESEARCH HIGHLIGHT

Photonic Molecular Science
Prof. Tsuyoshi Kawai

Light burns with new acids

R

esearchers at NAIST report a photo-acid generator (PAG) thatgenerates Lewis acids with a quantum yield that is vastly superior
to PAGs that generate Brønsted acids. The new PAG is based on
photo-chemical 6π-percyclization and is demonstrated to initiate thepolymerization of epoxy monomers and catalyze Mukaiyama-aldol
reactions.
PAGs are chemical species that release strong acids, either insolution or solid state, upon exposure to light. These acids can then be
used to activate various biological and photo-polymer systems.
Most PAGs form Brønsted acids and do so with great efficiency.
However, Brønsted acids limit options in terms of substrates andreaction mechanisms, particularly for organic synthesis when comparedto Lewis acids. Some of chemical substances are easily decomposed with
Brønsted acids but not with Lewis acids.
“Lewis acid catalysts are much useful but often unstable and require
careful introduction to reaction systems. Preferably, we would induce
Lewis acid catalysts remotely, like optical exposure,” explains NAIST
Associate Professor Takuya Nakashima, one of the lead researchers in
the project.
The new PAG depends on the addition of a triflate group toterarylene. The triflate group showed a high propensity to release fromthe terarylene upon exposure to UV light.
“We have focused on terarylene because its very high light-sensitivity, compatibility into polymer films and no oxygen/moisture inhibition.
We have also found non-linear
responses that can be used to greatly
enhance the light-sensitivity,” says
NAIST Professor Tsuyoshi Kawai,
another lead researcher. Indeed, thephoto-chemical quantum yield was
0.5, which is much higher thanstandard PAGs.
The resulting Lewis acid was
generated without any radical
intermediate and sustained for morethan 100 days. It was then used toinitiate the polymerization of epoxy
monomers, SU-8, and Mukaiyama-aldol reactions for benzaldehyde
and silyl enolates to produce silyl
aldols of different stereoisomers, thatwere not possible with Brønsted
acids formed with PAGs.
“This system opens new opportunities for Lewis-acid reactions. It is
the first to generate photo-activatedMukaiyama-aldol reactions,” says
Kawai.

Reference

Light irradiation onto the ambient inert new PLAG generates Lewis Acid as a versatile catalyst.
As the image depicts this process is like flipping a deck of cards and always coming up with the all-mighty card.

Mizutsu, R., Asato, R., Martin, CJ.,
Yamada, M., Nishikawa, Y., Katao, S.,
Yamada, M., Nakashima, T. & Kawai, T.
2019. Photo-Lewis acid generator basedon radical-free 6π photo-cyclization
reaction. Journal of the American
Chemical Society, 141, 20043–20047.

More information about the group’s research can be found at https://mswebs.naist.jp/english/courses/list/labo_07.html

44

NAIST Research Highlights

Materials Science

RESEARCH HIGHLIGHT

Supramolecular Science
Prof. Shun Hirota

Protons are transferred between the NiFe active site and protein surrounding through the
Cyt546 and Glu34 residues during the catalytic reaction of [NiFe] hydrogenase.

Microorganisms build the best
fuel efficient hydrogen cells

For all the advances technology has made throughout our lives, inmany cases it stands behind what nature can do. Ants can carry
5000 times their weight, and spider webs are five times stronger
than steel. Fuel efficiency is no different. In a new study seen in
Angewandte Chemie International Edition, researchers from NAIST
report new details on the proton transfer pathway of nickel-iron[NiFe]-hydrogenase using Fourier transfer infrared spectroscopy(FT-IR). This transfer is crucial for the hydrogen metabolism of microorganisms, and the study gives scientists a better understanding of how
to mimic nature in the construction of new biofuel cells.
Hydrogen metabolism is one of the oldest forms of energy production for life and one of the most intensely studied because of its significance in evolution. It has also attracted attention as it is a clean energy
source. Among the enzymes responsible for hydrogen metabolism,[NiFe]-hydrogenase is the most abundant and ancient.
Much is known about the enzyme. It reversibly oxidases hydrogenatoms through its Ni-Fe active site, which is surrounded by specificamino acids. However, notes NAIST Professor Shun Hirota, whomanaged the study, certain fundamentals in the chemical reactions need
to be understood before using this nanomachine to design biofuel
technologies.
“Hydride and proton coordinate with the Ni-Fe site in the protonation-deprotonation cycle, resulting in four hydrogenase states. But the
proton transfer pathway remains unknown,” he says.
One reason for the lack of clarity has been an inability to resolve
stretching frequencies of different hydrogen bonds. In the new work,

Hirota’s team, in collaboration with other researchers in Japan and
China, solved this problem by observing photoconversions of threehydrogenase states with FT-IR spectra.
Distinct absorbance frequencies revealed that one of the fourcysteines, cysteine 546, along with another amino acid, glutamic acid 34,
and an ordered water molecule are crucial for the transfer. The scientists
used the new information to deduce how the sulfur molecule of cysteine
546 and the acid group in glutamic acid 34 form hydrogen bonds toregulate the hydrogen transport.
“Our results show that cysteine 546 is a proton donor and acceptor in
the [Ni-Fe] hydrogenase cycle. They also demonstrate how a low-barrierhydrogen bond for glutamic acid 34 is formed and cleaved during thecatalytic cycle,” notes Hirota.
Microorganisms have adapted to a wider range of environmental
conditions than humans. They can be found in the comfortable climateof our bedrooms to the most hostile environments on earth. Thus,
seeing how the [Ni-Fe] site of [Ni-Fe] hydrogenase transfers protons
optimally provides a paradigm for researchers seeking to manufacture
high efficiency energy catalysts under a host of conditions.
“Life has spent billions of years adapting to energy. We believe it
gives us the best model for energy efficiency in the future,” says Hirota.
Reference
Tai, H., Nishikawa, K., Higuchi, Y., Mao, Z-w. & Hirota, S. 2019. Cysteine
SH and glutamate COOH contributions to [NiFe] hydrogenase protontransfer revealed by highly sensitive FT-IR spectroscopy. Angewandte
Chemie International Edition, 58, 13285‒13290.

More information about the group’s research can be found at https://mswebs.naist.jp/english/courses/list/labo_06.html

NAIST Research Highlights

45

Materials Science

IMPACT
Biomimetic and Technomimetic Molecular Science
Prof. Gwénaël Rapenne

Synthesizing moving
molecular machines andgoing beyond the boundaries
of nanoworld46

Inspired from living organisms and machines

Molecular gears were meshed

Molecular machine (nanomachine) research to create molecular-level devices that work in the extremely small nanometer (onebillionth of a meter) domain is a highly active research area. If one
can develop molecules that respond to external stimuli, such as
light and electricity, and act like robots, nanotechnological advances beyond the current technological boundaries can be achieved in
medicine and industry.
The enzyme ATP synthase is a typical example of a biomolecule
serving as a model of a molecular machine. ATP stores and releases
energy for vital activities. The lower half of this enzyme is buried
and fixed in the biological membrane. Owing to the potential
difference inside the membrane, the molecule spins at high speed,
similar to a motor, to incessantly produce ATPs.
Professor Gwénaël Rapenne, focusing on the mechanisms
underlying such moving molecules,1 has the ultimate goal of
constructing devices using molecular machines. “We choose two
approaches to achieve the goal: learning molecular structures fromexcellent functions of biological molecules and being inspired frommachines, such as motors and gears,” he explains.

Rapenne has been studying the manipulation of molecularmachines at the single-molecule level using a scanning tunneling
electron microscope. In 2013, he published a molecular motor
wherein the direction of rotation was switchable at will2 depending
which part of the molecule receive electrons.
Thereafter, in 2019, he succeeded for the first time in meshinggears of two adjacent propeller-shaped molecules and conveying arotary movement from one to another.3 This achievement has
opened up the possibility of custom-made molecular-scale factories
comprising multiple different molecular machines working together. This was followed by a new train of gears with rotative motionstransferred up to three molecules.4

NAIST Research Highlights

Synergy of chemistry and physics
Rapenne studied at Strasbourg University in France and received
his Ph.D. in 1998 under Professor Jean-Pierre Sauvage, a Nobel
laureate in chemistry for basic research on molecular machines. In
1999, he was appointed by Paul Sabatier University, where he beganmolecular machine research, specially focusing on single molecularNew functional molecules inspired by livingorganisms

As components, he focuses on double-decker complexes, whichhave a sandwich-like structure composed of a rare earth metal ion
and two macrocyclic ligands, such as porphyrins and phthalocyanines. “Ideally, I intend to create a molecular memory that works
above the temperature of liquid nitrogen (approximately -196°C
below freezing),” says Nishino.

Materials Sciencelevel experiments and attained professorship in 2011. He holds theprofessorship at NAIST since 2018.
“In France, synergy was achieved via close collaboration inwhich chemists synthesized the molecules and physicists investigated the principles of molecular movement. At NAIST, I intend to
conduct multidirectional studies via collaboration with experts ofbiomimetics,” he says.
In addition, in the International Collaborative Laboratory of
NAIST (Toulouse, France), research on the use of photochromic
molecules, which change their structure in response to light, as
switches for molecular motors is being conducted in collaboration
with members of the Tsuyoshi Kawai laboratory. “I have continued
molecular machine research for 20 years, and studies haveproduced results in directions that were unanticipated in the beginning. This may be the best part of the research,” says Rapenne.

Biological membrane-like porous materials
Assistant Professor Kenichiro Omoto is developing an entirely new
porous material composed of lipid bilayers forming biologicalmembranes. Although conventional solid-state porous materials,
such as activated carbon- and zeolite-based materials, arecomposed of rigid backbone, his target material is characterized by
the use of soft lipid bilayers as the wall which can bind biopolymers
with complex structures, such as membrane proteins, without
losing their activity. “I intend to develop porous materials thatallow proteins to work in pores. Such porous materials are expected
to work as catalysts and ion conductors utilizing functions of
biomolecules,” says Omoto.

Associate Professor Kazuma Yasuhara focuses on the role of biological membranes encapsulating cells and maintaining the intracelluAiming at winning nanocar race
lar environment. He developed an antimicrobial agent thatinteracts bacteria in the body and destroys their cell membranes to
Rapenne is one of the founder of the “Nanocar Race,” in whichkill them without inducing drug resistance. Based on the molecularsingle-molecule cars compete to promote and disseminate molecustructure of a natural antimicrobial peptide that binds andlar machine research. He participated in the first race in 2017 as apenetrates into bacterial membranes, he designed a simple
team member of the Center for Materials Elaboration and Structurmolecule by employing synthetic molecular frameworks with
al Studies (CEMES), a French national research institute. He will
enhanced antimicrobial activity.5
participate in the second race to be held in the spring of 2022 as the
In living membranes, someleader of the NAIST-CEMES
proteins work together with lipid
joint team. After joining thebilayers to exert various functions
NAIST, they designed andand have attracted attention as ansynthesized a new nanocar7
important class of drug discovery
called “Blue Buggy”. “We aretargets. Previously, isolation of
fully prepared for this race, and I
membraneproteins
without
believe this time we can win,” hecausing structural changes has beensays. The design of the molecules
challenging.
Yasuhara
has
has been long thought. “To hopedeveloped a functional polymer thatto win the race, you have to beorganizes membrane fragments infast but you need also to keep theseveral tens of nanometers containcontrol. The design is then a
ing membrane proteins into
compromise between opposite
disk-shaped
stablemolecularrequirements," he continues. The
The Blue Buggy.
aggregates called “nanodisc.”6
nanocar consists of a planar
Nanodisc is currently commerciallychassis made from porphyrinavailable from Avanti Polar Lipids, a world-wide reagent supplierlong of 2 nm and surrounded by four wheels to minimize contact
in the USA.
with the ground and two legs which are able to donate or accept“Synthetic polymers can partially replicate the superior function
electron making the nanocar dipolar.
of a protein with ingenuity. Molecules are designed and synthesizedInterviewed by Yoshinori Sakaguchi
as well as thoroughly examined including their function. With themotto ‘simply pursue what seems interesting,’ we have a broad
References
range of chemistry, physics, and biology interests. We pursue[1] C. Kammerer, G. Erbland, Y. Gisbert, T. Nishino, K. Yasuhara, G. Rapenne. 2019.
interdisciplinary research with our students,” says Yasuhara.
Chem. Lett., 48, 299.

Molecular memory
Assistant Professor Toshio Nishino is interested in the constructionof molecular machines and their application for molecular memories. His research aims to realize ultra-high density, high-speed
molecular memories by integrating molecular machines, each ofwhich can move and express the digital signals 0 and 1.

[2] U.G.E. Perera, F. Ample, H. Kersell, Y. Zhang, J. Echeverria, M. Grisolia, G. Vives, G.
Rapenne, C. Joachim, S.-W. Hla. 2013. Nature Nanotech., 8, 46.
[3] G. Rapenne, S.-W. Hla et al. 2019. Nature Commun., 10, 3742.
[4] G. Rapenne, F. Moresco et al. 2020. J. Phys. Chem. Lett., 11, 6892.
[5] C. Ergene, K. Yasuhara, E.F. Palermo. 2018. Polym. Chem., 9, 2407.
[6] K Yasuhara, J. Arakida, T. Ravula, S.K. Ramadugu, B. Sahoo, J. Kikuchi, A.
Ramamoorthy. 2017. J. Am. Chem. Soc., 139, 18657.
[7] T. Nishino, C.J. Martin, H. Takeuchi, F. Lim, K. Yasuhara, Y. Gisbert, S. Abid, N.
Saffon-Merceron, C. Kammerer, G. Rapenne. 2020. Chem. Eur. J., 26, 12010.

More information about the group’s research can be found at https://mswebs.naist.jp/english/courses/list/labo_13.html

NAIST Research Highlights

47

Materials Science

RESEARCH HIGHLIGHT

Biomimetic and Technomimetic Molecular Science
Prof. Gwénaël Rapenne

A 2 nm sized nanomachineable to spin and transfer
its rotational energyW

ith the celebration of the 50th anniversary of the moon
landing this year, it could be argued that the greatest scienceof the 20th Century was about big machines that could
travel the universe. The rise of nanotechnology is suggesting that the21th Century will be dedicated to much smaller machines that can
travel inside the smallest spaces including human cells. Researchers at
NAIST in partnership with research teams in the University Paul Sabatier (France) and Professor Saw-Wai Hla in Ohio University (USA),report in Nature Communications the latest nanomachine, a propellerthat can rotate at will in both clockwise and counterclockwise directions
and transfer this motion to another molecule like gears.
Nature has proven exceptional at designing similar machines byusing molecules that can convert optical, chemical or electrical energy
into interactions with the surface to generate motion. “For many
nanomachines, we look at nature as our model. There are many
examples of propellers with which organisms move in dynamic environments. Surprisingly, these natural nanomachines take the shape oflarge-scale propellers,” says NAIST Professor Gwénaël Rapenne, who
contributed to the new study.
Consistently, the propeller Rapenne and his colleagues designed
consists of three components: three blades each composed of anindazole, a stator consisting of five phenyl groups, and a ruthenium
atom that binds to the two and allow the rotation like a ball bearing.
One of the major differences is the conditions in which artificial

nanopropellers work. Where natural nanomachines tend to work inenvironments comfortable for life, artificial nanomachines can work inmuch harsher conditions. Rapenne demonstrates this point by attaching his machine to a gold surface and observing that some begin
swirling at extremely cold temperatures (near -200 oC). At the sametime no propellers move at -275 oC, verifying their ability to convert
thermal energy into movement.
The propellers also showed the capacity to rotate in different
directions in a controlled manner, but never to switch directions. This
was the result of how the propeller was attached to the gold surface,which caused a slight tilt in the stator. The direction of the tilt
determined the direction of the spin. This feature is reminiscent tomacroscopic propellers we see in the real world.
“The stator acts as a ratchet-shaped gear that imposes a unidirectional rotation,” notes Rapenne.
This is not the first time Rapenne has used gold to prove the capabilities of his nanomachines. Two years ago, he and colleagues organized
the world’s first nanocar competition using gold tracks. While he does
not expect to follow that effort with the first nano single propeller
competition, he does believe the new machines will serve an important
purpose in the nanoworld.
“Our propellers can displace nearby molecules, showing that they
can be used to move molecular loads for faster transfer of energy or
information,” he says.

Reference

Two molecular gears in action: Rotation of the first one is transferred to the next one.

Zhang, Y., Calupitan, JP., Rojas, T.,
Tumbleson, R., Erbland, G., Kammerer, C.,Ajayi, TM., Wang, S., Curtiss, LA., Ngo,
AT., Ulloa, SE., Rapenne, G. & Hla, SW.
2019. A chiral molecular propeller
designed for unidirectional rotations on asurface. Nature Communications, 10, 3742.

More information about the group’s research can be found at https://mswebs.naist.jp/english/courses/list/labo_13.html

48

NAIST Research Highlights

Innovative Research and Education Programs
NAIST constantly strives to renew its research and education programs toward producing scienceand technology researchers prepared to meet the demands facing tomorrow’s global scientific community. These programs are regularly awarded external funding for their wide-ranging benefits.

Program for Promoting the Enhancement of Research Universities (2013-2023)
The Japanese Ministry of Education, Culture, Sports, Science andTechnology (MEXT) launched the Program for Promoting theEnhancement of Research Universities in October 2013, which is a new
type of research funding in Japan that aims to enhance research capabilities by utilizing university research administrators (URA) who
implement intensive reforms to strengthen the research environment attheir respective universities. NAIST is one of 22 universities andresearch institutions selected to receive support through this program.
NAIST continues to conduct frontier-opening research while
expanding into new interdisciplinary fields in science and technology.
With the establishment of a university-wide strategic research
infrastructure, NAIST endeavors to leverage its abundant resources to

Formulating strategies
and plans based on
objective analysis dataattain the new research materials and facilities necessary for next-generation research, to disseminate its achievements and human resources
around the globe, and to further expand its global research andeducation network in order to contribute to the overall advancement ofscience and technology.
Projects being supported through this program include (1) the
Creating New Research Streams Program, which creates new researchdomains promising a high global profile, (2) the Sustainable Development of Research Capabilities Program, which enhances NAIST’s
world-class research capabilities, and (3) the Joint International
Research Program, which raises the global visibility and standing of
NAIST’s research capabilities.

Supporting the strategicacquisition of external
competitive research
funds

Enhancing theinternational
collaborative research
network

Reforming the research system to enhance
NAIST’s research capabilities

Top Global University Project (2014-2024)
In October 2014, NAIST was one of 37 universities selected for anotherprestigious MEXT initiative, the Top Global University Project. For aperiod of ten years, MEXT will support outstanding universities in theirefforts to reform institutional governance and collaborate with top
universities worldwide in order to strengthen international competitiveness.
Through the Top Global University Project, NAIST has committed

to enhancing its international graduate courses by (1) including a joint
degree scheme, (2) developing a new model for graduate education
based on top-notch research, (3) reforming institutional governanceand strategic agility, (4) creating a campus environment that supports
transdisciplinary education and cultural diversity, and (5) reorganizing
its three graduate schools into a single entity with a view to establishing
new, flexible research groups.

NAIST Research Highlights

49

The Graduate Schoolof Science and Technology
NAIST’s Guiding Concept: Education through Research
NAIST pursues research and education in an environment of interdisciplinary and international cooperation. Students and researchers haveaccess to world-class facilities in an exciting atmosphere promoting
individual achievements, collaboration across traditional research
fields, and flexible course curricula.

Research-Focused Environment:
NAIST was established without undergraduate programs to allow thefaculty to commit themselves towards achieving superior research
results to lead their respective fields.
Research-Based Education:
Through the research of our accomplished faculty and collaboration
with industry and academic partner institutions, NAIST’s students
learn both in traditional settings and through hands-on experience at
the forefronts of science and technology.

Multidisciplinary-focused Educational Programs
The seven Education Programs of the Graduate School of Science andTechnology span the three original fields of research at NAIST(information, biological and materials sciences) and include thedeveloping interdisciplinary fields that emerge independent oftraditional academic divisions to pursue current trends in science andtechnology. All laboratories belong to one or more Education Programand students choose the type of degree the will pursue depending on
their studies and the focus of their research.

Program ofInformation Science and Engineering

Program ofComputational Biology

Program ofIntelligent Cyber-Physical Systems

Program of Data Science

Program of
Biological Science50

NAIST Research Highlights

Program ofBionanotechnology

Program ofMaterials Science andEngineeringProgram of Information Science and Engineering
A focused information science program which fosters students able to support today’s dynamic advanced information society,implementing further achievements in information science in diverse fields and their wide-spread application. This program
enriches students’ broad interdisciplinary vision and cultivates cutting-edge specialized knowledge and skills covering computer
hardware, software and information network technology; computer/human interaction and media technology; and various systems
to fully utilize robotics and computer technology.

Program of Computational Biology
An interdisciplinary information science and bioscience program which fosters students who are able to collect and analyze thehuge amounts of data related to the phenomena of life, such as medical imaging data and the enormous amounts of bio-information
concerning genes, proteins, and metabolism, while fostering persons who will undertake the development of these technologies.

Program of Biological Science
A focused biological science program which fosters students able to facilitate societal development and environmental protection
through activities concerning areas such as the environment, energy, food supply, resources, life quality and health maintenance,
within industry and public institutions foreign/domestic. This program enhances students’ knowledge and cultivate expertise inareas from the basic principles of the phenomena of life to the biodiversity found at the molecular, cellular and individual level ofplants, animals and microorganisms.

Program of Bionanotechnology
An interdisciplinary bioscience and materials science program which fosters students who pursue new trends in bioscience basedon materials science understanding, and cultivates abilities necessary for the creation of novel functional materials to contribute to
the future of society, including development of pharmaceuticals and medical engineering materials, development of new polymers
which imitate biological functions, development of novel compounds to increase farming productivity, and exploration of new
cellular engineering to support regenerative medicine through an understanding of the molecular foundation of biogenic activity.

Program of Materials Science and Engineering
A focused materials science program which fosters students with the foundational knowledge of materials science and advanced
knowledge to fully utilize their expertise through a program spanning solid state physics, device engineering, molecular chemistry,
polymeric materials and bionano-engineering, and undertake next generation science and technology to maintain affluent living
and support societal development.

Program of Intelligent Cyber-Physical Systems
An interdisciplinary materials and information science program which fosters students able to holistically grasp areas including
functional material design, devices with new functions and real-world sensing, analytical device design, system structuring to fully
utilize analyzation results, and machine and robot control systems, who have specific, specialized knowledge and experience tosupport the social systems of this IoT era.

Program of Data Science
An interdisciplinary information, biological and materials science program which fosters human resources with a wide range ofexpertise in data-driven and AI-driven sciences related to information, biological, and materials science who will find hidden ‘value’and ‘truth’ through data processing, visualization, and analysis of huge amounts of collected data to contribute to next generation ofscience and technology, and societal development.

NAIST Research Highlights

51

Outgrow your limitshttp://w w w .naist.j p/en/