│ 実学 │ SCIENCE │サイヤンス│

JITSUGAKU
Showcasing the best research from Keio University

Applied econometrics

Quantum Computing:
Keio University launches
IBM Q Network Hub

A chance to slow
neurodegeneration

Issue 5September2019© Keio University

ON THE COVER
Restoration work on the Old Library on Mita Campus is now
complete after more than 2 years.
The restoration included a revolutionary retro-fitting technique to install base isolation devices underneath the building
without altering its form. The work was both challenging andmeticulous since the building is a nationally-designatedimportant cultural property built in the Meiji era.
Over the coming months, there are plans underway to establish the "Keio Historical Archive Space (provisional name)"
inside the newly restored Old Library. This space will be avenue to teach visitors about Keio’s rich culture, history, andtraditions, while sharing the founding principles that continue
to guide the university to this day.

© Keio University

Editorial

Excellence in Social andEconomics Impact│ 実学 │ SCIENCE │サイヤンス│

Issue 5September
2019

JITSUGAKU

Keio University is one of only three Japanese universities to be ranked
in the top 100 of the THE World University Impact Rankings 2019.

Showcasing the best research from Keio University

Yukichi Fukuzawa, the founder of Keio University, is internationallyrenowned for his visionary emphasis on encouraging scientificallybased knowledge (jitsugaku) for the betterment of society. More than
150 hundred years after the founding of the university, Fukuzawa’s
ideals continue to shape the activities of Keio as evidenced by theTimes Higher Education University Impact Rankings 2019 announced
Applied econometrics

Quantum Computing:
Keio University launches
IBM Q Network Hub

A chance to slow
neurodegeneration

Issue 5, September 2019

on April 3, 2019, which underscore the university’s global socioeconomic impact. Keio was ranked 91st, behind only two otherJapanese institutions: Kyoto University (48th) and the University ofTokyo (52nd).

WHAT IS JITSUGAKU ?
Jitsugaku is a way of learning about
the world pursued by Keio University’sfounder Yukichi Fukuzawa through theapplication of reason, observation,and verification. It is science in thetrue sense of the word and a powerfultool in Keio University’s never-ending
search for practical solutions toreal-life problems.

@ 2019 Keio University.
All Rights Reserved.
This publication may be reproduced in
its original form for personal use only.
Modiﬁcation or commercial use without
prior permission from the copyright holder
is prohibited.
Produced by:
Headquarters for Research Coordination
and Administration
Keio University
2-15-45 Mita
Minato-ku, Tokyo 108-8345, Japan

This global recognition of Keio’s contributions to society is basedon diverse and world-class research in areas ranging from the arts,
humanities, and social sciences, to the natural sciences, engineering,and medicine. This issue of Jitsugaku offers insights into the latest
research at Keio across all these disciplines.
Articles include a feature on “applied econometrics” regarding what
happens when the “invisible hand” does not work.
There are eight articles in this issue covering natural sciencesand engineering, including a closer look at the IBM Q Hub @Keio University for quantum computing and an article about howmechanical engineers discovered differences in the brains of
Neanderthals and early modern humans.

Further information
Keio University is Japan’s oldest instituteof higher education, founded in 1858 byeducator and intellectual leader Yukichi
Fukuzawa.
Jitsugaku is a print publication of theonline platform Keio Research Highlights,
which offers a taste of the importantresearch and scientiﬁc developmentsfrom Keio University.
Keio Research Highlights is published for
Keio University by the Partnership andCustom Media unit of Nature Research,
part of Springer Nature, and RTCorp.
www.keio.ac.jp
research-highlights.keio.ac.jp

Medical subjects are also included, with a feature about aninterdisciplinary approach to the treatment of hereditary hearing
loss using regenerative medicine and artificial intelligence, and two
articles on the effects of gut bacteria on human health and disease.
There is also an article that takes a deeper look at language, providing
insights into how people communicate verbally by unconsciously
adapting to different voices in noisy environments.
| September 2019 | JITSUGAKU | 001

Contents
001 Editorial
Excellence in Social and Economic Impact

Economics and Social Sciences
004 Applied econometrics #Empirical analysis of social interactions and knowledge spilloverin which the ‘invisible hand’ does not work
© 2018 RTCorp

006 Desperately seeking status: Sociology of organization #Researchers uncover patterns in the decisions of security analysts revealing
status-seeking behavior.

008 How costs related to changing the quality of
products impact firms #The costs firms incur when changing the quality of their products can determine
how they fare with respect to their competitors© JakkPhoto’s Portfolio on Shutterstock

Natural Sciences and Engineering
009 Diamond — the industrial scientist’s best friend — *From sensitive sensors to carbon dioxide recycling, diamond with a smattering ofboron atoms has a diverse range of applications

010 Solving the bucket challenge for remote-controlled excavators *Improving simulations of unmanned construction equipment can reduce risks forworkers in challenging environments© 2018 Yasuaki Einaga

011 Designer layered materials put a colorful twist on sensing *Layers of color-changing plastic can be tuned by hosting organic or metallic‘guests’, enabling easy-to-read measurements of heat and friction

012 Quantum computing:
Keio University launches IBM Q Network Hub #Keio University is the only host in Asia of the IBM Q Hub for quantum computing

013 Anatomy of the Neanderthal brain #© Avalon_Studio/Getty

Researchers reveal differences in the brains of Neanderthals and early modern
humans014 New type of optical waveguide for handlingcloud-computing data traffic #Researchers report a simple fabrication method for polymer-based single-mode
optical waveguides

015 Exciton fission for high-yield solar energy conversion #Quantifying multi-exciton generation for solar energy conversion in molecular© 2018 American Chemical Society.

002| JITSUGAKU | September 2019 |materials

016 Air pollution and environmental monitoring #Measuring the charging states of atmospheric particles offers accurate data
for formulating advanced models on the effects of particulates for humanhealthMedicine and related subjects
018 A chance to slow neurodegeneration *Drugs targeting a protein with a key role in neurodegeneration may slow the© Keio University

advance of the neurological disorder ALS

019 Cell therapy stacks up *A fiber mat that releases a growth factor enhances the survival of heart
muscle tissue transplanted in rats

020 Regenerative medicine and artificial intelligence #Advances in iPS cell-based therapy for treatment of hereditary hearing loss

022 Measuring oxygen deficiency andblood vessel permeability in tumors #© Keio University

Researchers develop a method for simultaneously mapping oxygen leveland spatially uneven vessel permeability in tumor tissue

023 Understanding kidney failure caused bycomplications of muscle injuries #A study on mice and humans unlocks new insight in the molecularmechanism behind rhabdomyolysis-induced acute kidney injury

024 Can gut bacteria protect infants against infection? #© 2018 Hidemi Misawa

Healthy bacteria in the gut of infants are a vital defence against gastrointestinal infections

025 Innovative polymer-based cancer drug delivery system #Modifying temperature and pH enhances drug delivery for cancer therapy

026 Gut bacteria can cause liver cancer #Bacteria in the gut alter fat in the body which promotes the risk for livercancer© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

027 Genes and congenital disorders #Mutations in one gene can manifest as a multi-organ disease

Arts and Humanities
028 Human speech: Taking your cues in Japanese accents #Insights into how people communicate verbally by unconsciously adapting
to different voices in noisy environments© Shutterstock*This article was made for Keio University by Nature Research Custom Media, part of Springer Nature.
# This article was made for Keio University by RTCorp.

| September 2019 | JITSUGAKU | 003

Economics and Social Sciences

Applied econometrics
Empirical analysis of social interactions and knowledge spilloverin which the ‘invisible hand’ does not workW

hy study
economics?

Nakajima became interested in the

After completing his undergraduate

validating theories using data while

studies at Kyoto University, Nakajima“I grew up with ataking a course on economics at theenrolled on a doctorate course in laborkeen interest in nature and wildlife in

Department of Agricultural Economics

economics at the Faculty of Econom-

the greenery-rich suburbs of Tokyo,”at Kyoto University. “But I found that

ics at New York University (NYU),

says Ryo Nakajima, Professor at thein other courses, such as rural sociol-

specializing in methodology of applied

Department of Economics of Keio Uni-ogy and farm management science,

economic analysis.

versity. “At high school I read a book

teaching tended to emphasize ideologythat led me to think not only about na-

based on hypotheses that were impos-

Features of economics courses

ture itself but about the coexistence ofsible to disprove; although in retro-in the US and Japan

human society with nature, especiallyspect I realize that this impression was

in rural society. This was the reason I

a product of inexperience,” recalls Na-

In the mid-1990s when Nakajima wasdecided to major in agricultural eco-kajima. “I remember rebelling against

a student at NYU, the curricula taught

nomics at university.”

these courses and decided to focus

at faculties of economics in Japan were

Economics is a dynamic and multifaceted area of research. © 2018 RTCorp004

only on economics.”

pragmatic aspects of economics in| JITSUGAKU | September 2019 |dif ferent from those in the United

via results of market transactions. As

spreads. I published the results in The

States. “ The biggest dif ference wasfar as relying on market transactions,

Review of Economic Studies in 20071.

content on Marxian economics,” says

it has been shown that voluntary and“It may be of interest to note that

Nakajima. “In Japan there were lec-

self-interested behavior by individuals

my choice of this research theme wastures on neoclassical economics, withwill lead to a desirable outcome with-in fact influenced by social interac-

Mar xian economics also designatedout external intervention. Adam Smith

tions with faculty members who wereas a compulsory subject. Meanwhile,

expressed this as persons being con-themselves studying social interaction

on curricula at American universities

trolled by the “invisible hand”.

at the Faculty of Economics at NYU at

the focus was on microeconomics andIn contrast, economic analysis of

the time. They were not my academic

macroeconomics; and this remains thesocial interactions focuses on directadvisors, but I cannot deny that con-case today.” Nakajima recalls studying

interactions occurring independently

tact with them affected my choice ofMar x’s capital theor y at the Depart-of transactions involving goods andresearch theme. I think this further

ment of Agricultural Economics atservices. For example, it is known that

goes to show that the range of volun-

Kyoto University. “I remember being

people’s health and longevity are great-tary decision-making by people is un-very surprised that there were oppor-

ly influenced by the people they inter-

expectedly limited, and I conclude thattunities to discuss this with American

act with on a daily basis, such as family

decision-making depends on whereclassmates and international students

members, friends and acquaintances.

you are and who you are with.”

while I was studying in the USA.”This is because behavior that is harmApproach to research

Nakajima has seen firsthand how theful to health, such as smoking andcollapse of socialism led to the decline

excessive eating and drinking is influ-

in the teaching of Marxian economics

enced by interactions with people who

Nakajima examines social interac-in Japan, with the result that there isare directly implicated in such habits.

tions using large-scale micro data onvery little difference in curricula taught

This behavior may be indirectly influ-

individuals employing two main meth-in Japan and the US today. “I think that

enced by friends of friends and evenods. The first is experimental researcheconomics undergraduates, not only inthe actions of strangers connected todesign. Since it is difficult to intervene

Japan and the United States but also inthem through social networks. The

in the decision-making of actual sub-other countries, use classic economics

important point to draw from this is

jects by carrying out randomized con-textbooks. Economics involves acquir-that even though decisions may seem

trol experiments, Nakajima uses situ-

ing knowledge by means of step-by-

to be the result of free will, people areations that can be regarded as natural

step methodologies using standard

influenced by their surroundings.

experiments, where random interven-

textbooks. So the main difference in

In circumstances in which individualtion occurs, formulates a hypothesis

undergraduate lectures on economics

actions are influenced by factors otherabout social interactions, and quanti-

given at Keio and at American universi-

than market transactions, the “invisible

fies the magnitude of interactions.

ties is the language in which they arehand” does not work, so the overall

The second approach is an analyticaltaught, rather than the content.”

results may not be desirable. Since it ismethod called structural estimation,

Nakajima adds that lectures andnot possible to predict the overall mac-consisting of the task of constructing

teaching content var y greatly forroscopic outcomes from a simple sum-an economic theor y model that ex-

graduate schools, with the differences

mation of individual micro-actions, it isplains people’s behaviors and estimat-

reflecting the characteristics of eachnecessary to consider the influence ofing the parameters of the model that

graduate school, or the personality of

individuals on other individuals as part

might best describe the observed ac-

supervising teachers, rather than dif-of a system of global social interaction.

tion pattern. “Based on the estimatedferences between Japan and the United“I wanted to find out more about themodel, we carry out predictive simula-relationship between micro- and thetion about people’s behavior and verify

overall macro-behavior so I decided to

the validity of the theoretical modelResearch on empirical analysis

focus my research activities on the em-by examining whether that predictionof social interactions

pirical analysis of social interaction,”can explain the behavior of real people

States.

says Nakajima. “In my NYU doctoralconsistently,” explains Nakajima.

In the traditional economic para-

thesis I described this by means of re-“Predictive simulation by modelling

digm, people’s economic behavior issearch on how youth smoking is influ-

is also used for policy evaluation. It

analyzed based on their interactions

enced by peers and how that influence

is possible to quantitatively calculate| September 2019 | JITSUGAKU | 005

Economics and Social Sciences

the effect of policies that have alreadyquantitatively measured the degree

tained degrees at the Graduate School

been implemented and to compare theof succession of scientific knowledgeof Science of the University of Tokyo,

impact of alternate policies that may

through guidance at the graduate

the effect of supervisor turnover was

be executed in the future and to clarify

school - in other words a guided rela-measured. The results show that re-in advance which is the best policy.”tionship,” says Nakajima. “ To that end,

search guidance of university supervi-

we introduced a value-added modelsors has a significant influence on thethat correlates the research results

research achievements of students.

Recent research highlightsof graduate students with the “qualFuture research

Nakajima is looking into the sociality” of the super visor and estimatedinteractions of experts who create new

the “quality” of research guidance. To

knowledge and have carried out empir-

identify the teaching guidance effect ofNakajima is cur rently research-

ical research. Researchers and inven-teachers, we focused on the separation

ing social interactions to measuretors are considered to “produce” newof faculty members due to mandatory

the impact of generational changes

knowledge, but most of the knowledge

retirement, transfer, death, and so on.”in researchers on the inheritance of“produced” is based on existing knowl-

When a professor leaves their job,knowledge in Japanese manufacturingedge. Previous research shows thatthe research guidance of students iscompanies and the connection to theresearchers and inventors incorporate

handed over to another professor, so

company’ productivity.

knowledge through direct contact withthe approach to the super vision of“We are also working on a project totheir colleagues. In other words, mostmaster’s and doctoral students in the

study how companies can incorporateof the expert knowledge is transmitted

laborator y will differ. Meanwhile, in

new knowledge and outside ideas, andand spread through social networks ofthe laboratory of the generation before

what kind of organizational structure ispeers, not by market transactions.

the professor left, the same person

most effective to utilize such knowledge.”

In a paper published in 2014, Naka-

conducts research guidance for gradu-

jima and colleagues traced the flow

ate students. By comparing differencesof knowledge of inventors using US

between generations of such researchpatent data and quantified the physi-

guidance environments as natural

cal distances over which knowledge

experiments, this research identified

spreads2.

the impact of changes in the quality of

In more recent collaborative re-research guidance due to changes insearch Nakajima and his collaborator

supervisors on the growth of researchanalyzed the transmission of scientificfindings by students. In empirical anal-

3knowledge across generations . “Weysis for physics researchers who ob-

Reference
1. Ryo Nakajima, Measuring Peer Effects on Youth
Smoking Behaviour, The Review of Economic
Studies, 74, p. 897-935, July 2007.
2. Yasusada Murata, Ryo Nakajima, Ryosuke
Okamoto and Ryuichi Tamura, Localized Knowledge Spillovers and Patent Citations: A DistanceBased Approach, Review of Economics andStatistics,96, p.967-985, December 2014.
3. Yuta Kikuchi and Ryo Nakajima, Evaluating
Professor Value-added: Evidence from Professor
and Student Matching in Physics, Institute for Economic Studies, Keio University, Keio-IES Discussion
Paper Series, 24 March 2017.

Desperately seeking status:
Sociology of organization
Researchers uncover patterns in the decisions of security analysts
revealing status-seeking behavior.

M006

any professions in-social factors at play? Are decisions per-hashi at Keio University and colleagues

volve decision making.

haps made to please a target customer

conducted a quantitative study of thisBut are profession-group with the aim of increasing one’s

behavior, known as status seeking.

als’ decisions always

status, implying actions that may objec-

The researchers looked at a large

based on independent analysis, or are

tively not be the best? Hitoshi Mitsu-

group of security analysts, whose job| JITSUGAKU | September 2019 |Tracking stock market fluctuations. © JakkPhoto’s Portfolio on Shutterstock https://www.shutterstock.com/g/jakkphoto 789104788

it is to issue recommendations on

into account stock coverage by rivalnature. Potential negative implications

publicly traded stocks. Ever y year,

analysts. Normal, objective decisions,of such overt status-seeking behavior

Institutional Investor magazine be-

not resulting from status-seeking be-

are that investors may make mistakes

stows ‘All-Star Awards’ on selectedhavior, would be solely driven by stockand that the assessment of firms may

analysts. These are highly prestigious

investment value.

become analyst-specific rather thanbased on industry performance.

awards, and ‘All-Stars’ experience

Mitsuhashi and colleagues tested

benefits and privileges not afforded

their hypotheses using a dataset on

This research on the behavior ofto ‘non-All-Stars’. All-Star status isanalysts’ coverage of US stocks fromanalysts is a valuable model for initial

temporar y, and results from positive

1995-2007. The data consisted of moreinsights on competitive environments

recommendations of investors — ana-

than 100,000 quarterly analyst stockof actors aware of the importance oflysts’ customers. Recommendations

por tfolio snapshots. Of par ticular

status, and it is notable for establish-

are largely service-oriented; criteriainterest are the reactions of analysts

ing links between dynamic markets

include responsiveness to investor

covering a given stock to a rival ana-

and human competitive behavior withneeds, promptness of returning phone

lyst, All-Star or not, also taking on the

conclusions such as that award criteria

calls and providing extra insight whenstock. The researchers observed thatfor status may not be related to behav-

necessary. Mitsuhashi and colleagues

such a competitive entr y by an All-ior that is beneficial to the market, andargue that driven by the goal of be-

Star increases the likelihood of otherthat consumers who use status as acoming (or remaining) an All-Star,

analysts who already have the stock inbasis of producer choice may make er-

analysts act to increase their visibility

their portfolio keeping it, but also of

roneous decisions.

to investors. In practice, analysts dotheir initiating coverage of new stocks.

this by continuously reassessing their

The researchers found that All-Stars

portfolio of managed stocks; specifi-

behave differently compared to non-cally, by dropping, keeping or starting

All-Stars, and that in general, the ana-

coverage of particular stocks, taking

lysts’ behavior is of a status-seeking

Reference
1. Bowers, A., Greve, H. R. & Mitsuhashi, H. Lookat me: Overt status-seeking behavior and competitive emergence among securities analysts.
Research in the Sociology of Organizations 50,
351-382 (2017).

| September 2019 | JITSUGAKU | 007

Economics and Social Sciences

How costs related to changing thequality of products impact firms
The costs firms incur when changing the quality of their products can determine
how they fare with respect to their competitors

Expanding into new markets

are additional costs related to the ‘re-firms that entered a new market andis a key step in the growth

positioning’ the firm must undergo inchose a quality level and price. The

of a firm, while understand-order to shift from the quality level ofdecisions over quality and price madeing which factors give aexisting products to that of the newby the two firms were then modelledcompetitive advantage is strategicallyone. These costs are higher if theand analyzed using game theory.

important. However, models that pre-gap in quality is greater, and include

The study found that repositioning

dict the positioning of different firms

new production facilities, know-how,costs reduced the ability of firms toin a new market often fail to capture all

distribution networks, marketing,dif ferentiate themselves from eachof the complex factors that determine

and advertising costs. Furthermore,other vertically, resulting in highly-

the positioning of a particular firm in

repositioning costs remain high evenpositioned firms being pushed to offer

relation to its competitors. Now, Shogo

if the quality of the product is lowered

products of excessively high quality,

Kurokawa and Nobuo Matsubayashi(for example, to sell in a market whereand vice versa. When firms had simi-from Keio University in Japan haveprices tend to be lower). In such cases,

lar quality positions, the quality levels

come up with a new theoretical model

costs are mainly related to maintain-of their products were sometimes thethat accounts for the costs incurred

ing the firm’s reputation and avoiding

reverse of their respective quality posi-

when changing the quality level ofbrand dilution.

tions, with the top-level product of the

products, revealing the significant

The authors studied a duopoly

lower-quality firm being better than

impact this can have in the final equi-model of vertical differentiation (thatthe bottom-level product of the higher-

librium outcome.

is, their products dif fer in quality

quality firm. Moreover, the firm withIf, when launching a new product orrather than features such as color)the higher-quality position sometimes

introducing an existing product to awhich took into account repositioning

generated smaller profits than its rival,

new market, the said product has thecosts to analyze how they changed theeven if its products were better. It wassame quality as existing ones, the only

outcome at equilibrium and the rela-found that, in particular, when the re-costs a firm incurs are those related

tive profitability of the two firms. They

positioning costs differed significantly

to its manufacture. Other wise, there

examined the case of two establishedbetween the two firms, as in the caseof pre-established and new firms, thelower-positioned firm could makehigher profits by strategically choosing a lower-quality product.
The authors thus showed that conventional wisdom stemming from standard models claiming that higher-quality positions are always advantageous
does not hold true in all situations.

References
1. Kurokawa S, Matsubayashi N. Price and quality
Revenues and costs008© Keio University| JITSUGAKU | September 2019 |competition with quality positions. J Econ Manage
Strategy. 27:71-81 (2018).

Natural Sciences and Engineering

Diamond— the industrial scientist’s best friend —From sensitive sensors to carbon dioxide recycling, diamond with a smattering of boron
atoms has a diverse range of applications

There is more to diamond

Strength and sensitivity

than its sparkle. The materi-ticular, Einaga is focusing on BDD’s
ability to electrochemically reduce car-al’s exceptional hardness andEinaga initially focused on develop-

bon dioxide — the biggest contribu-

thermal conductivity haveing BDD electrodes for electrochemi-

tor to global warming — to convert

seen it be used extensively in industry.

cal sensors. These sensors exploit thethe waste gas into useful products .

And modifying diamond’s structure

fact that many substances undergo“Forming useful compounds such as

can make it even more useful. For

electrochemical oxidation at a char-alcohols, aldehydes or formic acid by

example, adding boron atoms turns

acteristic voltage. When the analyte,electrochemically reducing carbon

diamond into a good conductor ofsuch as a heavy-metal ion in a water

dioxide is a very important and urgent

electricity. Such boron-doped diamondsample, is present, an easily detectabletopic,” Einaga says. Electrochemical(BDD) is finding uses as wide ranging

spike in current occurs at that voltage.

reduction has the potential to becomeas wastewater treatment, biomedical“The sensitivity is good because of thea large-scale method for recycling car-sensing, and conversion of carbon di-surface inertness of diamond,” saysbon dioxide emissions.

oxide emissions into useful chemicals.

Einaga. “Because the background

The team is also developing BDD

For the past 17 years, Yasuaki

current is very small, the ratio of theelectrodes for generating ozone — an

Einaga from Keio University’s Depart-signal to the background is high.” Theenvironmentally friendly disinfectant

ment of Chemistr y has been explor-

team is currently collaborating withused in hospitals, for example — asing BDD’s properties and pioneering

the private sector to develop various

a way to break down harmful com-new potential uses. Einaga and hiscommercial sensors, including heavy-

pounds in wastewater . “I can no lon-team have shown that BDD is ideal for

metal ones.

ger say what is the main application

2

3

making electrodes. As well as combin-

Being made of carbon, diamond

we study in our lab, because we areing high electrical conductivity withelectrodes are highly biocompatible

studying all these fields in parallel,”

exceptional hardness and stability,and have many potential biomedical

Einaga notes.

“diamond electrodes show highly in-applications. In a recent animal study,

After 17 years, diamond researchteresting and superior electrochemical

Einaga co-led a team that used a BDD

continues to hold great appeal for

properties compared to conventional

microelectrode sensor to monitor the

Einaga. “I am still fascinated by thiselectrodes,” Einaga explains. “Theyconcentration of a drug in the body ininteresting material, which has many

have great potential as next-generation

real time following intravenous injec-

faces — jewelr y, semiconductors,

functional materials.”

1

tion . The system provided time-re-superior electrodes — in spite of its

solved, tissue-specific data that reveals

simple structure.”

the drug’s effects with unprecedented
detail.
Recycling carbon dioxide
The array of potential uses for BDD
is so broad that Einaga’s research hasdiversified far beyond sensors. One
area is to use the BDD electrode as a
Conductive diamond in the form of needle-like microelectrodes makes excellent biocompatible sensors. © 2018 Yasuaki Einaga

stable, highly efficient electrochemical
catalyst for organic synthesis. In par-Reference
1. Ogata, G. et al. A microsensing system for thein vivo real-time detection of local drug kinetics.
Nature Biomedical Engineering 1, 654-666 (2017).
2. Natsui, K., Iwakawa, H., Ikemiya, N., Nakata, K.
& Einaga, Y. Stable and highly efficient electrochemical production of formic acid from carbon
dioxide using diamond electrodes. Angewandte
Chemie International Edition 57, 2639-2643 (2018).
3. Einaga, Y. Electrochemical Application of
Diamond Electrodes. In V. K. Sarin (Editor-in-Chief)& C. E. Nebel, Comprehensive Hard Materials 3,493-512. Elsevier (2014).

| September 2019 | JITSUGAKU | 009

Natural Sciences and Engineering

Solving the bucket challenge
for remote-controlled excavators
Improving simulations of unmanned construction equipment can reduce risks for workers
in challenging environmentsT

he tsunami that struck thehigh-fidelity simulators can solve some

Fukushima Daiichi Nuclearof the issues involved in planning anPower Plant in March 2011

effective construction process.”caused radioactive cesium

Ishigami cites an example of a typi-to leak into the surrounding soil. De-

cal challenge encountered by teleoper-

contaminating this land will be a prob-

ated excavators — remote operators

lematic legacy for generations to comecannot easily judge how much soil has— by some estimates, more than 20

been moved by the bucket, so may

million cubic meters of soil needs tooverload machines. Sensing how muchbe isolated. Researchers from Keiomaterial is in and around a bucket re-University are working on techniques

quires performing calculations in real

to help with this clean-up and othertime that are beyond the capabilities

dangerous situations by improving theof most virtual control systems.

physics behind systems for remote-To produce an algorithm capable ofand computer-controlled machinery1,2.

quickly and reliably testing interac-Moving mountains with a model

perienced by a bucket during a halfminute excavation in just a fraction of
a second.

tions between a bucket and the soil,“The sensor-embedded bucket di-

the Keio team modified an existing

rectly measures the force distribution

model, which had originally been de-

between the bucket and soil, which

Disasters such as the Fukushimaveloped to simulate how robots walkis unique,” says Ishigami. “It helps

incident and volcanic eruptions canon sand. Their technique calculates

clarify the key issues we need to work

make environments too dangerous

how much resistive force an object

on to improve our model’s accuracy.”

for construction workers to enter, pro-generates as it moves through granu-

Because the team’s technique canlonging repairs by weeks or months.

lar particles, with data coming frombe adapted to dif ferent shapes andCompanies in Japan are spearheadingparameters such as intrusion angle,

sizes, it could be used in simulating

the development of driverless equip-

penetration depth, and geometric fac-other parts of construction machines,

ment such as bulldozers, excavators,

tors that account for soil levels inside

including wheels, tracks, and blades.

and trucks that work autonomously or

and outside the bucket during excava-

Ishigami, with a background in robotic

are guided by operators stationed hun-tion.

space exploration, also sees opportuni-

dreds of kilometers away.
While advances in aerial drones andties in extraterrestrial excavation andDigging for answers

computer sensors are improving how

010

Improved computer models of the interaction
between an excavator bucket and soil could
help to make unmanned operation of excavatorsa reality. © Avalon_Studio/Getty

to apply the model on the Moon orthese machines interact with the envi-

The team’s trials compared simula-ronment, their efficiency is poor com-

tions of rotational and bulldozer-likepared with that of directly controlled

excavator motions to the actions of aequipment.

real bucket equipped with a grid of“Most of the work taking place intiny sensors in a soil mechanics test

this area is devoted to manufactur-bed. Measurements of the three-di-

ing real unmanned machines,” notes

mensional force distribution between

Genya Ishigami at Keio University’s

the soil and bucket proved the validity

Department of Mechanical Engineer-of their model — the algorithm could

ing. “But we believe that research into

predict the same trends in force ex-| JITSUGAKU | September 2019 |construction. “It would be interestingMars, where gravity is different,” henotes.
Reference
1. Yoneyama, R., Omura, T. & Ishigami, G. Modeling of bucket-soil interaction mechanics basedon improved resistive force theory. Proceedingsof the 19th International & 14th European-African
Regional Conference of the ISTVS, Budapest,
September 25-27 (2017).
2. Tsuchiya, K. & Ishigami, G. Experimental analysis of bucket-soil interaction mechanics using sensor-embedded bucket test apparatus. Proceedings of the 10th Asia-Pacific Conference of the
ISTVS, Kyoto, July 11-13, 2018 (Best Paper Award).

Designer layered materials put acolorful twist on sensing
Layers of color-changing plastic can be tuned by hosting organicor metallic ‘guests’, enabling easy-to-read measurements of heat and friction

Asmar t polymer devel-

can swell and hold water by absorb-

Oaki realized, however, that produc-

oped at Keio University

ing molecules between these sheetsing polydiacetylene sensors required

responds to stimuli bythrough a process known as intercala-a structure that was flexible enoughabsorbing dif ferent

tion. People learned as early as two

to change in response to an external

wavelengths of light, allowing minor

millennia ago that the intercalation offorce. “Layered materials such as liq-changes to objects to be visualized

different ‘guest’ particles into sheets

uid crystals or lipids have soft struc-

1-6that might escape other techniques .

could create rudimentar y dyes, andtures that give them dynamic prop-

For example, the polymer can indicate

applications based on this principle

erties,” he explains. “To get similar

how hard a pen presses on an object

continue to this day.

sensitivity and controllability, we usedthrough vivid color transformations.

One modern layered material being

This technology, which can also be

investigated by Yuya Oaki and his col-used to display three-dimensional

leagues at Keio University’s Depart-temperature changes, may be used toment of Chemistr y is a conductive

sense mechanical stress in material

plastic known as polydiacetylene. The

degradation, and for biomedical ap-

conjugated electrons that flow throughIn the team’s approach, a substrate,

plications such as diagnosing pressure

polydiacetylene make it sensitive tosuch as filter paper, is dipped into aulcers.

light — polymerization is usually indi-

solution containing long, floppy hydro-

cated by a color change. Because thecarbon chains with rigid diacetylene

particular color that emerges depends

cores, and then air dried. The result-on the length and twisting of theing thin film self-organizes into highly

Inspired by dirt

intercalation to tune the response tostimulus.”
Many layers, many uses

The clay minerals found in soil natu-

polymer backbone, researchers havealigned layers, similar to a liquid crys-

rally exemplify the versatility of lay-

explored ways to exploit these com-tal. The sample is subsequently im-ered materials. Consisting of stacked

pounds as chemical and biomolecularmersed in a solution of metallic ions,

sheets of alumina and silica, clays

sensors.

which intercalate between the organic
sheets.
Experiments revealed that different
metal ions enlarged the distances andaltered the structures of the organic
layers in distinct ways, creating a tunable output of possible colors. Whenone of Oaki’s students tested for heatsensitivity, the results showed the intercalated material responded to rises
or dips in temperature by changing
color within seconds — a surprise,
Oaki recalls, because most polydiacetylene hues are irreversible.
The team also discovered that mechanical force, such as grinding in a

The polydiacetylene material developed by Yuya Oaki and his team changes color based on responses
to external stimuli such as temperature.
Reprinted, with permission, from Ref. 1. © 2018 American Chemical Society.

mortar, could initiate color switching.
To refine this effect, they exchanged| September 2019 | JITSUGAKU | 011

Natural Sciences and Engineering

the metallic guests for more flexible

Japanese government for his research.

ones based on organic amines. The“Next, we hope to enhance the sensitiv-

new system enabled innovative detec-

ity by using an informatics approachtion of friction - for example, it could

and also to realize materials that arereadily indicate the number of times a

based on this polydiacetylene material,

pencil rubbed a particular spot.

and are responsive to multiple stimuli.”“It’s not easy measuring and visualizing applied friction forces, but ourcolor-change method can even indicate
accumulated amounts,” says Oaki,
who was recently awarded the Young
Scientists’ Prize of the Commendationfor Science and Technology by the

Reference
1. Okaniwa, M., Oaki, Y., Kaneko, S., Ishida, K.,
Maki, H. & Imai, H. Advanced biomimetic approach for crystal growth in nonaqueous media:
Morphology and orientation control of pentacosadiynoic acid and applications. Chemistry ofMaterials 27, 2627-2632 (2015).
2. Okaniwa, M., Oaki, Y. & Imai, H. Intercalationinduced tunable stimuli-responsive color-change
properties of crystalline organic layered com-pound. Advanced Functional Materials 26, 34633471 (2016).
3. Ishijima, Y., Imai, H. & Oaki, Y. Tunable mechano-responsive color-change properties of organic
layered material by intercalation. Chem 3, 509521 (2017).
4. Takeuchi, M., Imai, H. & Oaki, Y. Real-time
imaging of 2D and 3D temperature distribution:
Coating of metal-ion-intercalated organic layered composites with tunable stimuli-responsive
properties. ACS Applied Materials & Interfaces 9,16546-16552 (2017).
5. Ishijima, Y., Okaniwa, M., Oaki, Y. & Imai, H.
Two exfoliation approaches for organic layered
compounds: hydrophilic and hydrophobic polydiacetylene nanosheets. Chemical Science 8, 647653 (2017).
6. Terada, H., Imai, H. & Oaki, Y. Visualization andquantitative detection of friction force by self-organized organic layered composites. Advanced
Materials, 30, 1801121 (2018).

Quantum computing: Keio University launches IBM Q Network Hub
Keio University is the only host in Asia of the IBM Q Hub for quantum computingOn 17 May 2018 Keio
University announced
the launch of the IBM
Q Network Hub at its

Yagami Campus in Yokohama. “Thisis the first IBM Q Hub in Asia configured and authorized to access the
IBM Q cloud computing system,” says
Naoki Yamamoto, an associate professor and the chair of the Keio University Quantum Computing Center. “We
are building on Keio University’s 20
years of expertise in quantum computing to work with specialists at IBM to
support academic and industrial organizations to discover and harness thepower of quantum computing for both

Entrance to the common room at the IBM Q Network Hub at Keio University’s Yagami Campus in Yokohama. © Keio University

scientific and business applications.”

012

The first four industrial par tners inmore than 50,000 users from over 150

able to access IBM Q’s commercial 20

Japan to join the IBM Q Hub are JSR

academic institutes worldwide to un-

qubit cloud system, and will in future

Corporation, MUFG Bank, Mizuho Fi-

dertake over 1.5 million experiments

also be able to access a 50-qubit IBM

nancial Group, and Mitsubishi Chemi-

and produce more than 25 research

Q system.

cal Corporation.

publications.

The Keio University IBM Q Hub is

To date IBM has offered free access

Meanwhile, members of the Keiopart of a network of six IBM Q Hubs

to its IBM Q 5 qubit system, enabling

University IBM Q Network Hub are

across the world. The others are lo-| JITSUGAKU | September 2019 |cated at IBM Research (USA), Oakcollaborative research.

“Education and nurturing the next

Ridge National Laborator y (USA),

Members of the Keio hub havegeneration of experts in quantum com-

The University of Oxford (UK), North

multidisciplinar y backgrounds andputing, or ‘Quantum Natives’ is a ma-

Carolina State University (USA), andinclude researchers from private in-jor goal for us,” says Yamamoto. “We

The University of Melbourne (Austra-

dustr y, specialists hired to work at

are organizing programs for both ourlia). The hubs provide access to IBM

the hub, and Keio University students

domestic and international students to

Q systems, technical support, educa-

and researchers, including overseas

use the IBM Q Hub for writing algo-tional resources, and networking for

invited researchers.

rithms. We have high expectations.”

Anatomy of the Neanderthal brain
Researchers reveal differences in the brains of Neanderthals and early modern humansW

hy Neander thals

University and colleagues have virtu-

from computer tomography data of(Homo neanderthal-

ally reconstructed the brains of Nean-the skulls - a technique called compu-

ensis), a subspecies

derthals and early Homo sapiens, re-tational anatomy. The algorithm wasof archaic humans

vealing variations in brain morphology

developed and tested through compar-that lived until at least 38,000 years

that correspond to different social anding the skulls of living humans to theirago, were ultimately replaced bycognitive abilities.

brain structures.

moder n humans (Homo sapiens)

The researchers started from four

From the obtained morphologies,

remains unclear. Various hypotheses

adult Neanderthal and four adult early

the scientists derived impor tant pa-

have been put for ward, but a grow-

Homo sapiens fossil skulls, including

rameters such as cerebral and cerebel-

ing amount of evidence suggests thatthe well-known 30000-year old Cro-lar volume, and surface morphology.

the replacement may have come from

Magnon 1 skull. Importantly, most of

The cerebrum is the largest division of

dif ferences in neural or cognitive

the skulls stem from an epoch during

the brain and is divided into two hemi-

function — in other words, from brain

which the two species coexisted. Ogi-

spheres. The cerebellum, another partdifferences between the two species.

hara and colleagues used an algorithmof the brain, lies in the hindbrain andNow, Naomichi Ogihara from Keioto reconstruct the brain morphologies

two of its functions are regulation of

Neanderthal
Reconstructed brains of Neanderthals based on fossil skulls compared with those of early Homo sapiens.

Early Homo sapiens© Keio University| September 2019 | JITSUGAKU | 013

Natural Sciences and Engineeringbody movement (motor control) andthe morphology “of the Neanderthal

the cerebellum’s neuroanatomical or-

higher cognition (including language

cerebellum needs to be confirmed inganization may have caused different

and social abilities). Ogihara and col-future studies with a large number ofcognitive and social abilities of Nean-

leagues found that the cerebellum

cases”.

derthals and European early modern

was significantly larger for the early

To examine the relation between

humans. Citing the researchers, the

Homo sapiens than for Homo nean-cerebellar size and cognitive abili-“ability to adapt to changing environ-

derthalensis. Specifically, they foundties in more detail, the researchers

ment by creating innovation may havethat the right cerebellar hemispherelooked at large sets of data correlating

been limited in Neander thals andof Neanderthal brains are relatively(present-day) human brain morphol-

this difference possibly affected theirsmall, implying minimal connection to

ogy and cognitive performance. They

chance of sur vival and drove the re-that part of the cerebrum which plays

concluded that the cerebellar regions

placement process [of Homo neander-a major role in language processing.

are indeed involved in the so-called ex-

thalensis by Homo sapiens]”.

Since more data concerning this con-ecutive functions (cognitive processes

nection is needed to make conclusions

required for the control of behaviour),regarding Neanderthal brain function,

as well as language processing andand since preservation in the cerebel-

episodic memory.

lar region of the fossil skulls is not

The findings of Ogihara and col-optimal, the researchers point out that

leagues show that the differences inReference
1. Kochiyama, T., Ogihara, N., Tanabe, H.C.,
Kondo, O., Amano, H., Hasegawa, K., Suzuki, H.,
Ponce de León, M.S., Zollikofer, C.P.E., Bastir, M.,
Stringer, C., Sadato, N. & Akazawa, T. Reconstructing the Neanderthal brain using computational anatomy. Scientific Reports 8, 6296 (2018).

New type of optical waveguide forhandling cloud-computing data traffic
Researchers report a simple fabrication method for polymer-based single-mode
optical waveguides

Cloud-computing activity

University have now developed a new

expected to be used in computer chips

has increased enor-

kind of waveguide that is a promising— multimode waveguides cannot

mously in recent years,

component for state-of-the-art opticalachieve the necessary longer link dis-

generating ever more

networks wherein data is transported

tances and higher bandwidths.

data stored in ever-larger data centers.

as pulses of light.

The scientists developed a technique

For users to be able to continuously

A key proper ty of the waveguidecalled the “Mosquito method.” An

access their data, networks capable ofdeveloped by the researchers is thatorganic substance is first coated onto

handling the rapidly growing amounts

it is “single-mode,” not “multimode.”a substrate. Then, another organicof data traf fic within data centers

This is important for ensuring low-loss

viscous liquid (the core material) is

are needed. Researchers from Keio

integration with silicon waveguides

dispensed into the coating throughThe Mosquito method developed for fabricating polymer-based, single-mode optical waveguides with circular cores. © Takaaki Ishigure, Keio University

014| JITSUGAKU | September 2019 |a syringe needle, followed by a cur-guide cores, but also the control of thenents) and “interchannel crosstalk”

ing procedure. It takes no more thancore diameter, which has to be small(disturbances due to interfering sig-

15 minutes to make a single-modeenough to achieve single-mode opera-

nals from neighboring channels) werepolymeric waveguide 5 centimeters intion. The diameter can be reduced by

all found to be of sufficient quality tolength with 12 channels. A main advan-

lowering the dispensing pressure of

warrant proper operation. In the words

tage of the technique is that it does not

the syringe and increasing the speedof the researchers, “the single-mode

involve photomasks — relatively ex-with which it moves along the coating.

waveguides fabricated using the Mos-

pensive templates used in lithographic

The scientists per formed quality-

quito method are ver y promising formethods for etching out parts of a thincontrol checks of the waveguides they

off- chip interconnects.”

material.

fabricated. Optical power profile, signal

References
1. Kazuki Yasuhara, Feng Yu and Takaaki Ishigure,

Another impor tant aspect of theloss during propagation, misalignment

Mosquito method is that it not only en-

tolerance (in connections between theables the fabrication of circular wave-

waveguide and other optical compo-

Circular core single-mode polymer optical waveguide fabricated using the Mosquito method withlow loss at 1310/1550 nm, Opt. Express 25, 85248533 (2017).

Exciton fission for high-yield solar
energy conversion
Quantifying multi-exciton generation for solar energy conversion in molecular materialsIn molecular materials, the ab-have their spins pointing in the samecies, as the absorption of a single

sorption of one photon can re-direction. The triplet excitons are ini-

photon results in the generation ofsult in the formation of a singlet

tially strongly correlated, but they canmultiple electrical charges (i.e., multi-

exciton — a state formed by

be separated, and the electrons they

exciton generation).

an electron and a hole bound by theircarry can then be transferred to otherSinglet fission can happen withinelectrostatic attraction and with oppo-

molecules. This complex process isa single molecule in systems of twosite spins. In a process called singlet

ver y promising for applications inmolecular units covalently linked

fission, the singlet exciton splits into

solar energy conversion, because it

by an organic bridge (the process

two triplet excitons, that is, two exci-

opens up the opportunity of reachingin this case is called intramolecular

tons in which the electron and holevery high power conversion efficien-

singlet fission). This is advantageous
because we can quantitatively evaluate the photophysical processes andparameters such as kinetic constants
and quantum yields. Singlet fission
theoretically enables the performanceof the sequential photoenergy conversion process starting from the singlet
state and leading to electron transfer
with the radical ion pair quantum yieldapproaching 200%. However, the quantitative two-electron transfer process
through singlet fission has yet to bereported.

Sequential photoenergy conversion process from singlet fission to intermolecular electron transfer in thisstudy © Keio University

Shunta Nakamura, Hayato Sakai,
and Taku Hasobe of Keio University,| September 2019 | JITSUGAKU | 015

Natural Sciences and Engineering

together with colleagues from Kobe

was used to characterize the ultrafast

Thus, the authors thoroughly char-

University and Tempere University of

excited-state dynamics and measureacterized the sequential photoenergy

Technology (Finland) have quantita-

the rate of intramolecular singleton

conversion process from intramolecu-

tively characterized a sequential pro-fission, the triplet quantum yield, andlar singlet fission to intermolecular

cess involving intramolecular singlet

the rate of dissociation of the triplet-

two-electron transfers. As they com-fission and intermolecular two-electron

triplet state into individual triplet

ment in the paper, “such a moleculartransfer by using two tetracene-basedstates. Finally, the long lifetime of thesystem provides a new perspective formolecules linked by a biphenyl unit

triplet exciton, which is important for

construction of future solar energy(Tet-BP-Tet) as the singlet fission andthe electron transfer to happen, wasconversion systems.”

electron donor system, and chloranil

verified. Per forming experiments

as the electron acceptor system.

spanning ver y dif ferent timescales

The str ucture of Tet-BP-Tet wasallowed the obser vation of each ofstudied theoretically by density func-

these processes, which happen at verytional theor y, and experimentally bydifferent speeds. Next, the intermo-

absorption and fluorescence spec-

lecular electron transfer process was

troscopy. Femtosecond, nanosecond,studied, and its rate constant and yieldand microsecond transient absorption

were estimated.

Reference
1. Shunta Nakamura, Hayato Sakai, Hiroki Nagashima, Yasuhiro Kobori, Nikolai V. Tkachenko,
and Taku Hasobe, Quantitative Sequential Photoenergy Conversion Process from Singlet Fission
to Intermolecular Two-Electron Transfers Utilizing Tetracene Dimer. ACS Energy Lett. 4, 26- 31(2019).

Air pollution and environmental
monitoring
Measuring the charging states of atmospheric particles offers accurate data
for formulating advanced models on the effects of particulates for human healthInhalation of par ticulate mat-(WHO). In 2016, as many as 4.2 million

have been increased calls for greaterter is one of the top ten risks

people died due to the effects of partic-

awareness and monitoring of the air

to human health according toulates in the air. With these alarming

for potentially deadly particulates.

the World Health Organization

statistics, it is not surprising that there

The Keio Measurement system of Aerosol Charging State (K-MACS)

016| JITSUGAKU | September 2019 |© RTCorp“The health risks of inhaling par-2017 to February 2018.
The two main findings were that the
charging state of the atmospheric particles was different from the resultsof theoretical studies to-date (Fig. 2),
and that the par ticle charging statefluctuated markedly with changing
atmospheric conditions (water vapor
amount and entrained air mass) due toseasonal variations.3“These results offer new insights
into the changes of the charging stateFig. 1: Illustration and photograph of the Keio Measurement system of Aerosol Charging State (K-MACS)© Keio Universityof particles,” says Okuda. “ They willplay an important role in the accurate
evaluation of the ef fects of atmospheric particles on human health ona global scale.”ticles less than 2.5 micrometers, so-ture. My research is focused on deter-

called PM2.5, are well documented

mining the charging state of particles

with environmental agencies moni-in the air, which, surprisingly, is not

Related research conductedtoring par ticle-concentrations andwell understood.”by Tomoaki Okuda

issuing warnings to the public about
dangerous levels of PM2.5 in the air,”

Keio Measurement system ofsays environmental scientist Tomoaki

Aerosol Charging State (K-MACS)

Okuda, an associate professor at the

Okuda conducted a theoretical assessment of the performance of a parallel plate particle separator (K-MACS)

Depar tment of Applied Chemistr y,

Okuda and colleagues developed K-

instrument designed to measure the

Keio University. “However, recent re-

MACS (Fig. 1)1,2 as an inexpensive andcharging state of PM2.5 par ticles.

ports indicate that singly charged par-versatile system to continuously sepa-

Results yielded an optimal voltage

ticles are about six times more likely

rate and quantify the charging state of

to maximize the types of par ticles. 2

to be adsorbed into the respirator y

atmospheric particles ranging in size

This research addresses the question

tract than uncharged particles. So, anfrom 300 nm to 500 nm for short dura-of what happens to aerosol particles

accurate assessment of the effect oftions over a period of 12 months. “Wein humid conditions, such as haze.

air-borne particles on human healthstudied this range of particles because

A discrete element model showed arequires a much deeper understand-they have a larger concentration in thecorrelation between relative humidity

ing of not only the size of particles, butair,” says Okuda. Measurements ofand the amount of water contained

also their physico-chemical properties

these particles were taken at Keio Uni-in the particles that were found to be

including charge and surface struc-versity’s Yagami Campus from April

charged negatively or positively.4

References
1. Tomoaki Okuda, Yuma Gunji & I.W. Lenggoro,

Fig. 2: (Left) Charge distributions of measured (green) and theoretically calculated particles.
(Right) Variation of the volumetric humidity versus charged particles fraction. © Keio University

Measurement of the electrostatic charging stateof individual particles in ambient aerosol using
Kelvin Probe Force Microscopy, Earozoru Kenkyu
30, 190-197 (2015).
2. Takuto Yonemichi, Koji Fukagata, Kentaro Fujioka & Tomoaki Okuda, Numerical simulation ofparallel-plate particle separator for estimation of
charge distribution of PM2.5, Aerosol Science andTechnology (2019).
3. Ayumi Iwata, et al., Seasonal variation in atmospheric particle electrostatic charging states determined using a parallel electrode plate device,
Atmospheric Environment, 203, 62-69 (2019).
4. Yuanping He et al., Atmospheric humidity andparticle charging state on agglomeration ofaerosol particles, Atmospheric Environment, 197,
141-149 (2019).

| September 2019 | JITSUGAKU | 017

Medicine and related subjects

A chance to slow neurodegeneration
Drugs targeting a protein with a key role in neurodegeneration
may slow the advance of the neurological disorder ALS

A

molecular pathway that

osteopontin might be a key to under-

matrix metalloproteinase-9 (MMP-9),

becomes active in vul-

standing the selective disease process

which renders neurons susceptible

nerable subpopulationsof ALS. “It’s expressed abundantly into degeneration. This explains whyof neurons in people

motor neurons serving ALS-resistantosteopontin deficiency initially delays

muscles,” Misawa says.

ALS. On the other hand, osteopontinwith the debilitating neurologicaldisease amyotrophic lateral sclerosis

The researchers have now deter-

sends signals that protect against in-(ALS) has been uncovered by Keiomined that this protein plays a key

flammator y damage from brain glial

University researchers 1. Therapies

role in establishing the tipping point

cells, so that its absence ultimately

targeting this pathway could slow theof vulnerability to ALS, and they haveleaves neurons vulnerable to destruc-

progress of this incurable condition.

identified osteopontin-activated mo-tion.

The late cosmologist Stephen Hawk-

lecular pathways that indicate which

These findings suggest that osteo-

ing was the best known ALS sufferer.

cells will go from being protected topontin could be a potential drug target

Hawking lived for 55 years after diag-becoming vulnerable to degeneration.

for ALS therapy. Misawa hypothesizes

nosis, but about half of ALS patientsTo assess this protein’s function,that blocking osteopontin’s activation

die within three years of onset as thethe researchers knocked out the geneof MMP-9 in early-stage ALS patients

steady loss of motor neurons gradu-

that encodes it in a mouse model of

could slow disease progression. His

ally robs sufferers of control over their

ALS. Osteopontin deficiency initiallyteam is now using more-sophisticatedbodies.

delayed the onset of neurodegenera-

mouse models to study this pathway

Dif ferent types of motor neurons

tion and muscle loss in these animals,

in greater detail.

control specific kinds of muscle move-but the disease progressed faster thanment, and some are more likely to suc-usual once it began to manifest.

cumb to ALS than others: motor neu-

This reflects osteopontin’s dual role.

rons controlling slow-twitch muscles

On the one hand, it stimulates the in-are largely resistant to degeneration,

duction and activation of the enzyme

References
1. Morisaki, Y., Niikura, M., Watanabe, M., Onishi,K., Tanabe, S., Moriwaki, Y. et al. Selective expression of osteopontin in ALS-resistant motor neurons
is a critical determinant of late phase neurodegeneration mediated by matrix metalloproteinase-9. Scientific Reports 6, 27354 (2016).

whereas those controlling fast-twitch
muscles are susceptible. There is additional complexity — a subset of theselatter motor neurons perishes early in
ALS, while another sur vives until its
second wave, during which patientslose most voluntary movements.
“ The different vulnerabilities of different types of motor neurons is oneof the long-standing mysteries for ALS
researchers,” notes Hidemi Misawa at
Keio University’s Faculty of Pharmacy.
This has led to a search for biological markers that clarify the nature ofthis susceptibility and enable early
discrimination of endangered motor
neurons.
Misawa’s team recently obtained
evidence that the cell signaling protein
018| JITSUGAKU | September 2019 |Motor neurons from a patient with ALS, where osteopontin is shown in gray. Blue indicates brain glial cells
attacking the neuron. © 2018 Hidemi Misawa

Cell therapy stacks up
A fiber mat that releases a growth factor enhances the survival ofheart muscle tissue transplanted in ratsA

new tissue engineeringfabricating a fibrous mat out of syn-out the local release of the growth fac-

technique co-developed

thetic resin and then spraying it withtor, the tissue tended to die off insideby Keio University

nanoparticles containing a growth fac-

the rats.

scientists promises to

tor that accelerates the formation of“This research could expand theboost the regenerative capacity of cellblood vessels in transplanted cellularpossibility of cellular tissue transplan-transplantation therapy for heart dis-tissue.

tation in regenerative medicine,” says

1ease . This technique could also assist

To test the regenerative potential of

Nagase, noting that his team is con-the transplantation of other kinds ofthe new biomaterial, Nagase's teamtinuing to improve the method. “ Thecells.

cultured cells from the ventricles ofsystem leads to the successful trans-

Heart cells regenerate themselvesrats to create pancake-like sheets ofplantation of relatively large cellular

at a glacial rate, and consequently

heart muscle tissue. The researchers

tissue, which cannot be transplanted

damage sustained during a heart at-placed six of these sheets on top ofusing the conventional procedure.”tack is often permanent. An exciting

one another and then implanted theNagase considers that adding aavenue that researchers are exploring

multilayered tissue stacks onto thegrowth factor-releasing mat could also

to repair damaged hearts is to artifi-

dorsal subcutaneous tissue of rat —work for transplants of other kinds ofcially grow cells outside the body andboth with and without the growth-cell sheets. For example, people withthen transplant them in the heart. But

factor-impregnated fiber mat added toliver damage might benefit from thera-

heart muscle cells grown in flat sheets

the top of the tissue pile.

pies involving sheets of hepatocytes,

can be transplanted only a few layers

Two weeks later, sheets with the mat

the primary cell type in the liver. “Thethick — any deeper and the cells start

produced cell layers that were aboutsystem could be broadly applied in

to die because they do not get enoughtwice as thick as those generated bytransplantation medicine,” Nagase

oxygen and nutrients.

sheets lacking the mat. Mature blood

notes.

Now, Kenichi Nagase of Keio Uni-

vessels also more readily infiltrated

versity's Department of Pharmaceuti-

the matted implants, bringing with

cal Sciences and his co-workers havethem red blood cells that nurtured thedeveloped a simple strategy thattransplanted heart muscle tissue withovercomes this problem. It involves

essential oxygen and nutrients. With-

To boost the regenerative capacity of heart cells, Keio University researchers
first made a fibrous mat out of synthetic resin.
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Reference
1. Nagase, K., Nagumo, Y., Kim, M., Kim, H.-J.,
Kyung, H.-W. et al. Local release of VEGF using
fiber mats enables effective transplantation oflayered cardiomyocyte sheets. Macromolecular
Bioscience 17, 1700073 (2017).

Kenichi Nagase and his team then sprayed the fibrous mat with nanoparticles
containing a growth factor that accelerates the formation of blood vessels intransplanted cellular tissue. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim| September 2019 | JITSUGAKU | 019

Medicine and related subjects

Regenerative medicine
and artificial intelligence
Advances in iPS cell-based therapy for treatment of hereditary hearing lossM

asato Fujioka, Ma-says Fujioka. “But in reality, this is notof hereditar y hearing loss, Pendredkoto Hosoya, andpossible because the inner ear is filled

syndrome1. Pendred syndrome causes

their colleagues atwith lymph inside the bone that makes

progressive deafness and no effective

the Depar tment of

it inaccessible to collect cells for ex-

therapies are available. In genetically

Otorhinolaryngology, Head and Neckamination and observation to monitor

modified mouse models, however, theSurger y, Keio University School ofprogression of hearing loss. So, we

disease does not lead to progressive

Medicine, are searching for methods

devised a new approach based on first

deafness as is observed in humans.

to treat genetic hearing loss — an ex-

producing iPS cells from patients and

The iPS cells were prepared fromtremely challenging area of medicine

then inducing inner ear cells fromthe blood of patients and used towith no potentially useful strategies tothese iPS cells. Our early results are

induce cells of the inner ear. The

cure such ailments at present.

ver y promising and we expect themmechanisms causing deafness were

Fujioka and Hosoya are investigat-

to lead to in vitro procedures forthen studied. The results showed thating the possibility of using regenera-

pathophysiological analysis and drug

the abnormal protein known as pen-tive medicine, specifically iPS cells, toscreening.”

drin only accumulated in the patient’s

model human inner ear cells. “Ideally

The Keio researchers used patient-cells of the inner ear, and notably, that

we would like to obtain samples ofderived iPS cells to discover the cause

this protein was made of aggregates

inner ear tissues by direct biopsy,”of one of the most common forms

similar to those of neurodegenerative

Application of iPS cells in studying hereditary hearing loss

020

| JITSUGAKU | September 2019 |© Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine

diseases such as Alzheimer’s disease.

disease, and physicians must be aware

Trials on 16 people will yield 4,800

Further analysis showed the innerof them. So, I would like to develop

sets of data, and 14,400 measurement

ear cells to be vulnerable to cellular

secure procedures to collect accurate,

results--a significant amount of “big-stress, and that hearing loss gradually

time-dependent physiological data ofdata.” The point is that all 16 patients

progresses due to the death of a par-the functions of the inner ear.”being monitored are limited to theticular type of inner ear cell--a finding

As an example, Fujioka describes

mutations of the same gene, and “sev-proposed as “inner ear degeneration.”

the treatment of Pendred syndrome,eral different mutations in one single

The researchers also searched fora disorder characterized by hearing

gene will be included in our trials,”therapeutic dr ugs to prevent cellloss and repetitive dizziness where

says Fujioka. There are expected todeath and discovered for the first time

the conditions of patients can var y

be individual differences, but it is athe possible therapeutic effects of ra-significantly with time. Frequent hear-homogeneous population compared topamycin, which is already used as aning tests are required to monitor the

Ménière’s disease and senile deafness.

immunosuppressant. This researcheffects of treatment. This is a perfect

It is expected to be an ideal grouputilizing patient iPS cells yielded unex-

example of lending equipment to pa-

to create prototypes of analysis algo-pected findings that imply phenomena

tients to collect biological information

rithms.

obser ved in Alzheimer’s disease arewith Internet of Things (IoT) technol-“I hope that this IoT clinical trial sys-also occurring in the inner ear. Thisogy that could be monitored in realtem can become a prototype for future

pioneering research opens up the pos-time by the patient’s physician.

clinical trials for inner ear disorders,sibility of a major breakthrough in the“We are planning IoT trials with 16

as well as a health management tool

treatment of deafness, including senile

patients for 10 months,” explains Fujio-

for a wide range of users handlingdeafness.

ka. “So, three physiological examina-

easy to use equipment that is not nec-

tions per person per day will produce

essarily medical devices used in hospi-

The future role ofabout 300 days of data. We will moni-tals.”

artificial intelligence

tor the effects of drug administrationand the Internet of Things

on the patient’s symptoms.” Fujioka
adds that by monitoring changes in“I was interested in regenerative

the inner ear function in the same

medicine during my high school days

patient and using machine learning al-

so I wanted to study at the Keio Uni-

gorithms, it may be possible to predictversity School of Medicine,” says Ho-vertigo attacks before they occur.

Reference
1. Makoto Hosoya, Masato Fujioka, Takefumi
Sone, Satoshi Okamoto, Wado Akamatsu, Hideki
Ukai, Hiroki R. Ueda, Kaoru Ogawa, Tatsuo Matsunaga, and Hideyuki Okano, “Cochlear Cell
Modeling Using Disease-Specific iPSCs Unveils a
Degenerative Phenotype and Suggests Treatments for Congenital Progressive Hearing Loss”,
Cell Reports, 18, P68-81, January 03, 2017.

soya. “I was really impressed by the
research of Keio’s Professor Okano,Physiology, and Professor Fujioka,
Otolaryngology, so I decided to start
conducting research on inner ear regeneration. Now, as medical doctors
we have to expand our horizons andlearn about artificial intelligence (AI)as well.”
The Keio team stresses the increasing inroads AI is making in medicine,in par ticular radiology, pathology,
dermatology, and diagnosis. “I thinkthat similar waves of AI will reachotorhinolar yngological diseases,”says Fujioka. “I think that the biggest
challenge for advances in inner ear
medicine is collecting physiological
data. The conditions of patients canchange rapidly, such as in Ménière’s

IoT-based monitoring of patients with ear ailments© Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine| September 2019 | JITSUGAKU | 021

Medicine and related subjects

Measuring oxygen deficiency andblood vessel permeability in tumors
Researchers develop a method for simultaneously mapping oxygen leveland spatially uneven vessel permeability in tumor tissueIn tumors, newly formed blood

after injecting a fluorescent dye, fluo-

found to be higher in normal tissue

vessels tend to have an abnor-

rescence images were recorded every

than in tumor tissue; in the latter, ves-

mal tissue distribution -- vessel

minute. Image processing techniques

sel networks were generally more

permeability and oxygen de-

were then applied to quantify vessel

complex. Regarding vessel permeabil-livery are spatially more uneven thanpermeability and how it changes overity, the scientists found that for normal

normal. To better understand tumor

time. (Fluorescence was excited bytissue it was generally evenly distrib-

mechanisms and to optimize anti-

irradiation with a continuous-wave la-uted, whereas for tumor tissue there

cancer drug deliver y strategies, it isser.)was greater heterogeneity.

important to be able to quantify bothDuring the permeability measure-

Previous methods could only achieve

blood vessel permeability and local

ment process, for the same field of

mean results for tissue regions or

hypoxia (oxygen deficiency). Kosuke

view of the microscope, the tissue

for the entire tissue, and combining

Tsukada and colleagues at Keio Uni-

oxygen partial pressure (a measureoxygen partial pressure mapping withversity have now developed a method

for the presence of oxygen) was quan-permeability measurements was notenabling the simultaneous measure-tified through phosphorence. A phos-

possible at all. This demonstration byment of both permeability and hypoxia

phorent substance was injected in the

Tsukada and colleagues shows that itin tumor environments.

mice, after which the phosphorenceis feasible to simultaneously measure

The researchers imaged the flow oflifetime was measured; the latter cantumor vessel permeability and oxygen

blood, made fluorescent, in tumors im-

be related to oxygen concentration.

partial pressure in vivo. The scientists

planted in mice. The mice were put on(In contrast to fluorescence, phos-

believe that “[their] findings could be

the stage of a confocal laser scanning

phorence was triggered by a pulsed

applied to improve anticancer drug de-microscope (a type of microscope usedlaser.)

livery and radiotherapy by identifying

for reconstructing 3D structures) andThe oxygen par tial pressure was

the dependence of local tissue oxygenation on the vessel structure and hemodynamics,” and anticipate that “thismethod can be applied to investigate
other issues, such as visualization of
the relationship between parietal cell
dynamics [(processes taking place inthe stomach)] and vessel permeability
caused by hypoxia.”

Reference
1. Oda, K., Iwamoto, Y. & Tsukada, K. Simultane-

Tumor angiogenesis (black arrows) in murine breast cancer (white circle) grown on a mouse back skin
© Kosuke Tsukada, Keio University

022| JITSUGAKU | September 2019 |ous mapping of unevenly distributed tissue hypoxia and vessel permeability in tumor microenvironment. Biomed. Phys. Eng. Express 2, 065017(2016).

Understanding kidney failure causedby complications of muscle injuries
A study on mice and humans unlocks new insight in the molecular mechanism behindrhabdomyolysis-induced acute kidney injury

R

habdomyolysis is a syn-phages in the kidneys.

extracellular traps are present in thedrome caused by muscle

Now, writing in Nature Medicine, Ju-blood of mice with rhabdomyolysis-

injur y: damaged skeletal

nichi Hirahashi from the Keio Univer-induced AKI, but not in that of the con-muscles break down andsity School of Medicine and colleagues

trol group. Macrophages and platelets

release myoglobin (a protein thatput forward a new hypothesis for theclearly play a role, as depleting thosestores oxygen in muscles) in themechanism: the released heme acti-

cell types inhibits renal injur y. The

bloodstream. This can lead to kidneyvates platelets that interact with mac-

importance of Mac-1 in the disease isdamage and acute kidney injury (AKI),

rophage antigen-1 (Mac-1, a receptor)

highlighted by the obser vation thata life-threatening condition. Different

and induces the generation of reactive

mice not expressing it show a renal

types of muscle injuries can lead tooxygen species, histone citrullination,function similar to that of healthy

rhabdomyolysis, including excessive

and the resulting release of macro-mice, even though they exhibit evi-exertion during sports, lack of oxygen

phage extracellular traps (METs) —dent muscle degradation; METs arein the muscle, medications and drug

an immune response normally aimed

reduced or absent in this case. Mov-

abuse, as well as injuries sustained in

at immobilizing and killing microorgan-

ing on to humans, the authors foundnatural disasters or wars.

isms. The METs damage tubules andevidence supporting the hypothesis

The molecular mechanism underly-

promote AKI. It is the first time METs

that METs are responsible for rhabdo-

ing rhabdomyolysis-induced AKI ishave been demonstrated to contribute

myolysis-induced AKI.

still largely unknown. There is strong

to the pathogenesis of a disease.

A treatment that reduces the forma-

evidence that myoglobin and heme (aThe authors star ted by studying

tion of platelet-induced METs in vitro

molecule containing an iron ion) re-a mouse model of rhabdomyolysis.

markedly prevented renal damage

leased from the necrotic muscle cells

They verified the presence of METs

in mice. “Early volume-repletion andand reactive oxygen species play ain the kidneys, linking it to increased

renal-replacement therapies haverole, as does the infiltration of macro-tubular damage, and obser ved thatbeen established for rhabdomyolysisinduced AKI; however, the delivery of
medical supplies is often not feasible
shortly after disasters”, write the authors. “Our results suggest that inhibitors of Mac-1 and/or direct inhibitors
of METs [...] might be new therapeutic strategies for the preventionof platelet-mediated MET formation
and associated renal tubule injury in
rhabdomyolysis-induced AKI.”

Reference
1. Koshu Okubo, Miho Kurosawa, Mako Kamiya,

A Proposed New Mechanism For Rhabdomyolysis-induced AKI © Keio University

Yasuteru Urano, Akari Suzuki, Kazuhiko Yamamoto,Koji Hase, Koichiro Homma, Junichi Sasaki, Hiroaki
Miyauchi, Tatsuo Hoshino, Matsuhiko Hayashi, Tanya N Mayadas & Junichi Hirahashi, Macrophageextracellular trap formation promoted by plateletactivation is a key mediator of rhabdomyolysisinduced acute kidney injury. Nature Medicine,24, 232-238 (2018).

| September 2019 | JITSUGAKU | 023

Medicine and related subjects

Can gut bacteria protect infants
against infection?
Healthy bacteria in the gut of infants are a vital defence against gastro-intestinal infectionsThe human gut harbours

same microbiota that they were inocu-

a host of bacteria, known

lated with present in their faeces.

infection. Modulation of their immune
system did not affect their susceptibil-

as the gut microbiota. In

The neonatal microbiota was devoid

ity to infection. The importance of thehealthy individuals, micro-of two common orders of bacteria,

Clostriadales species was further high-biota is vital for proper digestive func-

Clostridiales and Bacteriodales. Like

lighted by the fact that the neonataltioning, the synthesis of certain vita-

human infants, mice induced with neo-

microbiota played a role in harbouringmins, and protecting the body against

natal microbiota were also more prone

this strain in later stages of life.

infections by external bugs. Infants

to colonization and infection by two

The researchers conclude that,are particularly susceptible to orally

disease-inducing bacteria. Interest-“neonatal microbiota contribute to theacquired infections, which is tradition-

ingly, when these mice were supple-acquisition of protective Clostridia

ally attributed to their underdeveloped

mented with the adult microbiota, thebefore weaning and is a critical event

immune system. However, given thatincidence of infectibron was reduced.

that prevents the growth of enteric

their gut microbiota is considerably

Could the reason for these differences

pathogens in the gut early in life.” Thedifferent from that of adults, could thislie in the two missing neonatal bacte-authors have previously shown thealso be factor? In a collaborative study,

rial strains?

protective role played by gut bacteria

researchers at Keio University now
have an answer.

The neonatal microbiota mice werein suppressing allergic airway inflam-then supplemented with either Clos-

mation, as well as potentiating the

The team collected microbiota fromtridiales or Bacteriodales strains. Uponef fects of the cholera vaccine. The

infant/neonatal (4-day-old) and adultexposure to the two infectious strains

regulation and maintenance of healthy(7-week-old) mice and introducedof bacteria, it was now seen that only

gut microbiota is therefore importantthem into age-matched germ-free

the Clostriadales strain could protect

at all stages of life.

mice, which subsequently had thethe mice against a gastro-intestinal

Reference
1. Kim, Y.G. et al, Neonatal acquisition of Clos-

Gut bacteria protecting babies from intestinal infections © Keio University

024| JITSUGAKU | September 2019 |tridia species protects against colonization bybacterial pathogens. Science 356, 315-319 (2017).
2. Yun-Gi Kim, Kankanam Gamage Sanath Udayanga, Naoya Totsuka, Jason B. Weinberg, Gabriel
Nunez, & Akira Shibuya. Gut Dysbiosis Promotes
M2 Macrophage Polarization and Allergic Airway
Inflammation via Fungi-Induced PGE2. Cell Hostand Microbe 15, 95-102 (2014).
3. Kim, D. et al. Nod2-mediated recognition of
the microbiota is critical for mucosal adjuvant
activity of cholera toxin. Nature Medicine 22, 524530 (2015).

Innovative polymer-based cancer
drug delivery system
Modifying temperature and pH enhances drug delivery for cancer therapy

S

uccessful delivery of drugs towater repellent, positioned itself on

sensitivity was indispensable for the re-cancerous tissues in the bodythe inside of the sphere and formed

lease of DOX. Cells infiltrated by DOX

remains a challenge. Current

its core. Doxorubicin (DOX), an anti-

were subsequently killed, proving thedr ug deliver y systems arecancer drug, was then loaded into theeffectiveness of this system. It was also

micelles.

confirmed that only micelles, without

based on prolonging drug circulatingin the bloodstream. However, these

The next step was manipulating thesystems prevent the drug from enter-temperature to facilitate a targeteding cancer cells, which results in the

uptake of these micelles. Cancer cells“ This two-step drug delivery systemloss of drug activity. Yuki Hiruta andgrown in the lab, were heated to 42°C.

demonstrates potential for tumor-spe-colleagues at Keio University haveThis temperature, well above normalcific chemotherapy with the combina-

devised a delivery system that can bebody temperature, was enough to in-tion of local hyperthermia”, concludes

tricked into doing so, successfully.

duce the polymer chain to change fromthe team. Since the micelles developed

DOX, had no effects on the cells, proving their safety.

The research team used two uniquehydrophilic to hydrophobic, resulting

in this study will not enter cells atpolymers to build their system: one

in several micelles clumping together.

normal body temperature, these willtemperature-sensitive and one pH-

The aggregated micelles could then be

be spared. Not only does the systemsensitive. The two polymers were

easily taken up by the cancer cells. In-

devised here ensure entr y of drugs

chemically bound together to form

tracellular endosomes/lysosomes haveinto cancer cells, but also provides aa diblock polymer. When several di-an acidic environment within, resulting

strategy to specifically target them byblocks were immersed in water, they

in a low pH. This low pH disrupted theincreasing their temperature.

arranged themselves into micelles.

core polymer arrangement, releasing

The temperature-sensitive polymer be-

free DOX within the cancer cells. Freeing hydrophilic, or attracted to water,

DOX cannot escape from the micelleformed the outer “corona” of this mi-core when a pH-resistant polymer wascelle. The pH-sensitive polymer being

used for the core, indicating that pH-

Reference
1. Yuki Hiruta, Yuki Kanda, Naoya Katsuyama &Hideko Kanazawa. Dual temperature- and pHresponsive polymeric micelle for selective andefficient two-step doxorubicin delivery. RSC Advances 7, 29540-29549 (2017).

A graphical representation of the micelles containing doxorubicin. © Yuki Hiruta, Keio University| September 2019 | JITSUGAKU | 025

Medicine and related subjects

Gut bacteria can cause liver cancer
Bacteria in the gut alter fat in the body which promotes the risk for liver cancerNon-alcoholic steatohepati-

reported a mechanism by which the mi-tis (NASH) is a common

crobiota might induce NASH-associatedcause of liver damage,

HCC.

currence of NASH-associated HCC.
The fat content in the livers of thesemice was then examined. Indeed, their

wherein there is an accu-

For their research, the team first

livers contained high levels of certain

mulation of fat in the liver. This condi-

induced NASH in mice. Feeding thefats such as cholesterol and bile acids.

tion often leads to hepatocellular carci-

mice with a high-cholesterol high-fat

However, accumulation of these mol-noma (HCC), i.e., liver cancer, at later

diet called STHD- 01 without adminis-

ecules was also found in the liver andstages. Scientists have linked bacteria in

tration of tumor initiators not only led

feces of the antibiotic-treated mice.

the gut, also known as gut microbiota,

them to develop NASH, but also HCC

What changes did the gut bacteriawith the incidence of NASH-associatedwithin 41 weeks. As expected, the miceinduce then, that could have led to can-HCC. However, the exact nature of thistreated with antibiotics that reduced thecer? Upon rigorous investigation of therelationship is unknown. Hidetsugu

microbiota showed almost no signs offat profiles, it was obser ved that long

Saito and colleagues at Keio University

HCC in their liver. This confirmed thesaturated fatty acids and secondary ana-

and other institutions have recently

involvement of the microbiota in the oc-

logues of the bile acids were key players. Secondar y bile acids were highly
prevalent in the feces of HCC mice, butwere depleted in the antibiotic-treatedmice. It is therefore likely that the gut
bacteria convert primar y bile acids tosecondary bile acids.
The next step was to see if secondary
bile acids are directly linked to cancer.
For this purpose, liver cells grown in
the lab were treated with secondary bile
acids. As expected, these acids activateda cancer-inducing pathway in the cells.

Liver pathology and enzymes (9w)

© Shoji Yamada, Keio University

This cancer pathway was also operational in the livers of STHD-01 fed mice.
This study revealed a novel mechanism by which the gut microbiota canmodulate the normal metabolism of
fat to induce cancer. Patients sufferingfrom NASH, who already have a highproportion of bile acids in their liver,are at a higher risk of developing HCC
because their gut bacteria will convert
those bile acids to their toxic counterparts. Monitoring gut bacteria closely in
NASH patients might reduce this risk.
References
1. Yamada S., Takashina Y., Watanabe M.,

Number of tumors (41w)

026© Shoji Yamada, Keio University| JITSUGAKU | September 2019 |Nagamine R., Saito Y., Kamada N. and Saito H.
Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitisassociated hepatocellular carcinoma in mice.
Oncotarget, 9, 9925-9939 (2018).

Genes and congenital disorders
Mutations in one gene can manifest as a multi-organ diseaseC

HARGE syndrome

showing properties of other cell types.

tempted to understand if it had a moreis a rar e congenital

CHD7 was thus the primary factor in

specific role with regards to CHARGE.

condition. It results inmaintaining the CNS “lineage” of cells.

Gene analysis on CHARGE-patienta varied set of str uc-

How then, did CHD7 single-handedly

derived cells revealed two candidates

come to regulate an entire lineage?

as its target: SOX21 and BRN2. Bothtural anomalies in the body, especiallyaround the head and face. A conun-

To assess this, Kohyama’s team per-of these genes are also involved in the

drum in the world of genetics is how

formed a gene analysis. Since genes

healthy development of the ner vousin conditions such as CHARGE, muta-

drive all the different functions in oursystem.

tions in one single gene can lead tobody, those that are the direct target“Our study provides insights intosuch a diverse set of abnormalities.

of CHD7 would help understand its ef-

the longstanding question regarding

Jun Kohyama and colleagues at Keiofects better. CHD7 was found attached

the causes of multiple anomalies in

University have recently been studying

to a specific set of genes known as

CHARGE syndrome patients,” con-the gene implicated in CHARGE syn-“super-enhancers” (SE). The SEs playclude the authors. They showed how

drome, CHD7, and explained how it

an important role in maintaining theanomalies in a single gene can switch

relates to head and facial deformities.

identity of different cell types. Thus,

the structural and functional integrity

Given that these abnormalities arise

CHD7 binding to SE in NE cells isof cells during development, resulting

during developmental stages of the fe-important for controlling the fate andin a multi-organ malformation. Giventus, the team first employed neuroepi-

development of NE cells. Anotherthe advances we now have in genetic

thelial (NE) cells: these cells give riseinteresting function of CHD7 that was

testing, this study highlights the im-to the central nervous system (CNS),

revealed was its activation of “enhanc-

por tance of monitoring the CHD7

i.e., the brain, eyes, and ears, as theers.” These enhancers are genes thatgene in human fetuses.

fetus develops. It was first noticed thatare specific for CNS development.

CHD7 was mandatory for the NE cells

After understanding how CHD7

to retain their identity. When CHD7

plays a role in maintaining the integ-

was suppressed, the NE cells started

rity of NE cells, the team finally at-

Knockdown of CHD7

Reference
1. Chai M. et al. Chromatin remodeler CHD7
regulates the stem cell identity of human neuralprogenitors. Genes and Development 32, 165-180(2018).

© MuhChyi Chai, Keio University| September 2019 | JITSUGAKU | 027

Arts and Humanities

Human speech: Taking your cues inJapanese accents
Insights into how people communicate verbally by unconsciously adapting
to different voices in noisy environmentsYukiko Sugiyama’s intereston the perception of speech instead ofof a sentence equivalent to the English

in Japanese pitch accent

its production.”‘he wants...’ or ‘he has a good...’.

began during her graduate

Now, writing in Phonetica, Sugiyama

Each listener was exposed to blocks

studies in the US. “Spoken

describes the use of acoustic stimuli

of both natural and edited speech; theforms of languages can be roughly

obtained by removing the periodicity

accuracy for edited speech was about

divided into either stress accent lan-of F0 from natural Japanese speech

65%, compared to a little over 95% forguages like English, or tone based

and substituting it with white noise,natural speech. The fact that listeners’

languages like Chinese,” explains

while keeping all the other acoustic

responses exceeded chance level in-

Sugiyama. “But how do we classify

properties intact, to see if a group of

dicates the presence of other cues for

pitch accent languages like Japanese?

native Tokyo Japanese speakers would

accent besides F0.

My goal is to answer this question.”still be able to identify words.

Analysis of the duration and ampli-

Japanese employs the so-called fun-Sugiyama selected 14 two-syllable

tude of test words showed no signifi-

damental frequency (F0) as the main

words that differ only in respect to thecant differences in syllable durationcue to differentiate words that contrast

presence or absence of an accent on

between accented and unaccented

only in accent. In the absence of F0,

the last syllable. Out of all the disyl-words; a reliable difference in ampli-

which is roughly analogous with thelabic words that differ only in accent,tude was, however, obser ved. The

speech produced in whisper, listeners

she selected those that cannot be pro-

implication of this research is thatcan use other acoustic information

duced with more than one accent type,amplitude acts as a secondary cue forto infer the meaning of words. Is thisand then restricted the set to words

Japanese accent, whereas duration

true also for Japanese?

that would be likely familiar to partici-

does not play an important role.

“Reports based on syllable duration

pants, and excluded words that were“For practical purposes, I hope myand intensity — acoustics of speech —typically used in compounds. Because

research can help in the development

do not show if listeners can use themthe onset and offset of an utteranceof high performance hearing aids and © Keio University

to distinguish words that differ only in

exhibit acoustic proper ties specificcochlear implants.”

accent,” says Sugiyama. “My approachto their locations in a sentence, theis completely
different. I am focusingON
THE COVER

words were embedded in the middle

Reference
1. Yukiko Sugiyama, Perception of Japanese Pitch

Accent without F0.Phonetica 74, 107-123 (2017).

Restoration work on the Old Library on Mita Campus is now
complete after more than 2 years.
The restoration included a revolutionary retro-fitting technique to install base isolation devices underneath the building
without altering its form. The work was both challenging andmeticulous since the building is a nationally-designatedimportant cultural property built in the Meiji era.
Over the coming months, there are plans underway to establish the "Keio Historical Archive Space (provisional name)"
inside the newly restored Old Library. This space will be avenue to teach visitors about Keio’s rich culture, history, andtraditions, while sharing the founding principles that continue
How do we communicate verbally by unconsciously adapting to different voices in noisy environments? © Shutterstock
to guide the university to this day.
028

| JITSUGAKU | September 2019 |© Keio University

THE KEIO MEDICAL SCIENCE PRIZE

The 2018 Keio Medical
Science Prize Laureates

OBJECTIVE
The Keio Medical Science Prize gives recognition to the outstanding and creative achievements of researchers in the fieldsof medicine and life sciences, in particular those contributing toscientific developments in medicine. It aims to promote worldwide advances in medicine and life sciences, to encourage theexpansion of researcher networks throughout the world, and tocontribute to the well-being of humankind.

PRIZE
Laureates receive a certificate of merit, medal, and a monetary

Feng Zhang
I am greatly honored and humbled to receive the
Keio Medical Science Prize, which has been awarded to many brilliant scientists over the years. Having
the work that my team and I have done to develop
genome editing tools recognized in this way is anincredible distinction, and it inspires us to do evenmore to find ways to improve human health. On
behalf of all the scientists that have contributed tothis discovery, thank you.

award. The award ceremony and commemorative lectures areheld at Keio University.

NOMINATION AND SELECTION
Nominees must be researchers in medicine or life sciences
closely related to medicine, and preferably currently active intheir field of research. The Keio Medical Science Prize is aninternational award.

1. An invitation is sent out to academics and researchers allover the world each year, inviting them to nominate acandidate for the Prize.
2. The Committee reviews the nominations and submits arecommendation to the Board.
3. The Board makes the final decision and formallyannounces the laureate(s).

Masashi Yanagisawa

YEARLY SCHEDULE (Subject to change)

I am truly honored to receive the prestigious Keio
Medical Science Award and feel humbled going
through the prominent list of previous laureates. My
achievements would not have been possible without
the teamwork of my lab members and esteemedcollaborators and I would like to accept this award
on behalf of my entire team. Looking back, I realizethat exploratory research has always been my styleever since the start of my career. I went into the fieldof sleep research not because of my own planning
but through simple observations of experimental
phenomena. From here on out, I plan to remain free
and unbiased, asking hard questions and exploring
the scientific mysteries that lie before us.

• Call for nominations: late January• Deadline for nominations: early March• Prize announcement: mid-September• Award ceremony: November or December at Keio University

www.ms-fund.keio.ac.jp/en/

Headquarters for Research
Coordination and Administration
Keio University 2-15-45 Mita, Minato-ku
Tokyo 108-8345
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