実学 | Sc i e n ce | サイヤンス

Issue 2
August 2016

JITSUGAKU
Showcasing the best research from Keio University

A change of heart

Catch of the day on ice

Positioned for excellence

Reprogramming connective
tissue cells to repair damage

Netting carbon fromnatural gas reserves

A sensing system to measureperformance in motion

Seiyo Jijo (Things Western), vol. 1
by FUKUZAWA Yukichi
1866 (Keio 2)
Three volumes, woodblock
L. 22.5 cm, W. 15.4 cm ea.
Fukuzawa Memorial Center for Modern Japanese Studies,
Keio University

ON THE COVERI

n 1862, London hosted its second
world’s fair. More than 6 million
people from 39 countries attended
the London International Exhibition on
Industr y and Art, including a mission
representing the Tokugawa shogunate inJapan. Keio founder Yukichi Fukuzawa
was appointed official translator for thedelegation, and documented his experiencesin one of the most widely read books of thetime, Seiyo Jijo, or Things Western.
Published in 1866, the first volume of Seiyo
Jijo was a bestseller and introduced revolutionary ideas that influenced a feudal Japan on thecusp of major social, economic and political

upheavals. By 1868, the Meiji Restoration
had restored power to the emperor andushered in a period of modernization andWesternization to Japan. Two later volumes of
Seiyo Jijo were published in 1868 and 1870.
Seiyo Jijo clearly details many foreign concepts and major technological advances thatFukuzawa observed during his travels. It offered the most current guide to the West for a
globally isolated Japanese public. Even the ideaof an exhibition would have been a novelty,
which Fukuzawa described as “a conventionof products.” While museums are important
repositories of knowledge and innovation— “a new gadget of yesterday can be a uselessthing today,” explained Fukuzawa. “The pointof holding expositions is to teach and learn

from each other, and to take advantage of eachother’s strengths. It is like trading intelligenceand ideas.” The book also formulates politicalsystems of the West — democracy, monarchy
and the parliamentary system.
The title page of Seiyo Jijo depicts many ofthe most impressive technologies, including
the steam engine, electricity and telegraphy. A
courier in a Western outfit runs above electric
power cables — representing a new form of instantaneous communication. A hot-air balloon
glides high above the mountains, a steamshipsails across the open sea and a steam-driven
locomotive cuts through a tunnel. “There wasnothing that didn’t look new,” wrote Fukuzawa,“learning about their origins and functions,
there was nothing not amazing.”

Contents3

実学 | S c ie n c e | サイヤンス

JITSUGAKU
Editorial

Longevity, security, and creativity

Inside Keio

Igniting Japanese social innovation

6

4

Page 6

Feature article

Motion sensors for sporting excellence8

A gentler approach to remote control
Reducing unstabilizing vibrations in remotely controlled systems

9

T cells launch targeted attack on tumors
Protein fragment could harness the immune system against leukemia

10

The price of a personal touch for lung cancer therapy

8

Affordable personalized treatments for lung cancer patients in Japan

11
Page 8

12

Survival threat emerges from within
industrial clusters
Clustered plants are more vulnerable to natural disasters

Page 13

Feature articles

Leading the race against dementia
Anti-inflammatory interactions
14

Emphasizing words with a bit of a stretch
Lengthening Japanese consonants to convey meaning and emphasis

15
Page 14research-highlights.keio.ac.jp

Fine-tuning the brain’s circuitry

A protein pair manages the development of neuronal connections

14

Contents

Page 16

Feature article

17

Learning from master farmers
17

16

Single photons for quantum cryptography
Carbon nanotubes emit single photons attelecommunication wavelengths

18

Mending broken hearts
Converting fibroblast cells directly into beating heart muscle cells

19

Locating people using radio waves
Tracking a person’s whereabouts without the aid of
a portable device
Page 18

Page 20

Feature article

22

Finding where mind, brain, and body meet

22

20

Sticky bacteria switch on immune cells
Bacteria trigger an immune response by adhering to the gut wall

23

Icy cages hold a clean energy secret
Purifying natural gas by trapping carbon dioxide in water crystals

24

The secret to successful aging
Keeping inflammation at bay can help people live past 100
Page 22

実学 | S ci e n c e | サイヤンス

JITSUGAKU@ 2016 Keio University.
All Rights Reserved.
This publication may be reproduced in its
original form for personal use only. Modification or commercial use without priorpermission 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
Further information
Keio University is Japan’s oldest institute of higher education, founded in1858 by educator 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 developments from
Keio University.
Keio Research Highlights is publishedfor Keio University by the Partnership andCustom Media unit of Nature Research,
part of Springer Nature.
www.keio.ac.jp
research-highlights.keio.ac.jp

Jitsugaku | September 2015

Editorial
実学 | S c ie n c e | サイヤンス

JITSUGAKULongevity, security,and creativity
Since its founding, Keio has upheld the principles of social responsibility,
lifelong learning, and leadershipAs one of 13 top-tier universities selected under theJapanese government’s Top Global University Project,
Keio University continues to lead Japan’s internationalization efforts. The ten-year initiative, launched in2014, seeks to raise Japan’s profile in global university rankings.
To achieve this goal, Keio has committed to investing significant
resources in sharpening its edge as a world-leading research university and extending its legacy of contributing to society.
Japan and the world currently face many critical challenges,
including rapidly aging populations, declining birthrates andenvironmental, economic and social instability. There is also
an urgent need for innovative solutions. In these times of greatchange, Keio is following the advice of its founder, Yukichi
Fukuzawa, to contribute to humanity through learning andjitsugaku (science). He aspired for students, alumni and faculty
members at Keio University to be model leaders in society.
To address these challenges, Keio has launched transdisciplinary
research and education initiatives in three key areas: longevity,
security and creativity. These global, cross-cutting initiatives will
help to realize a world in which, inspired by innovative ideas, people live longer, better lives in safer, more sustainable communities.
The second issue of Jitsugaku offers a peek into this newworld and is a testament to the multidisciplinary nature of research at Keio University. The 5 feature articles and 12 researchhighlights in this publication cover areas as wide ranging as
robotics, agriculture, disaster risk reduction, immunology,
clean energy and sports science. From discovering the secrets ofsuccessful aging to reducing healthcare costs, research at Keio
University is original, progressive and socially responsible.

research-highlights.keio.ac.jp

実学 | S ci en ce | サイヤンス

Issue 2
August 2016

JITSUGAKU
Showcasing the best research from Keio University

A change of heart

Catch of the day on ice

Positioned for excellence

Reprogramming connective
tissue cells to repair damage

Netting carbon fromnatural gas reserves

A sensing system to measureperformance in motion

Issue 2, August 2016

WHAT IS JITSUGAKU?
Jitsugaku is a way of learning
about the world pursued by
Keio University’s founder
Yukichi Fukuzawa throughthe application of reason,
observation, and verification.
It is science in the true sense of
the word and a powerful tool in
Keio University’s never-ending
search for practical solutions toreal-life problems.

3

Inside Keio

The Old University Library on
Keio’s Mita campus.

IGNITING JAPANESESOCIAL INNOVATIONK

eio university is the oldest andone of the most prestigious
universities in Japan, with ahistory that dates back morethan 150 years. Located in the heart ofTokyo, Keio is a forward-looking, progressive institution founded on principles of scientific realism and Western philosophy, andis focused on enhancing the globalization of
education in Japan.
Keio was founded by Yukichi Fukuzawa(1835–1901), an educator and intellectual

Keio University Library is the only
library in Asia to own a copy of the
Gutenberg Bible.
4

leader who is considered a pioneer of modern
Japan. Fukuzawa was born to a samurai family during the final years of the Edo period.
He founded Keio Gijuku in 1858, as a school
for Western learning in Edo, today’s Tokyo.
Keio Gijuku was characterized by its tenetsof self-respect and independence of mind
combined with an emphasis on jitsugaku(science). The school began offering university education in 1890, setting up its firstdepartments in literature, economics and law,and has since continued to establish a firm
reputation as a leading university in Japan.
Indeed, Keio has a long history of attractingsome of the world’s brightest minds. For
example, in 1922, the year after he won theNobel Prize in Physics, Albert Einstein visitedthe university to deliver a five-hour speech,
his first in Japan, in front of an audience ofover 2,000 people.
Fukuzawa believed the best way forJapan to catch up with Western technology
and social systems was to always strive forprogress and enlightenment, and provide

the academic and moral education needed
to create a generation of wise and capable
leaders. Graduates of Keio include prominent
leaders and historical figures in all walksof life, including former prime minister,
Junichiro Koizumi, and highly regarded
people in the Japanese business world such as
Toyota Motor Corp’s incumbent chief executive officer, Akio Toyoda. Notable astronauts,
writers, scientists, intellectuals and artists also
number among Keio alumni.
This is also reflected by Keio’s 9th placeranking in the Times Higher Education Alma
Mater Index: Global Executives in 2013. The
index ranks institutions by the number of degrees they have awarded to CEOs of Fortune
Global 500 companies.
Thinking for oneself, taking responsibility for one’s actions and jitsugaku are basic
principles held dear by Fukuzawa that Keio
continues to uphold to this day. Fukuzawa emphasized the importance of freedom, equality
and lifelong learning. He noted, “Heaven
does not create one man above or below
Jitsugaku | August 2016

Inside Keioanother man.” Fukuzawa is honoured on the
10,000 yen note, Japan’s highest denomination.

sustainable society while nurturing the next
generation and maintaining the health of
those in the prime of life and beyond.
Applying jitsugaku to solve“Today, Japan has the world’s highest longlobal problems
gevity rate. If we can establish our country
Keio is a comprehensive higher education as a model for a vibrant and prosperous
institution located on six campuses across aging society, it means that we can set a
the greater Tokyo area. It has 10 under- precedent for other countries that are also
graduate faculties, 14 graduate schools and graying. Keio University continues to makeapproximately 30 research centers and in- intellectual contributions to Japan and thestitutes, including a university hospital. The world to create such affluent aging societies,”
institution’s affiliates include two primary says Keio University President Atsushi Seike.
schools, three junior high schools, andIn recognition of its strengths in research
five high schools, including one in New and education, Keio University was recently
York. Keio is a unique academic entity that selected by Japan’s Ministry of Education,offers lifelong education. Keio has partner- Culture, Sports, Science and Technology as
ships which include 300
one of the 13 top Japanese
overseas institutions anduniversities in the 2014
“Keio University
7 international organiTop Gl ob a l Un ive rs it ycontinues tozations in 49 countries.
Project. This 10-year grant
make intellectualPartner universities
will further strengthen
contributions toinclude Harvard Medical
Keio’s capacity to promote
Japan and the
School, Columbia
research and education inworld to create
U n i v e r s i t y, S t a n f o r dvarious important fields.
such affluent
University, the University
Under the Top Global
aging societies.”of Oxford, and the
University Project, Keio will
Un ive rs it y of L ond on .
set up three clusters focusInternational organization partnerships ing on Longevity, Security, and Creativity,
include the Asian Development Bank, the which will all contribute to its goal of attainInternational Bank for Reconstruction and ing sustainable development of a super-maDevelopment and UNESCO. To further ture society. These three multidisciplinary
boost its research capacity, the university clusters will draw on Keio’s unique heritage
has intensified existing collaborations with of innovation and jitsugaku, and harness the
16 research universities and institutions, power of the university’s strong network ofprimarily in the United States and Europe.
collaborations with industry, academia andDrawing on its vast research expertise, Keio international organizations.
is now focused on solving challenges in order
For example, the Longevity Cluster will
to realize a prosperous super-mature society. focus on developing innovative solutions toThis includes finding ways to promote a the problems posed by aging societies. It will

Keio University founder Yukichi Fukuzawa’s autobiography, Fukuo Jiden ,has been translated into almost a dozen languages.
www.keio.ac.jp

Handwritten manuscripts andletters by Albert Einstein donated to
Keio University.

adopt a three-pronged holistic approach thatwill involve considering health matters, sociopolitical issues and technological solutions;examples of each of these aspects include thedevelopment of regenerative medicine basedon stem cell technology, research into thepolitics of aging societies, and the use of robots to undertake nursing duties, respectively.
In the Security Cluster, Keio researchers
will explore security issues relating to social,economic and geopolitical risks. Such security issues include global pollution, cybersecurity in financial markets and regional
security in East Asia.
Meanwhile, researchers in the Creativity
Cluster will investigate telecommunication
and analytical technologies as well as new
materials such as plastic optical fibers. In
addition, they will investigate new formsof expression in new media and participate
in inter-university consortia such as the
Global Innovation Design program. Finally,
Keio Business School, the first in Japan tobe accredited by the Association to Advance
Collegiate Schools of Business, will undertake research on topics that include value
creation through outstanding marketing andhuman resource management.
By consistently emphasizing the philosophy of jitsugaku, Keio will continue to provide
leadership for the future through its commitment to education, research and medicine.
Its progressive environment helps students
and researchers in their pursuit of excellence,both as researchers and as individuals, andenriches global society.
5

Feature article

Motion sensors
for sporting
excellence6“Newton’s laws cover all sporting
activities,” says Ohgi, now an associate
professor at Keio University’s Graduate
School of Media and Governance. “Themechanical properties can be formulated
in almost the same way for people andhorses. Once we understand the fundamental physics involved, we can comprehend the mechanics of any sport.”
Stroke by stroke
Ohgi first worked on using accelerometersand gyroscopes, known as inertial sensors, to analyze athletic performance in
1995, when the watch manufacturer Casio
provided his supervisor with funding toresearch the development of a sporting
wristwatch. After investigating thetechnology’s potential in martial arts andbaseball, he naturally turned to the sport
he excelled at — swimming.
Traditionally, coaches used cameras
to visually assess sports performance,
but the bubbles and splashes generated
as swimmers ploughed through thewater would often obscure the picture, limiting the capture of key data.
“Usually swimming training is a matterof trial and error, with swimmers andcoaches trying out new stroke techniques. But nobody really knows which
techniques are best,” says Ohgi. “Using
inertial sensors, we can calculate thestroke propulsive force to assess themost efficient techniques.”

The accelerometersand gyroscopes foundin today’s smartphones
can be used to improve
the performance ofswimmers, ski jumpers,
and golfers, among
other athletes.

© 2016 Yuji Ohgi, Keio UniversityA

s a young man, Yuji Ohgi
spent several hours a day inthe swimming pool perfecting his stroke. These countless hours of practice paid off — at theage of 20 he competed in the preliminary
trials to join the Japanese swimming teamfor the 1988 Olympic Games in Seoul.
While he was not quite fast enough tomake the team, the experience helped
shape his career. Ohgi soon hit on theidea that accelerometers and gyroscopes(used by today’s smartphones to gettheir bearings) might help athletes andtheir coaches work out the optimal
body positions and movements toimprove performance. This inspiration
laid the foundations for 20 years ofinnovation and discovery in the field ofsports biomechanics.
Most of Ohgi’s work focuses of humanathletes, but not all of it. In one project,
he is applying his expertise to bettercharacterize the movements of thoroughbred racehorses using special treadmills
designed to take their weight.

© 2016 Yuji Ohgi, Keio University

Lightweight smartphone sensors and Newton’s laws ofmotion can help athletes maximize their performance

Jitsugaku | August 2016

Feature article

After scrapping some earlier models, in2006 he developed a waterproof data loggerthat could be strapped around a swimmer’s
wrist and wirelessly send data on acceleration
and angular velocity to a poolside device1.
More recently, he has used chest-strapbased sensors, and he is currently developing
software for swimming training.
Jump and swing
Ohgi has applied the same ideas he developed for swimming to many other sports.
In ski jumping, for example, athletes moveat great speeds over large distances, making it
difficult to capture movement and positioning in detail, even with high-speed cameras.
Since 2005, Ohgi has been refining a systemthat deploys seven inertial sensors on ajumper’s body and one each per ski, as well
as a laser scanner to track trajectory2. The
system can be used to measure aerodynamic
forces during jumps and provides better
understanding of the effects of small changes
in body positioning.
research-highlights.keio.ac.jp

Ohgi also worked with Keio University
colleague, Associate Professor Ken Ohta, ina collaboration with the Japanese electronics company Seiko Epson Corporation todevelop a lightweight golf-swing analysis
tool. Again using inertial sensors, thedevice provides players with data on swing
path, club and club-head speed, face angle
and efficiency of energy transfer fromthe body to the club shaft. The device
was launched in Japan in 2014, and theUnited States and South Korea in 2015.
Not only sportspeople benefit from
Ohgi’s work; he is involved in a study led
by colleagues at Keio’s Sports Medicine
Research Center on whether regularexercise can reduce cognitive decline
and dementia. As part of the study, he isusing Microsoft’s Kinect motion-sensing
device to develop a way to analyze elderly
people’s gaits.
Looking to the future, Ohgi envisions
technologies that generate data on sporting
performance will come into their own at the2020 Tokyo Olympics. As co-chair of thescientific committee of the Japan Swimming
Federation, he hopes to initiate a projectusing machine learning to identify the characteristics of swimmers from video footage.
This, says Ohgi, will form part of theresearch foundations for a much more
technologically advanced experience forthose watching the games and other sporting
events remotely. “I believe that by 2020,
television audiences will be able to monitor
things like the speed and energy expenditureof their favorite athletes,” he says. 
References
1.

Nakashima, M., Ohgi, Y., Akiyama, E. &Kazami, N. Development of a swimming
motion display system for athlete swimmers’ training using a wristwatch-styleacceleration and gyroscopic sensor device.
Procedia Engineering 2, 3035–3040 (2010).

2.

Ohgi, Y., Hirai, N., Murakami, M. & Seo, K.
Study of ski jumping flight based on inertia sensors in The Engineering of Sport 7,
Vol. 2 (eds Estivalet, M. & Brisson, P.) 157–164(Springer Paris, 2008).

7

Research highlights

Improving the communication between remote mechanical systems and their human controllers can lead to more precise movements.

A gentler approach toremote control

R

emotely controlled devices offera safe way to perform hazardous
tasks, such as bomb disposal or
activities in radioactive areas.
Eiichi Saito and Seiichiro Katsura from Keio
University’s Department of System Design
Engineering have developed a method forincreasing the stability and precision ofthese remotely controlled systems1.
Remote-controlled robots in risky
settings may need to grab an object firmly
enough not to drop it, but not so tightly
as to damage it. This balance is achieved
through a concept known as feedback: therobot’s movements are automatically adjusted based on measurements of the forces8

between the grabbing tool and the object.
The same type of give-and-take is needed todirect robots to precise locations.
However, because the robot and its
human controller are at different locations,
there is a time delay between the input
from the controller reaching the robot andthe feedback reaching the controller. This
time delay can make the system vibrate andbecome unstable.
The Keio team proposed a novel time-delay compensation scheme that models thesystem as a series of oscillating masses
connected by springs. They introduced
infinity-order equations to this mass-andspring concept to predict vibrations acrossa wide range of frequencies. Since timedelay is a type of infinite-order problem
that works across all frequencies, using
these equations in the algorithm that
determines the feedback in their systemhelped to reduce the deleterious effects ofthe vibrations.
“From an engineering point of view,
it is better to use a simple model, but
high-speed adjustments in position leadto high-frequency vibrations,” explains
Katsura. “So there is a trade-off between
simplicity in control design and suppressionof these vibrations. We introduced so-called
infinite-order modeling and control to solve
the trade-off issue.”
Jitsugaku | August 2016

© ktsimage/iStock/Thinkstock

Unstabilizing vibrations in remotely controlled systems can be
reduced using an elastic feedback method

Research highlights

The researchers experimentally validated
their approach in a simple mechanicalsystem comprised of a computer-controlled motor that moves an object to adesired position. This system was thencontrolled by a second computer that
acted as the remote controller. A timedelay of 25 milliseconds was artificiallyadded between the two computers. The

team first tested a common alternative
approach for reducing the negative effectsof time delays known as the Smith predictor. This alternative method achieveda steady final position, but fell almost amillimeter short of the intended target.
Saito and Katsura’s method reached thesteady end-state in the same time but witha higher accuracy.

“At present, the system only considers
a position-control system,” says Katsura.
“In future work, we hope to extend this toforce-control systems too.”
Reference
1.

Saito, E. & Katsura, S. Time delay compensation using equivalent elastic force feedback. IEEJ Journal of Industry Applications
4, 688–695 (2015).

T cells launch targeted attack
on tumors
Discovery of a protein fragment gives rise to a new strategy for harnessing
the immune system against leukemia© 2016 Maiko Matsushita, Keio University

A

protein fragment newly identified by Keio researchers1 andexpressed in leukemia cells
points to a target for developing novel immunotherapies to combat thedeadly blood cancer.
Scientists have known for more than adecade that many tumor cells, and cells
from leukemia blood cancers in particular,
express a protein called PEPP2 that can
trigger an immune response (see image).
However, it was unclear what part of theprotein specialized immune cells calledkiller T cells recognized and latched on to.
A team led by Maiko Matsushita, a hematologist and cancer immunologist at Keio
University, went in search of the elusive site
on PEPP2 to which white blood cells bind
— a site known as the epitope. They synthesized 24 fragments of the PEPP2 protein.
Using immune cells from healthy donors in
the laboratory, they singled out one PEPP2
fragment — a nine amino-acid stretch —that roused the killer T cells into action.
With this small protein fragment, “wecould induce anti-PEPP2 killer T cells withresearch-highlights.keio.ac.jp

strong activity,” Matsushita says. “This encouraged us to believe that this epitope might
be useful for many leukemia patients.”
To boost the expression of PEPP2 on
leukemia cells, and increase the potency of
the anti-PEPP2 T cells, Matsushita and hercolleagues exposed the leukemia cells to adrug that removes chemical marks fromthe DNA. These marks, known as methyl
tags, restrict gene expression, and theresearchers found that the ‘demethylating’drug increased levels of PEPP2 expressedin the leukemia cells. The cells were

subsequently more vulnerable to attackfrom killer T cells.
The findings could pave the way for a new
therapeutic strategy for combatting leukemia,
a disease that kills more than 250,000 people
globally each year. Matsushita envisions a
scenario in which scientists genetically engineer a patient’s own T cells in the laboratory
so that they respond to PEPP2 more actively
and efficiently. Those cells could then be
infused back into the patient together witha drug that takes away the methyl tags fromthe DNA of the cancerous cells in the body.

Leukemia cells expressing the surface protein PEPP2 (labeled bright green) that immune cells in the bodycan recognize.

9Research highlights

PEPP2 is also expressed in leukemia stem
cells, which are one of the reasons fordisease relapse.”
Reference
1.

Matsushita, M. et al. Identification of novel
HLA-A*24:02-restricted epitope derived
from a homeobox protein expressed inhematological malignancies. PLoS ONE 11,
e0146371 (2016).

The price ofa personal touch forlung cancer therapy
Personalized treatments are an affordable option forimproving the lives of lung cancer patients in JapanP

ersonalized treatments for lungcancer patients can help them
live longer, with fewer side effects, at a marginal expense to
the Japanese healthcare system, finds ananalysis by Keio University researchers1.
The analysis justifies adopting personalized
treatments for the most fatal form of cancer
worldwide, which kills around 1.6 million
people every year.
“We’re facing a new era of personalized medicine,” says study lead Hisashi
Ur u s h i h ar a , f rom Ke i o Un ive rs it y ’s
Research Laboratory of Drug Development
and Regulatory Science. He foresees thatscreening for specific genetic traits willsoon be standard in medicine in the formof companion diagnostic tools that assess
the potential benefits and risks of a specificdrug to a specific patient. “Companion diagnostics will drastically improve treatment
outcomes, making optimal therapy possible,”says Urushihara.
10

Consider the drug gefitinib, which inhibits a protein called epidermal growth factor
receptor (EGFR). EGFR is elevated onlyin certain types of cancer, including themost common form of lung cancer, nonsmall-cell lung cancer. A landmark study
in 2009, the Iressa Pan-Asia Study, showedthat gefitinib treatment slowed lung cancer

progression in patients with EGFR genemutations (between 10 and 30 per cent ofpatients), but was almost completely ineffective for patients lacking this mutation.
The challenge for Urushihara’s team wasto justify the increased cost to the healthcare
system of a genetic test and tailored gefitinib
treatment compared to standard chemotherapy. “Every country is suffering fromthe increased cost of medical care,” says
Urushihara. Several countries have adopted
policy measures to incentivize healthcarethat carries the best value for money.
Using models of disease progression and
EGFR prevalence, the researchers estimatedthe quality of life gained by personalizationof lung cancer treatments. EGFR-positive
patients were given gefitinib, while EGFRnegative patients underwent standard
carboplatin–paclitaxel chemotherapy.
Then they asked if the treatment wasgood value, assuming that patients would be
happy to pay JP¥5 million for a year of good
health (reduced to JP¥1.5 million after accounting for the percentage covered by thenational healthcare system). The answer was
yes: for only JP¥122,000 (US$995) per patient, adopting standard EGFR screening fornon-small-cell lung cancer would improve
all patients’ survival by the equivalent of
13 days of good health because they received
the best treatment for their condition. In all
the scenarios modeled, around 89 per centof patients would gain outcomes justifying
the small premium for EGFR screening andOffering the best medicine while addressing growing healthcare costs is a serious challenge for many countries.

Jitsugaku | August 2016

© daizuoxin/iStock/Thinkstock

The approach would need to be tested
in animal models and then in humanclinical trials. But if it proves safe andeffective, it could greatly benefit patients
who don’t respond to existing drugs or
who experience disease recurrence.
“ F o r t h o s e p a t i e n t s ,” M a t s u s h i t asays, “immunotherapy targeting PEPP2
might be a good treatment option, sinceResearch highlights

treatment. Targeted gefitinib treatment
allows “patients to spend more time with
their families and lead more active lives,
while contributing to society,” he says.

Reference1.

Narita, Y. et al. Cost-effectiveness analysis
of EGFR mutation testing and gefitinib asfirst-line therapy for non-small cell lungcancer. Lung Cancer 90, 71–77 (2015).

Survival threat
emerges from within
industrial clusters
A combination of microeconomics andquake-engineering reveals greater vulnerability ofclustered manufacturing plants to natural disasters© tupungato/iStock/ThinkstockS

etting up local factories in close
proximity to competitors canbring enormous opportunities
for growth, but poses a highrisk of long-term failure to recover from a
massive earthquake, according to a study byan international team of economists led by
Toshihiro Okubo at Keio University1.
“Many people believe that industrial agglomeration in large cities makes companies
resilient to natural disasters,” Okubo says. “Butour study reveals a lot of negative aspects.”
Many studies have looked at how natural
disasters undermine global, regional andlocal economies in developing countries, but
few have focused on developed economies.
This type of analysis matters for Japan because of the imminent threat of another large
earthquake following the devastating shakethat hit the northeastern Tohoku region ofJapan in 2011.
The researchers looked into the 6.9-magnitude earthquake that struck the western portcity of Kobe in 1995, claiming 4,500 lives.
They used the government’s highly detailed
mapping data, building-level surveys, andresearch-highlights.keio.ac.jp

plant-level economic surveys, created using
an advanced geographic information system.
The data assigned one of five colors to eachof the 1,846 manufacturing plants across thecity according to the degree of damage they
had incurred. The researchers used this information to calculate the associated percentage
loss of value for each building, area and road.
Leveraging Okubo’s expertise in theoreticaland empirical studies of economic geography
and international trade in the presenceof firm heterogeneity 2, the team createdvarious parameters for assessing the effect ofearthquake damage on plant survival and theimpact of clustering on long-term survival.
“By combining an economic approachwith earthquake engineering, we learned thateven though plants in clusters survived theearthquake, many of them suddenly failed
after five to ten years,” says Okubo.
Manufacturing industries such as therubber and non-ferrous metals industries
were heavily clustered and their plants wereseverely damaged. Damaged plants weremore likely to fail than undamaged plants
within the same cluster amid increased
competition and cannibalization, rather
than cooperation to survive difficult times.
Such negative impacts of building damage
persisted much longer than expected. “Theresult also reaffirmed the importance ofstrengthening structures to make them more
quake resistant,” says Okubo.
Okubo’s cross-disciplinary approach
matches well with Keio’s commitment topractical research. “We were able to understand the long-term impact of earthquakes,
which economic data alone could not have
explained.” He is now expanding his researchscope to cover the aftermath of other disasters, including the Tohoku quake and nuclear
accidents in Fukushima.
References
1.

Cole, M. A., Elliott, R. J. R, Okubo, T. &Strobl, E. Natural disasters, industrial
clusters and manufacturing plant survival.
RIETI Discussion Paper Series 15-E-008 (2015).

2.

Baldwin, R. E. & Okubo, T. Heterogeneousfirms, agglomeration and economic geography: Spatial selection and sorting. Journal of
Economic Geography 6, 323–346 (2006).

Factories that group together in industrial clusters are exposed to a high risk of failure up to ten years after sufferingdamage from a major earthquake.

11

Feature article

Leading the race against dementia
Exercise could hold the key to reducing cognitive decline in aging populations

Step by step
Oguma’s approach focuses on prevention over treatment.
Recalling her early career as a physician at Keio University
Hospital, she says: “I saw lots of patients with serious diseases,
such as cardiovascular diseases and cancer, and I started tothink about how to prevent or postpone their diseases byimproving their lifestyles.” Oguma continued this researchwhen she moved to Boston to attend the Harvard T.H. Chan
School of Public Health as a graduate student. Now an associate professor at Keio, she aims to reduce the number of people
with obesity and cognitive decline by improving public healthand reducing society’s healthcare burden.
Research by Oguma1 and others has shown that even a
modest increase in daily physical activity can make a difference.
Regular activity, such as walking to work or the store, climbing
stairs, or even gardening, lowers the risk of heart disease,diabetes, and depression, as well as helping to prevent obesityand knee or lumbar pain. Oguma incorporated these findings
as part of a team conducting a systematic review for Japan’s
Ministry of Health, Labour and Welfare into new guidelines forphysical activity in 2013. The guidelines recommend 60 minutes of moderate to vigorous daily physical activity as optimal,
but emphasize that as little as 10 minutes a day is beneficial.

© 2015 Yayoi Kibayashi, Keio UniversityModern medicine faces a dilemma of its own
making. While people have longer lifespans,aging populations can become an unmanageable burden for healthcare systems. The
resolution could lie in readjusting what we classify as healthcare.
As the country with the world’s oldest population, Japan isparticularly attuned to the specific ailments of senior citizens.
Dementia already afflicts more than three million Japaneseand will affect more lives as the population continues to age. At
Keio University’s Sports Medicine Research Center, researcher
Yuko Oguma is investigating whether regular exercise, which
reduces the risk of obesity, heart disease, and depression, could
also help delay cognitive decline. “Preventing cognitive decline isa national problem,” she says. “It is very important for our society
to work on health management and not just medication.”

Elderly residents in the central-eastern city of Fujisawa, Japan, exercising
as part of Keio University’s ‘+10 project’ to increase their daily activity
by ten minutes.

and public health initiative, which aims to increase seniorcitizens’ daily physical activity by 10 minutes. The program
targets elderly communities in the coastal city of Fujisawa,organizing calisthenics groups and offering training videos
and support. “Doing ten minutes of physical activity is better
than nothing,” she explains. “Sixty minutes would be muchbetter, but ten minutes is a good start.”
Physical activity is known to increase blood flow to thebrain and to increase the concentration of a protein importantfor neuronal growth and maintenance called brain-derived
neurotrophic factor. Using data from the +10 project, Oguma
hopes to discover whether increased physical activity can
prevent cognitive decline. Her team, in collaboration withdementia specialists at Keio University’s School of Medicine,uses questionnaires and an iPad application to assess participants’ cognitive function.
The graduate school is also using the 2020 Tokyo Olympics
to raise awareness. “Instead of just watching athletes do sports
on television, this is a very good opportunity to increase
physical activity in the population,” Oguma says. “I wantphysical activity to become part of people’s routine. If people
can lead healthier lives within their communities, our aging
population will put less strain on the healthcare system.”
Reference

An activity a day
Oguma now runs the Graduate School of HealthManagement’s ‘+10 project’, a combined research program12

1.

Oguma, Y. et al. Physical activity decreases cardiovasculardisease risk in women. American Journal of Preventive Medicine
26, 407–418 (2004).

Jitsugaku | August 2016

Feature article

Anti-inflammatory interactions
The influence of intestinal bacteria on gene expression in immune cells could be the key
to treating inflammatory bowel disease

Reprinted by permission from Macmillan Publishers Ltd: Nature Immunology Ref. 3, copyright 2014T

he past 100 million years of evolution havedeveloped a complex relationship between
bacteria and the human gut. These bacteria areessential because they break down nutrientsthat we cannot process, but, conversely, our immune
systems must be constantly alert to the possibility that they
will trigger an inflammatory response. Rapidly unfolding
research that includes cutting-edge work at Keio University
is revealing the importance of epigenetic mechanisms tothis interplay, in which intestinal bacteria influence gene
expression in immune cells. The findings present novel
opportunities for the treatment of inflammatory bowel disease,which affects more than 3.5 million people worldwide.
Epigenetics and immunity
Epigenetic mechanisms involve chemical modifications of
DNA molecules and histones, the proteins around which
they are wrapped. These modifications alter gene expression
and, consequently, cell function. The significance of epigenetics was described by the British biologist and geneticist,
Conrad Waddington, as early as 1942, but the mechanisms andtheir full implications are still being unraveled.
“Nowadays, human epigenetic studies are common,” says
Koji Hase from the Keio University Graduate School of
Pharmaceutical Science. The US National Institutes of Health(NIH), for example, launched the Roadmap Epigenomics
Mapping Consortium in 2008, which has since revealed theepigenomic landscape in various human tissues and cells,
and could lead to state-of-the-art therapies for cancers andautoimmune diseases. “Epigenetics in the immune system,

however, is an emerging research field that has rapidly developed since the turn of the century,” says Hase1.
Immunity to inflammation
Research at Keio University, undertaken by several scientists,
has focused on the epigenetic effects of intestinal bacteria on
immune cells. “Keio University is now the center of microbiome and epigenetic studies in Japan, and researchers here areleading the worldwide initiative in microbiome studies,” says
Hase. Notable researchers include Kenya Honda, who heads
research on the regulatory effects of the microbiome on the immune system, Takanori Kanai, who was the first to initiate fecal
microbiota transplantation in Japan, and Akihiko Yoshimura,
who leads studies on the epigenetic regulation of immune cells.
Hase’s own work has shown that a metabolite called butyratethat is produced by intestinal bacteria is involved in the epigenetic regulation of regulatory T cells2,3, which are central to the
suppression of inflammatory responses. Butyrate was foundto induce the differentiation of regulatory T cells in mice.
Disruption of this epigenetic regulation caused severe inflammation of the intestinal lining known as colitis (see image)3, but
the disease was prevented by treatment with butyrate2.
“Our findings not only link butyrate to microbe-mediatedinduction of regulatory T cells in the colon, but also provide
evidence for the therapeutic application of butyrate in inflammatory bowel disease,” says Hase.
Although the Keio University research has established theimportance of intestinal bacteria in the epigenetic regulation of
immune function, the precise molecular mechanisms behind
this regulation are not known. Determining them is Hase’s
next step. “Gut-derived metabolites might behave as ‘external
hormones’ to regulate host immunity and metabolism,” he says.
“I would like to take advantage of metabolomics to identify themolecular components of such host–microbe signaling.”
References
1.

Obata, Y., Furusawa, Y. & Hase, K. Epigenetic modifications of
the immune system in health and disease. Immunology and Cell
Biology 93, 226–232 (2015).

2.

Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504,
446–450 (2013).

3.

Obata, Y. et al. The epigenetic regulator Uhrf1 facilitates theproliferation and maturation of colonic regulatory T cells.
Nature Immunology 15, 571–579 (2014).

100 μmDisrupting the epigenetic regulation of regulatory T cells in the intestinal
lining of mice causes inflammation, shown by the green fluorescent markers.
research-highlights.keio.ac.jp

13Research highlights

Stretching out speech components such as vowels in English or consonants in Japanese can be used to emphasize just how much we mean something.

Emphasizing words witha bit of a stretchJapanese speakers adjust the length of
consonants to convey the strength oftheir conviction about a subject, according to a study by Shigeto Kawahara
at The Keio Institute of Culture andLinguistic Studies1.
Unlike in English, the meaning of words inJapanese can vary dramatically depending onwhether the consonants are pronounced aslong or short sounds. Lengthen the ‘t’ in theword for ‘outside’ (soto), for example, and you
could be saying ‘softly’ (sotto). But consonant
lengthening can also be used to emphasize thedegree of meaning a speaker wishes to convey,
as in the English vowel-based example, ‘Thankyou sooooo much for reading’. “Nobody
really studies these phenomena of lengthened
consonants and vowels even though it is very
common in everyday speech,” says Kawahara,14

who wanted to experimentally quantify thelevels of distinction that could be conveyed
through lengthening.
Kawahara and his colleague Aaron Braverat Texas Tech University selected four consonants — t, d, s, and z. Seven undergraduate students were given two adjectives foreach consonant and instructed to lengthen
the consonant to indicate emphasis in thecontext of a sentence. For example, for‘uzai’, which means ‘annoying’, the phrase
would be ‘ano koogi uzai’ or ‘That lecture isannoying’. Participants were asked to repeat
the sentence with varying levels of emphasis, in a randomized order, either with noemphasis or with anywhere up to five levelsof emphasis, as in ‘ano koogi uzzzzzzai’.
The researchers used a phonetics software
package called Praat to generate waveforms

and spectrograms from the recordings that
could be used to visually and statistically pinpoint the number of durational distinctions
participants were able to convey. Kawahara
was surprised by the results: “We initiallythought that 3 or 4 degrees would be themost, but they managed to do 6!”
But are people able to recognize thesesubtle distinctions without technologicalintervention? In a previous study about
English vowel lengthening conducted in
the United States, Kawahara found that
listeners are not very good at picking up
on these distinctions. “The exact value ofemphasis doesn’t practically matter — itis sort of a selfish thing like ‘Here’s what I
want to say’.” Kawahara plans to carry out asimilar perception analysis for the Japaneseconsonant lengthening study.
Jitsugaku | August 2016

© Fuse/Thinkstock

Consonants can be lengthened to convey both meaning and emphasis in JapaneseResearch highlights“This is a very understudied area,” he points
out. “It would be interesting to branch out
and examine other languages.” The findings
could potentially be used to improve artificial
intelligence or voice recognition software.

Reference
1.

Kawahara, S. & Braver, A. Durational
properties of emphatically lengthened
consonants in Japanese. Journal of theInternational Phonetic Association 44,
237–260 (2014).

Fine-tuning
the brain’s circuitry
A protein pair manages the proper development ofneuronal connections essential for motor learningand neurological healthA
Reprinted from Ref. 1, Copyright 2015, with permission from Elsevier

mechanism that controls theformation and elimination ofneuronal connections in thebrain’s motor center, the cerebellum, has been discovered by researchers led
by Michisuke Yuzaki and Wataru Kakegawa at
Keio University1. The process remains active
over the course of a lifetime, and may be associated with certain neurological disorders.
Voluntary movement in the cerebellum isgoverned by signals transmitted at synaptic
junctions between climbing fibers andWild type* * *neurons called Purkinje cells. “In immature
animals, each Purkinje cell is innervated bynumerous climbing fibers,” says Kakegawa.
“But as the animal grows, one climbing fiber— referred to as the winner — is strengthened, and the remaining weak climbing
fibers are gradually eliminated.” Kakegawa
and Yuzaki identified a protein that might
control this ‘pruning’, and set out to test
their hypothesis.
They generated genetically modified micelacking the protein known as C1ql1, whichC1ql1-null* * * *** ** * * *

* *Climbing fibers form numerous synapses (red) with Purkinje cells (green; asterisks indicate cell bodies) in the
cerebellum of normal, wild-type mice (left). In mice lacking the protein C1ql1 (right), climbing fibers form a greatly
reduced number of synapses with Purkinje cells.

research-highlights.keio.ac.jp

is specifically produced by climbing fibers.
Purkinje cells in these mice retained multiple
climbing fiber connections, but failed toestablish the formal synaptic linkages needed
for normal signaling (see image). In contrast,
mice producing high levels of C1ql1 initiallyestablished excess connections, but pruned
these down to a single winner within days.
“This suggests that C1ql1 contributes to thestrengthening of winner climbing fibers andthe elimination of excess weak climbing
fibers during development,” says Kakegawa.
Su b s e qu e nt e x p e r i m e nt s re ve a l e dthat C1ql1 establishes fully functional
climbing fiber–Purkinje cell synapses bybinding a receptor protein called Bai3. The
effects of Bai3 deficiency were essentially indistinguishable from those seen in mice lacking C1ql1, generating disruptions in synapse
formation that interfered with the capacity
to learn motor skills. The climbing fiber
pruning process normally initiates roughly
a week after birth, but the researchers were
surprised to discover that the signals remain
active throughout adulthood. Experimentsthat prevented C1ql1–Bai3 interaction in
genetically normal adult mice undid thepruning process, resulting in impaired motor
learning. However, the researchers could restore normal connectivity in adult mice thatgrew up lacking C1ql1 or Bai3 by enablingproduction of these proteins.
Kakegawa believes that these findings
may offer important insights into humanhealth. “Synapse dysfunctions have been
observed in mouse models of psychiatricdisease and in individuals with neurological disorders,” he says. “Furthermore, theBai proteins have been associated withpsychiatric symptoms.” A top priority for
Yuzaki’s team will be to explore this signaling pathway and to learn whether these
proteins and their relatives perform similarroles elsewhere in the brain.
Reference
1.

Kakegawa, W. et al. Anterograde C1ql1
signaling is required in order to determine
and maintain a single-winner climbing
fiber in the mouse cerebellum. Neuron 85,
316–329 (2015).

15

Feature article

Learning from master farmers
Keio researchers are applying information technology to capture andspread the agricultural wisdom of Japan’s aging farmers

C

Old wisdom
The seeds of Shinjo’s initiative were actually sown years
earlier in conversations with his grandfather, a vegetable
farmer. “My grandfather would ask his vegetables how muchwater they needed,” Shinjo recalls. Of course, the vegetables
could not respond, but Shinjo remembers that his grandfather evaluated the condition of his plants in a very similar
way to Ooyama.
Japanese farmers are some of the most productive andefficient in the world, but this admirable status is under
threat because the most experienced farmers are aging fast.
In terms of calories per acre, Japanese agricultural output
is almost ten times greater than that in the United Statesand more than twice that of the most efficient agricultural
nations in Europe, such as Germany. Yet the average age ofJapan’s farmers is rising steadily; it increased from 59 years
in 1995 to nearly 66 in 2010.
“Two million of our 2.6 million experienced farmers
will retire in the next ten years, and successors are in short
supply,” says Shinjo. “We need to act fast to capture andspread their knowledge.”
Agri-informatics
The Keio Agri-infoscience Laboratory uses information
technology to capture the methods of the most successful
farmers and then applies a software system to assess the data
and distribute the best methods to younger farmers. This ‘AI
Agri-Culture’ process offers advice through a decision-making
support system. The precious input to the system comes from16© 2015 Atsushi Shinjo, Keio University

omputer scientist Atsushi Shinjo is using
modern technology to gather and disperse theaccumulated wisdom of Japan’s expert farmers
thanks to an encounter in 2009 with prize-winning tomato farmer Yutaka Ooyama from Tochigi Prefecture,a few hours’ drive north of Tokyo. “I watched Ooyama as heinspected his tomatoes and found differences between his
viewpoints and those of novice farmers,” says Shinjo. Thisobservation inspired Shinjo to establish the Agri-infoscience
Laboratory at Keio University’s Shonan Fujisawa Campus, aninstitution dedicated to maintaining “a balance between thelatest technology and the rich natural environment.”

An expert farmer records his work using an eye camera system.

the wisdom and good practice of a network of exemplary
farmers, or takumi (“masters” in Japanese).
The farms of the takumi experts are monitored using
sensors to capture data on growing conditions, including
temperature, irrigation and water levels, and chemical treatments. These technical data are combined with information
on farming decisions and activities throughout the year,
which the farmers record on software developed for mobile
phones. The Keio researchers then collate and analyze thedata and present it for use by less experienced farmers on
computer tablets linked to a cloud-based network. The end
users can install sensors on their own farms to help them
replicate the conditions used by the takumi farmers, while
also benefiting from more descriptive guidance.
Trials of this approach have already proved successful
in Japan and Thailand. “Mandarin orange farmers haveachieved a 20 per cent improvement in fruit quality using
our system,” reports Shinjo. A trial version of the software
will be further evaluated during 2015 and a vendor will
provide a commercial version before the end of 2017.
“Eventually, I want to apply our system to underdeveloped countries that already face food crises,” says Shinjo.
“This is one of the most important issues facing the world.
Hopefully, we can help novice farmers to become experts asfast as possible,” he adds.
Jitsugaku | August 2016

Research highlights
When the electron (e) and hole (h) of an exciton recombine in asingle-walled carbon nanotube they produce a single photon.

Single photons
for quantum cryptography
Carbon nanotubes that emit single photons at telecommunication wavelengths
and room temperature could be useful for quantum cryptography© 2015 Hideyuki Maki, Keio University

S

ingle-walled carbon nanotubes canemit single photons at room temperature and at wavelengths used
for telecommunications, according
to research by Keio University scientists1. This
makes them very attractive as single-photon
sources for quantum cryptography systems.
Quantum cryptography is an emerging
technology that uses the quantum-mechanical properties of photons to encrypt information. The laws of quantum mechanics ensurethat any attempt to intercept the information
would garble it. For quantum cryptography to become commercially viable, lightsources are required that produce just one
photon at a time and at wavelengths used fortelecommunications.
Takumi Endo, Junko Ishi-Hayase and
Hideyuki Maki at Keio University have discovered that single-walled carbon nanotubes
research-highlights.keio.ac.jp

meet both criteria with an unexpectedbonus — they generate single photons atroom temperature. “We expected that single-walled carbon nanotubes would be suitable materials for single-photon sources attelecommunication wavelengths,” says Maki,
who led the research. “But we were very
surprised that they produced single photons
at room temperature.”
The researchers used a superconducting
single-photon detector to measure andanalyze the light emitted from the nanotubes for temperatures from 6 to 300 kelvin(room temperature). The results revealed
that the nanotubes exhibited ‘photon antibunching’ over the full temperature range— a sure indicator that they were emitting
single photons.
Single-walled carbon nanotubes containquasiparticles called excitons that consist ofa negative electron and a positive hole. In
the case of ‘localized’ excitons (that is, those
restricted to a narrow area), a single photonof light is emitted when the electron fills
the hole in a process called recombination(see image).
Localized excitons tend to become non-localized with increasing temperature, making
it less likely that single-photon emission
will occur. The scientists suspect, however,that a sleeve of randomly arranged carbon
atoms on the nanotube shields it from directcontact with air, which allows the localized
excitons to exist at high temperatures. Thismeans that the nanotube’s optical properties
could potentially be fine-tuned using external coatings, for example.
A further advantage of these nanotubes
is that they can be readily incorporated on
silicon chips.
17

“Since single-walled carbon nanotubes
can be directly grown on silicon chips, nanotube-based emitters can be easily combinedwith silicon photonics,” notes Maki. This,
together with the fact that the nanotubes
do not require cooling, makes on-chipsingle-photon sources a feasible proposition— something that would greatly facilitate
widespread uptake of quantum cryptography. The researchers intend to improvethe efficiency of single-photon generation
by nanotubes and apply a nanotube-based
single-photon source to current quantum
cryptography technology.
Reference
1.

Endo, T., Ishi-Hayase, J. & Maki, H. Photon
antibunching in single-walled carbon
nanotubes at telecommunication wavelengths and room temperature. Applied
Physics Letters 106, 113106 (2015).

Mending broken
heartsA small RNA molecule can convert fibroblast cells
directly into beating heart muscle cellsK

eio researchers have founda direct and efficient way toconvert mature cells from one
type to another. The techniquecould eventually be used to stimulate a patient’s connective tissue cells to become thebeating heart muscle cells that will repair
their damaged hearts.
“Heart failure is the number two killer inJapan,” says Masaki Ieda at Keio University
School of Medicine, who led the study. And
cardiovascular diseases remain the leading

Human heart muscle cells (red) generated from fibroblasts by direct reprogramming.

18

cause of death worldwide, affecting an estimated 17.5 million people annually.
Many research groups are trying to create mature cell types that could be used inregenerative medicine, but mostly via thestem cells route. Ieda and his co-workers
are world leaders in exploring an alternative, direct path. In 2010, they were among
the first groups to report direct reprogramming, when working with neurons andcardiac cells1.
“Direct reprogramming is faster and simpler than stem-cell-based methods and carries no risk of tumor formation,” says Ieda.
In their most recent study, Ieda and hiscolleagues, in collaboration with otherJapanese research centers, found an efficient way to convert connective tissue cells
known as fibroblasts into beating heart
muscle cells called cardiomyocytes2.
The researchers found that a small RNA
molecule known as miR-133 can repress
the activity of a key regulatory gene in a
way that promotes the desired reprogramming into cardiomyocytes1. The miR-133
molecule is one of many microRNAs thatcan silence gene activity by binding to
the larger messenger RNA molecules thatcarry genetic information from DNA to be
decoded into active proteins. Overall, themiR-133 molecules block the activity of alarge set of genes that make cells fibroblasts,
while at the same time allowing other setsof genes that generate cardiac cells to become active.
Uncovering this fine detail about themechanism by which fibroblasts can be
reprogrammed into heart muscle cells
should greatly assist efforts to move thecurrent explorator y studies into realtreatments. While Ieda used cultured
cells in his study, he believes that similar
techniques might eventually be possible
in human patients. “We think we could
reprogram fibroblasts into beating heartcells in situ,” says Ieda.
Ieda now plans to explore ways to makethe reprogramming process more efficient.
In addition to the ultimate aim of repairing
beating hearts, this work could also generate
Jitsugaku | August 2016

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Research highlights

Research highlights& Srivastava, D. Direct reprogramming offibroblasts into functional cardiomyocytes
by defined factors. Cell 142, 375–386 (2010).

cells that can be used for modeling heartdisease and testing potential new drugs.
References
1.

Ieda, M., Fu, J.-D., Delgado-Olguin, P.,
Vedantham, V., Hayashi, Y., Bruneau, B. G.

2.

Muraoka, N. et al. MiR‐133 promotes cardiac
reprogramming by directly repressing Snai1and silencing fibroblast signatures. The
EMBO Journal 33, 1565–1581 (2014).

Locating people using
radio waves
A person’s whereabouts could soon be tracked
without the aid of a portable deviceK© mishabokovan/iStock/Thinkstock

eio researchers have devised
a way to accurately locate anindividual’s position using only
a remote antenna by exploiting
the way that the human body interacts withradio signals1. The scheme has the potential
to revolutionize remote patient monitoring,ambient intelligence for smart homes, andintrusion detection in security applications.
To be located, a person usually needs
to hold a device containing a transceiver

designed to interact with global positioning
system (GPS) satellite signals or wireless orcellular networks. Mobile phones serve thispurpose well, but in applications where relying on a device is too risky, such as in patientmonitoring, location methods without adevice are necessary.
Several device-free localization methods
that do not require the involvement of
individuals have been proposed, but theiraccuracy is often poor due to the difficulty

in separating the location signal fromsignal ‘noise’. Tomoaki Ohtsuki and Jihoon
Hong from the Department of Information
and Computer Science at Keio University
have developed a system that combines
sophisticated signal processing with a specific distribution of antennas to detect the‘fingerprint’ of human-body interaction
with ambient wireless radiation without
the noise interference that has plagued
previous attempts.
The human body is an electrical conductor, which means that it diffracts, reflects
and refracts radio signals emitted by wirelessnetwork transmitters in a very specific way.
By analyzing these wireless signals using amathematical concept called the eigenvector,
Ohtsuki and Hong have been able to extract
not just the fingerprint of human-modified
wireless signals, but also the direction of
signal, with unprecedented accuracy.
“Using special signal processing techniques, we can extract enough informationfrom the signals to estimate the direction of
the individual,” says Ohtsuki. “While conventional schemes are subject to signal noise,
our technique separates the signal and noise
components, making signal processing stable
and robust and allowing us to achieve highlocalization accuracy.”
One of the most important features ofOhtsuki’s localization system is its compatibility with existing network infrastructure.
“Our scheme involves some antennas andsignal processing, just as in current cellular
systems and WiFi networks, so our approach can substitute into existing systems
relatively easily.”
Ohtsuki and Hong have further refined
their approach to be able to detect specificmovements of the tracked individual, suchas falling, adding value to an already promising technique. The team is also working
on expanding the system’s capacity to track
multiple individuals.
Reference
1.

A new signal processing scheme can locate a person by detecting their body’s interaction with ambient
wireless signals.

research-highlights.keio.ac.jp

Hong, J., Ohstuki, T. Signal eigenvector-based
device-free passive localization using arraysensor. IEEE Transactions on Vehicular Technology 64, 1354–1363 (2015).

19

© KrulUA/iStock/Getty Images Plus

Feature article

Finding where mind,
brain, and body meet
Emotions arise in brain regions that link the triad of mind, body and brain

20

Jitsugaku | August 2016

Reproduced from Ref. 2 and licensed under CC BY 4.0 (creativecommons.org/licenses/by/4.0/legalcode) © 2015 Umeda, Harrison, Gray, Mathias and Critchley

Feature article

Magnetic resonance imaging scans comparing volumes of graymatter in postural tachycardia syndrome (PoTS) cases with controls. Brain areas where people with PoTS have less gray matterthan controls are shown in green. Areas where controls have lessgray matter than people with PoTS appear in red.

S

atoshi Umeda loves music. In his youth, he learned to play the
piano, trumpet, and double bass. Beautiful music evoked“marvelous” emotions in him, and he often wondered how
these feelings were created inside his body and mind.
So began his interest in psychology. In 1992, he joined a master’s
program at Keio University’s Department of Psychology, later
going on to complete a PhD. He enjoyed Keio’s “free and independent” atmosphere and became intrigued by the James–Langetheory of emotion, which emphasizes the mind–body interaction
for understanding emotion. “It suggests that bodily feelings comefirst and emotional feelings follow,” says Umeda.
“A turning point for me was reading Antonio Damasio’s book
Descartes’ Error. The error was to think that the mind and the
body were separate,” he explains. “I decided then to scrutinize
the mind–brain–body triad.” Now a professor at Keio, Umeda has
spent the last 15 years studying this triad and has gradually homed
in on certain brain regions where he suspects it is embodied.

“The key brain area involved in understanding other people’semotions appears to be the medial prefrontal cortex,” he says. And
it is no coincidence that this region is located next to the salience
network, he adds. “We understand others’ emotional states byfeeling our own bodily states simultaneously.”

Frightening palpitations
Damasio’s book also reminded Umeda that studying faulty or damaged brain areas can often illuminate what the intact area does.
So he is investigating people whom he suspects may have a faulty
salience network, with a view to better understanding its function.
These people have postural tachycardia syndrome (PoTS) and experience an abnormal increase in heart rate when they stand up.
“They feel unpleasant and frightening symptoms such as palpitations, light-headedness, clouding of thought, and blurred vision. They
are also prone to chronic fatigue and psychiatric symptoms such as
depression, panic attacks, and anxiety,” says Umeda.
He was lead author of a ground-breaking
The heart of the mattermagnetic resonance imaging study pub“We understandOur ability to feel our own bodies, including
lished in 2015, which compared the brains
others’ emotional
our awareness of sensations like sweating andof 11 patients with PoTS with 23 normal
states by feeling ourheartbeat, is known as interoception. Umeda
controls2. This was the first study to show thatown bodily states
reasons that regions of the brain that process
the brains of people with PoTS are different
simultaneously.”interoception might be where the mind, brain— their salience networks are smaller thanand body meet.
normal (see image).
A prime candidate appears to be a brain region known as the
He is now using functional magnetic resonance imaging tosalience network. It consists of two adjacent brain areas: the anterior see whether people with the condition respond normally to
cingulate cortex, which controls bodily functions such as heart rate emotional challenges.
and blood pressure, and the insular cortex, which receives input fromBeautiful music, and the strong emotions and bodily feelings it elicthe heart and other organs and is known to be involved in emotions. its, continue to inspire Umeda and his research. For a long time he conProcessing of both emotions and interoception within this network ducted the university orchestra, and he still plays the piano at home.
probably explains why bodily feelings accompany emotions.
Looking for evidence of a connection between interoception and References
emotions, Umeda and his team investigated whether there was a 1. Terasawa, Y., Moriguchi, Y., Tochizawa, S. & Umeda, S. Interoceptive
sensitivity predicts sensitivity to the emotions of others.
link between people’s awareness of their own heartbeat and their
Cognition and Emotion 28, 1435–1448 (2014).
ability to read the emotions of others. They discovered that those
2. Umeda, S., Harrison, N. A., Gray, M. A., Mathias, C. J. & Critchley, H. D.
who are more aware of their own hearts beating are better able to
Structural brain abnormalities in postural tachycardia syndrome:
A VBM-DARTEL study. Frontiers in Neuroscience 9, 34 (2015).
tell whether other people are happy or sad1.
research-highlights.keio.ac.jp

21Research highlights

Sticky bacteria switch on immune cells
Adhesion of pathogenic bacteria to the intestinal wall activates
an immune response

I

ntestinal immune cells are spurredto action by the attachment ofpathogenic bacteria to the gut
lining, according to researchfrom Keio University1. Their discovery
highlights the importance of physical interaction in triggering the immune response,and could improve treatments to balance
the overproduction or underproduction ofthese immune cells in various diseases.
Pathogenic bacteria invade the intestinal
wall by adhering to the epithelium anddisrupting the epithelial barrier, explains
Kenya Honda, who led the study. “That’s
pathogenic bacteria’s pattern: adhesion,
disruption, and invasion.”
Immune cells which are abundant in thesmall intestine, known as Th17 cells, block
this process by stimulating epithelial cells
to produce anti-microbial peptides andstrengthen the tight junctions between
22

them, which maintain the epithelial barrier
In rodents, resident gut microbes known
as segmented filamentous bacteria are potent inducers of Th17 activity. Receptors
on the Th17 cells are known to recognize
the foreign antigens, but Honda suspectedthat adhesion might also play an importantrole in triggering the immune response.
“Segmented filamentous bacteria are very
sticky bacteria,” he says (see image).
To test the importance of physical contact,
however, Honda’s team first had to overcome the challenges of culturing the bacteria and developing non-adhesive mutants.
The breakthrough came with an experiment by Yoshinori Umesaki at the Yakult
Central Institute. Umesaki introduced segmented filamentous bacteria from rats into
microorganism-free mice, and vice versa.
The reciprocal colonization experiments
showed that adhesion is host-specific — theforeign bacteria couldn’t adhere to the intestinal lining of their new hosts — and that
Th17 cells weren’t induced in the absence ofbacterial adhesion.
To study the process in humans,
the researchers had to identify similar
Th17-inducing bacteria colonizing thehuman intestine. They isolated 20 strainspresent in fecal samples from ulcerative
colitis patients that were not present inhealthy patients. When these strains wereintroduced to microorganism-free mice,
they adhered to the lining of the colon,
where they activated Th17 cells.
Diseases like ulcerative colitis andCrohn’s disease have been linked to an imbalance in the gut microbiome, so correcting the imbalance could cure the disease, orat least alleviate symptoms.
Eventually, Honda’s team aims to use
microbiome engineering as a way to treat
Jitsugaku | August 2016

© 2016 Kiminori Toyooka and Seiko Narushima, RIKENElectron micrograph of sticky segmented filamentous bacteria (long strands) attached to epithelial cells.

Research highlights

patients with an overactive immune response, such as in autoimmune disorders,or a weak immune response. “For example,
HIV-infected patients have fewer Th17 cells

in their gut,” explains Honda. “If we could
identify a nice set of Th17-inducing bacteria, those could be applied to treat HIV orother diseases.”

Reference
1.

Atarashi, K. et al. Th17 cell induction by adhesion of microbes to intestinal epithelial
cells. Cell 163, 367–380 (2015).

Icy cages hold a clean energy secret
Water crystals can purify natural gas by selectively trapping
carbon dioxide moleculesUnconventional sources ofnatural gas, such as so-called‘flammable ice’ reserves
located in the Sea of Japan,
may soon find wider use thanks to carbon capture technology developed by
Keio researchers1.
Generating electricity from natural gas
instead of coal or oil is a promising way
to reduce greenhouse gas emissions. This
energy, composed primarily of methane(CH4) and other light hydrocarbons, burns
cleaner than other fossil fuels because itis relatively free of impurities like carbon dioxide (CO2) and hydrogen sulfide.
However, rising demand means that lower-quality natural gas supplies, with trickier
purification requirements, are being targeted for extraction.
Chemical absorption and membrane separation are typical techniques used to remove© 2016 Ryo Ohmura, Keio University

CH4

CO2 impurities from natural gas. But thesetreatments suffer from disadvantages such as
the use of corrosive liquids and the need toconstantly clean clogged filters. Ryo Ohmura
and colleagues from Keio University’s
Department of Mechanical Engineering investigated a way to avoid such complications
by using simple water molecules with surprising gas-trapping abilities.
Clathrate hydrates are ice-like complexes that form naturally on ocean seabeds,
where temperatures plummet and pressures are enormous. These conditions cause
water molecules to hydrogen-bond into
cages and trap gases such as CH4 or CO2 atdensities tens to hundreds of times greaterthan possible through typical compression
techniques (see image).
The hydrates are also selective, explains
Ohmura, and only stabilize when the gas
compound fits suitably inside the aqueous

cage: molecules too big or too small cause
the complex to collapse. Since CO2 molecules are larger than CH4 molecules, thehydrates can be used to purify natural gas
by selectively encapsulating and removing
unwanted CO2.
The team tested the carbon-capturingperformance of hydrates under conditions
that model the continuous operations of
natural gas refineries. Using a small-scale
reactor, they passed a CO2–CH4 mixture
through a hydrate slurry and analyzed
compositions for over 35 hours. Eventually,steady-state conditions — with significantly reduced CO2 concentrations —were reached.
The researchers then compared theexperimental data to computational algorithms designed to uncover the thermodynamic and kinetic factors behind hydrate
purification. “With more accurate models,

CO2+
Water molecules
Guest molecules
Hydrates

Hydrates, compounds that trap gas molecules inside cages of ice, have diverse applications, from carbon capture to consumer goods.

research-highlights.keio.ac.jp

23Research highlights

to inject champagne-like effervescence into
ice creams and jellies.
Reference
1.

Tomita, S., Akatsu, S. & Ohmura, R. Experiments and thermodynamic simulations forcontinuous separation of CO2 from CH4 +CO2 gas mixture utilizing hydrate formation. Applied Energy 146, 104–110 (2015).

The secret tosuccessful aging
Keeping inflammation at bay can help
people live past 100

Alarge study of the elderly inJapan has found that having
low levels of inflammation in
the body is the most important
predictor of a long and healthy life1.
The findings suggest that drugs that regulate the body’s immune system could also help
people remain mentally sharp and disease-freewell into their 80s, 90s, 100s, and possibly
beyond. “Anti-inflammatory medications area potential intervention to slow aging,” says
Yasumichi Arai, a geriatrician-scientist at the
Keio University School of Medicine in Tokyo.
About 0.05 per cent of Japan’s population
is aged 100 and older, which means thecountry has more so-called centenarians per
capita than anywhere else in the world. Araiand his colleague Nobuyoshi Hirose (see image) have been studying these elderly people
for more than 15 years.
In 2000, they launched the Tokyo
Centenarians Study to look at people aged
100 years and older; in 2002, they began theJapanese Semi-supercentenarians Study to
examine those over 105; and in 2008, they
started the Tokyo Oldest Old Survey on
Total Health, which considered people aged2485 and up. All participants in these studies
underwent extensive medical examinations,
including DNA analyses, cognitive studies
and various physiological functions tests.
Arai, Hirose and their colleagues pooleddata from the various cohort studies, including some of the centenarians’ children,
and, in total, investigated the health of
1,554 individuals to determine the most important biological driver of successful aging.

They found that low levels of markers forchronic inflammation trumped all other indicators of whether a person might reach extreme old age, including blood cell numbers,
metabolism, and liver and kidney function.
The Keio team also looked at the lengthof telomeres — the caps at the ends of chromosomes that are thought to continuously
shorten with age and eventually lead to thecessation of cell growth — in collaboration
with researchers at Newcastle University in the
United Kingdom. They found that telomere
size was not a predictor of successful aging,although most of the centenarians and theirchildren managed to maintain long telomeres.
“People with the lowest inflammatoryburden have the best chance of survival,and have higher physical and cognitive
function,” Arai says.
Arai is now looking for safe and effective
anti-inflammatory drugs that could be prescribed to improve the quality of life ofolder people. “Because aging is the greatest
risk factor for a majority of chronic diseases,” Arai says, “interventions targeting aging itself are promising to elongate humanhealth-span.”
Reference
1.

Arai, Y. et al. Inflammation, but not telomere length, predicts successful ageing
at extreme old age: A longitudinal study ofsemi-supercentenarians. EBioMedicine 2,
1549–1558 (2015).

Keio researcher Nobuyoshi Hirose (left) with the oldest man in history, Jiroemon Kimura, who died in 2013at the age of 116.

Jitsugaku | August 2016

© 2015 Nobuyoshi Hirose, Keio University

we can identify ways to improve the hydrate formation, and understand long-term
CO2 capture more precisely,” says Ohmura.
This technology has other, intriguing applications that could even change what we
eat for dessert. Ohmura and his team are developing hydrates embedded with CO2 thatcan carbonate frozen food — a potential way

The Keio Medical Science Prize
Objective
The 2015 Keio Medical
Science Prize Laureates“

I thank the Selection Committee forthis wonderful award.
I am fortunate to work
alongside students andcolleagues committed
to identifying new ways
to enhance the nutritional health of infants,
children and adults, living in different parts of
the world, by studying the interrelationships between our gut microbiomes and diets. Studies ofthe microbiome are allowing us to see ourselves
as intimately connected to the microbial world,
prompting us to consider another dimension of
our human biology and evolution, and inspiring
us to be better stewards of our precious microbial resources.

“

Jeffrey I. Gordon“

It is a great honor
for me to receive The
Keio Medical Science
Prize 2015. I have beenworking on autophagy,
an intracellular degradation system, for morethan 27 years by using
yeast. Identification of
the genes in yeast responsible for autophagychanged the research. It is becoming clear that
autophagy plays an important role in a varietyof cellular events and is related to certain diseases. It has been a great pleasure for me to sharemany exciting findings with my very talented
colleagues. I would like to express my sincere
thanks to all of them.

“

Yoshinori Ohsumi

The Keio Medical Science Prize is an international prize that gives recognition tothe outstanding and creative achievements of researchers in the fields of medicine and life sciences, in particular those contributing to scientific developments
in medicine. It aims to promote worldwide advances in these fields to encourage
the expansion of researcher networks throughout the world and to contribute to
the well-being of humankind.

Prize

Laureates receive a certificate of merit, a medal, and a monetary award. The
award ceremony and commemorative lectures are held at Keio University.

Nomination and Selection

Nominees must have made an outstanding contribution in the fields of medicine
or life sciences closely related to medicine, and must be currently active in theirfield of research.
1.
2.

3.

An invitation is sent out to academics and researchers all over the world
each year, inviting them to nominate a candidate for the Prize.
The Keio Medical Science Prize Selection Committee reviews the nominations, selects laureates through a rigorous review process, and submits arecommendation to the Board.
The Board makes the final decision and the President of Keio University
formally announces the laureate(s).

Yearly Schedule (Subject to change)••••

Call for Nominations: Late January
Deadline for Nominations: Early March
Prize Announcement: Mid-SeptemberAward Ceremony: November or December at Keio University

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

Headquarters for Research
Coordination and Administration
Keio University
2-15-45 Mita, Minato-ku,
Tokyo 108-8345,
Japan
www.keio.ac.jp
research-highlights.keio.ac.jp

Keio Research Highlights
A portal into Keio University’s
cutting-edge science and innovation
Research highlights
Informative and accessible articles that engage thewider public with some of the groundbreaking
research at Keio University.

Features
An in-depth look at some of the latest discoveries
that contribute to Keio University’s‘spirit of science’.

Newsletter
Subscribe to receive regular email updates and keep
abreast of the innovations produced by our researchers.

Visit: research-highlights.keio.ac.jp