実学 | Sc i e n ce | サイヤンス

Issue 3
May 2017

JITSUGAKU
Showcasing the best research from Keio University

100 years of excellence
Medical innovation since 1917

Stroke of genius

Healing the brain with robots

Junk foodBacterium found that digests plastic

Physics rewritten

Dark matter jolts LHC experimentCelebrating 100 years of
Keio medicine in 2017
The Keio University School of Medicine was established in 1917, with renowned microbiologist Shibasaburo Kitasato serving as its first dean. Kitasato’s vision of unity between
basic medical research and clinical medicine has guided the school since its inception.
Over the past 100 years, Keio University School of Medicine has become a major center
for world-leading medical research and education, and plays an indispensable role in thedevelopment of medical care in Japan.

ON THE COVER
1920 KEIO UNIVERSITY HOSPITAL OPENS

T

he open i ng c eremony for t he Keio
Un i v e r s i t y H o s p i t a l w a s h e l d o nNovember 6, 1920 and the first general
meeting of the Keio Medical Society was held
on November 8 of the same year. Keio Igaku,
the Journal of the Keio Medical Society was firstpublished in 1921. The Building for Preventive
Medicine & Public Health (Institute of Preventive
Medicine) was completed in 1929, thanks todonations from the Rockefeller Foundation.

Contents3

実学 | S c ie n c e | サイヤンス

Editorial

Hundred years of medical excellence

Research highlights
6Star-crossed models of white matter disease7

Building a colorectal cancer library

8
9
10

11

11

12
14

tive to realize
ciety where
le live better,er lives

curitytive to assure
er, moreainable society

Integrative
Approaches

Page 17Creativity

research-highlights.keio.ac.jp
Initiative to bolster
innovation in
education

4

Neural support cells are implicated in childhood diseases of thebrain’s fatty high-speed transmission lines
Biobank of colorectal cancer ‘organoids’ reveals cancer’s secrets

Sealing the deal on leak-proof cells

Scientists discover the unusual geometry that holds mammalian 		skin together, even while shedding

Beta-blockers not better for heart surgery patients

Page 6

Japan-wide study shows a widely used heart drug does not 		
improve bypass results

Brain regions controlling emotion pass from mothers
to daughters
Women are more likely to inherit brain structures linked to 		depression from their mothers than their fathers

Page 8Feature articles
16

ngevity

Inside Keio

A prize for science visionaries

Page 4

6

JITSUGAKU

Preserving more than words
Mind over machine
Measuring the tremors of an earthquake-savvy public
Western roots in Japanese manga

Inside Keio

A global research hub

17Page 16

Contents

19

Research highlights
19

Making light of a dark matter

20

Female flies have soft spots for male genitalia

21
Page 19

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23
Page 23

24
25
26
27

Page 26

28

The see-sawing behavior of dark-matter particles might have jolted experiments 		
at the Large Hadron Collider
The reproductive tracts of female fruit flies have evolved to minimize damage caused
by matingA bit of chaos benefits light-driven devices

Random features in nanoscale photonic cavities can help miniaturize devices that 		
control optical data

Beaks of canny crows adapted to tool use

Bill structure assists New Caledonian crows in using twig hooks to catch grubs

Beauty is in the prefrontal cortex of the beholder

Noninvasive electrical brain stimulation can alter our appreciation of art

Simulation solves Venus atmosphere mystery

Waves of air create cold regions around the poles of our nearest planetary neighbor

Plastic-munching bacterium foundNew discovery could lead to a safer solution to plastic pollution

Chain-walking chemistry installs new carbon bonds

Wandering catalyst activates carbon atoms to form carbon–carbon bonds

Catching up with the influenza virus

New diagnostic tests could quickly reveal a flu infection in its early stages

Dimming the lights on cancer cells

Fluorescent probes selectively taken up by tumorous tissue could be used for early
disease detection

実学 | S ci e n c e | サイヤンス

JITSUGAKU@ 2017 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

JITSUGAKU

Hundred years of
medical excellence

Keio celebrates a century of education, research, and clinicalservice in the medical and life sciencesT

he year 2017 marks the 100th anniversary of Keio
University School of Medicine, a global center of learning, medicine, and research in the heart of Tokyo. For the
past century, the school has upheld the mission set out by
its founding fathers: visionary leader and educator, Yukichi Fukuzawa,
and respected microbiologist, Shibasaburo Kitasato. Fukuzawa was astrong advocate for social change informed by reason and education,
which Kitasato, who served as the School’s first dean, realized throughan equal commitment to basic and clinical medicine.
The School of Medicine inspires young students to become pioneers in the world of medicine, and backs scientific developmentsthat lead to paradigm shifts in the medical and life sciences. Every
year, Keio University rewards researchers that exemplify these
ideals, with the Keio Medical Science Prize. This prize has gained
global prominence as a prestigious reward for excellence andinnovation, even anticipating seven Nobel laureates (see page 4).
For more than 150 years, Keio University has thrived under the
motto of jitsugaku. In November 2016, it established a new institute that will strengthen its promise to realize a world where people live safer, longer, and more creative lives. The Keio University
Global Research Institute will coordinate multidisciplinary
research aimed at addressing the challenges facing Japan and therest of the world in an era of political, social, and environmental
upheaval (see page 17).
The articles in this third issue of Jitsugaku reflect Keio’s ongoing
efforts in this direction, from revealing the links between manga
and western literature, to discovering how crows’ beaks adapted totool use, and discovering plastic-eating bacteria. We hope that you
will join us on our journey into the next hundred years.

research-highlights.keio.ac.jp

Issue 3, May 2017

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 toolin Keio University’s never-ending search for practical solutions to real-life problems.

3

Inside Keio

A prize for science
visionaries
The Keio Medical Science Prizerecognizes scientific developmentsthat have led to paradigm shifts inmedical and life sciencesEvery year since 1996, Keio University
has honored the world’s most outstanding medical researchers withThe Keio Medical Science Prize, a
globally recognized award that reflects theuniversity’s commitment to excellence andinnovation in education, research and medicine. Remarkably, the prize has anticipatedthe Nobel Prize on multiple occasions, andseven winners of the Keio Prize have goneon to become Nobel Laureates.
The history of the Keio Prize dates to theearly 1990s, when a Keio alumnus called
Mitsunada Sakaguchi presented a gift to theuniversity that aimed to spur research in thelife sciences and stir the aspirations of young
medical scientists.
Sakaguchi had graduated from the prestigious Keio University School of Medicine in
1940. Half a century later, he had not forgotten
his alma mater and in 1994, his donation offive billion Japanese yen was used to establish
the Keio University Medical Science Fund. His
donation, equivalent to US$50 million, wasfollowed several years later by an additional
two billion yen. Sakaguchi wished for themoney to be used to commend outstanding
researchers, encourage medical research andits creative progress at Keio through grants,
and promote worldwide medical advances.
The Keio Medical Science Prize is a key
project of the Keio University Medical
4

The 21st Keio Medical Science Prize went to Japanese immunologist Tasuku
Honjo (center right) and Swedish evolutionary biologist Svante Pääbo (center
left). Keio University President Atsushi Seike (right) and professor and dean of
the Keio University School of Medicine, Hideyuki Okano (left), congratulated
the laureates at an awards ceremony in Tokyo.

Science Fund, which also provides grants
for research and international exchange. It
recognizes outstanding researchers of any
nationality, nominated and selected througha rigorous evaluation process. Laureates
today receive a certificate of merit, a medal,
and a monetary award of 10 million yen(equivalent to US$88,000).
Over the past two decades, the prize has
gained prominence as the only one of its
kind bestowed by a Japanese university
focusing on medical and life sciences. It
receives a large number of nominations
from all over the world and has recognizedresearchers from Japan, the United States,
Australia, Sweden, and France, covering awide range of research, from the discovery of
infectious proteins to cellular self-digestion.
Global pioneer
Keio University, Japan’s oldest private institute of higher learning, was established in1858 by educator and leading intellectual
Yukichi Fukuzawa, who championed reason,
observation and verification in science.
Today, it ranks among the top ten universities
in the world for the number of degrees it has
conferred to chief executives, according to
the Times Higher Education. Its well-connected network of alumni include three former
prime ministers, the first Japanese woman to
go to space, and many Olympic medalists.

The Keio University School of Medicine
was established in 1917, with microbiologist
Shibasaburo Kitasato serving as its first
dean. Kitasato was a strong defender of theegalitarian ideals of science for society. He
fostered not just doctors, but the next generation of ‘physician scientists’ committed topursuing knowledge for the public good.
Keio’s mission “is to be a constant sourceof honorable character and a paragon of
intellect and morals for the entire nation,”Fukuzawa said in 1896. He aspired forevery member of Keio “to apply this spirit
to elucidate the essence of family, society,and nation. They will not only articulate thisessence in words, but also demonstrate itin their actions, and by so doing make Keioa leader of society.” These words resonate
today in the high standards set for laureatesof The Keio Medical Science Prize.
Significant contributions
Selection of those laureates — one Japaneseand one non-Japanese each year — is apainstaking task. Every winter, the KeioPrize committee gathers to begin a year-longprocess that considers recommendations
from all over the world. Candidates are
critically assessed for their accomplishments
through a rigorous, four-stage vetting
process. By the autumn, the winners
are announced.
Jitsugaku | May 2017© 2017 Keio University

Inside Keio
The result of those deliberations is a
prize that is unique in recognizing “not justworld-firsts, as is often the case with theNobel Prizes, but also cumulative researchthat has an impact on human health,” says
Hideyuki Okano, professor and dean of the
Keio University School of Medicine andchairman of the prize selection committee.
This distinction is an important one, he says.
Significant contributions to medical sciencecan take many different forms.
Keio laureates are selected for having precipitated a paradigm shift in the life sciences.
Their original research must have contributed to medical advances. Prizewinners arerevered not only for what they have alreadyrevealed about the world, but also for the
many more discoveries to come. As such,the committee favors younger researchers
who are likely to maintain an active involvement in their work long after receiving theaccolade — a criterion that distinguishes the
Keio Prize from the Nobel.
Nobel promise
From the beginning, the Keio Prize proved
its acuity. The first two laureates in 1996 were
American neurologist Stanley Prusiner andJapanese neuroscientist Shigetada Nakanishi.
Prusiner had discovered prions, a type of infectious protein that causes many neurodegenerative diseases such as scrapie in sheep
and mad cow disease in cows. One year
later, in 1997, he received the Nobel Prize inPhysiology or Medicine for uncovering this“new biological principle of infection”.
For his part, Nakanishi developed aground-breaking technique for determining
the structure, and eventually the function, ofneural receptor proteins. In the years since
winning the award, the tools he developed
have brought into view a deeper understanding of the inner workings of the brain,from learning to memory and movement.
One in every five laureates has since goneon to receive a Nobel Prize.
In 1999 Keio recognized AustralianAmerican biologist Elizabeth Blackburn forher discovery of telomerase, the enzyme
responsible for capping the ends of chromosomes. The protective caps, known as
www.keio.ac.jp

telomeres, have been foundto play an important rolein cellular aging and theimmortality of cancer cells.
A decade after receiving the
Keio Prize, Blackburn wasawarded a Nobel in 2009.
Most recently, the Nobel
Prize in Physiology or Medicine
2016 went to Japanese molecular biologist Yoshinori
Ohsumi, one year after hereceived the Keio Prize.
Ohsumi determined theprocess by which cells degrade and recycle their own
contents, known as autophagy.
He described the Keio medal as “agreat honor”.
Cancer targets and Neanderthals
On 1 December 2016, Keio inducted its
newest laureates at a grand event completewith a student string orchestra at Kitasato
Memorial Hall, Keio University Schoolof Medicine. Japanese immunologist
Tasuku Honjo, who discovered a promising
drug in the fight against cancer, and Swedish
evolutionary biologist Svante Pääbo, who
is responsible for sequencing the entire
genome of our distant ancestors, theNeanderthals, were the recipients.
“Both professors, Honjo and Pääbo, areoutstanding researchers who exemplify thecriteria of the prize: advancing medical andlife sciences, cultivating new paradigms andcontinuing to be active in research,” says
Okano, who welcomed the audience of 300,
including many high-profile guests. Keio
University President Atsushi Seike congratulated Pääbo and Honjo on their accomplishments before conferring them with certificatesand medals decorated with the Keio colors,
blue and red. “This year’s awards celebrate atruly wide scope of research, with one having
an impact on lives in the future and the otherreaching far back in time,” he said.
Both laureates gave commemorative
lectures after receiving their awards. Honjo
described The Keio Medical Science Prize asa “visionary” award that takes a long-termview of the value ofbasic research. “I am very
honored by the prize andextraordinarily humbled to beamong such outstanding recipients,” he said. “Curiosity was
the starting point of my career as
a medical researcher. Fortunately,
this has led to results that may bebeneficial to many people.”“I am deeply honored toreceive the prize,” said Pääbo
in his acceptance speech. “Ishare this award with many
people in my laborator yand elsewhere.”The 2016 nomination process
involved a total of 3,142 academics
and researchers from Japan and overseas,
representing 40 countries. More than 100
nominations were put forward and assessedby members of the selection committee together with a large panel of experts from external institutions and Keio University. “Theselection, the achievement, I find it very
rewarding,” says Okano, who has alreadybegun the exhaustive process of choosing
the 2017 laureates.
A lasting legacy
In many ways, The Keio Medical Science
Prize encapsulates the founding principles
of Keio’s School of Medicine, which strives
to be a pioneer in the world of clinical andmedical studies. In 2017, the school willturn 100, and it has invited former prize
laureates to give commemorative lectures atthe centennial celebrations.
By honoring researchers who embody
Keio’s ideals in their work, The Keio Medical
Science Prize acts as a driving force for
ambitious young scientists. Students at
Keio’s School of Medicine are welcome at
the annual award ceremonies, and given
an opportunity to see researchers who are
active in the global frontlines.
“We hope that the prize will inspire young
students in particular,” says Okano. “It is
our hope that Keio Medical Science Prize
Laureates serve as role models in terms of how
they approach and conduct their research.”
5

Research highlights

Star-crossed models of whitematter disease

Improved models of thebrain’s communication
network, known aswhite matter, could
explain how diseases
develop early in life.

Japanese researchers have gained new
insights into childhood brain diseases by manipulating gene expression
in laboratory mice1. The work, led
by Kenji Tanaka at Keio University’s Schoolof Medicine, offers a new view of the tissue
that constitutes almost half the human brain.
White matter is the brain’s communication network. It consists of long6neura l proj e c t ions wrapp e d in fatty
tissue that acts as insulation to speed up
transmission of electrical signals between
brain regions.
D est r uc t ion or defe c t ive de velopment of white matter leads to diseases
called leukodystrophies, which include
two disorders that Tanaka’s work foc u s e d on — A l e x an d e r d i s e a s e an dmegalencephalic leukoencephalopathy
with subcortical cysts (MLC).
A l e x an d e r d i s e a s e an d M LC b ot hdevelop in infants and both are caused
by mutations in genes expressed in starshaped brain cells called astrocytes. In
Alexander disease, the gene GFAP seems
to be involved, and MLC1 is implicated in
MLC. Healthy astrocytes are known to help
Jitsugaku | May 2017

© ALFRED PASIEKA/SCIENCE PHOTO LIBRARY/Getty

Neural support cells implicated in childhood diseases of the brain’s
fatty high-speed transmission linesReprinted from Ref. 1, Copyright 2016, with permission from Elsevier.

Research highlights

maintain white matter, but how the genetic
mutations in these cells cause white matterdegeneration is unclear.
One obstacle to solving the mystery wasthat mouse versions of these diseases either
did not exhibit the characteristics of humanleukodystrophy, or the disease only developedin old age. “We needed a new model in which
the onset is in the developmental period tomimic the human disease,” explains Tanaka.
His team developed new mouse models
of astrocyte-related leukodystrophy using atechnique they had previously developed tomanipulate gene expression, called Flexible
Accelerated STOP Tetracycline Operator(tetO)-knockin (FAST). The FAST systemenabled the researchers to create mice inwhich Mlc1 was deleted and mice in which
Mlc1 was overexpressed.
Deletion of Mlc1 caused leukodystrophy
in old, but not young, mice. By contrast,
mice with overexpressed Mlc1 developed
white-matter abnormalities early in life,
similar to the infantile onset of MLC in
humans. Further experiments showedthat overexpression of Mlc1 in astrocytes
disrupted the energy-dependent balance of
sodium and potassium inside and outside
the cells, leading to astrocyte swelling andwhite matter damage.
While the implications for humans are notyet clear, Tanaka has some ideas. “Disruptionof energy balance or the balance of sodium
and potassium might cause human leukodystrophy, and correction of these imbalances
could improve the disease.”
The team plans to further investigate
the role of astrocytes in the development
and maintenance of white matter. They
are also using the FAST technique tostudy the role of proteins that support
neural growth and survival in resilienceand susceptibility to stress in models ofneuropsychiatric diseases. 

Building a colorectal
cancer library
Biobank of colorectal cancer ‘organoids’
reveals cancer’s secretsThree-dimensional tumors grownfrom cells of colorectal cancer patients are being used by Japanese
researchers to explore how benign
tumors transform into malignant metastatic cancer that claims nearly 700,000 lives
around the world each year.
Their library of ‘organoids’ offers a unique
opportunity to observe colorectal cancers as
they would behave inside the human body.
“Until recently, cell lines and rodents havebeen the only living tools for cancer research,
but these models may not fully reflect thecharacteristics of the clinical cancers. Thishas caused a bottleneck in translation frombasic science to clinics,” says Toshiro Satoof the Department of Gastroenterology andHepatology at Keio University School of
Medicine, who led the study.
Colorectal cancer organoids are clusters ofcells that form a mini-tumor, with the samestructural features as the original tumor.
To build the library, Sato and colleagues
collected cells from 52 tumors in 43

patients with colorectal cancer, including
a number of rare subtypes. These samples
were cultured with factors that mightactivate or repress particular signaling
pathways known to affect cell growth.
Each tumor sample thrived under a unique‘niche factor’ microenvironment.
The result was a library of 55 colorectal
cancer organoids, each with the same
molecular signature as its in vivo counterpart. They also replicated the same cellular
structure when transplanted into an animalmodel (see image)1.
The biobank has already provided somevaluable insights into colorectal cancer
growth and metastasis. For example,
b ecaus e the team tailored the nichefactors to each tumor, they were able
to see which niche factors the tumors
needed for growth, and which ones they
didn’t require.
While healthy intestinal stem cells are
dependent on certain niche signals to grow,the researchers noted that tumors appear

Reference
1.

Sugio, S., Tohyama, K., Oku, S.,
Fujiyoshi, K., Yoshimura, T. et al.
Astrocyte-mediated infantile-onset leukoencephalopathy mouse model.
Glia 65, 150–168 (2016).

research-highlights.keio.ac.jp

100 μmThree-dimensional tumors grown on a dish and transplanted into animal models (right) develop similarcellular structures as the original colorectal cancer cells taken from patient tumors (left).

7Research highlights

to have negated some of these growth
restrictions through genetic mutations.
“We referred to this phenomenon as
niche-independent growth,” says Sato.
“By profiling the niche factor requirements of each tumor organoid, we foundthat the transition from a benign adenoma tocancer, frequently accompanies this loss ofniche-dependency.” Interestingly, this sameprocess did not appear to influence thetransition from early cancer to advanced
metastatic cancer.
The study showed that while samples
from the original tumor and from its metastases were almost identical genetically, themetastatic organoids were still much more
likely to metastasize when transplanted into
the animal model.

This suggests some other mechanism, unrelated to genetic mutation is causing cancers
to spread; a mechanism that we are yet to
identify and target with treatment.
Reference
1.

Fujii, M. et al. A colorectal tumor organoidlibrary demonstrates progressive loss ofniche factor requirements during tumorigenesis. Cell Stem Cell 18, 827–838 (2016).

Sealing the deal on leak-proof cellsThe human body sheds an estimated
200 million skin cells every hour,but doesn’t leak. How the bodymaintains this protective barrier,despite such extensive cellular turnover has
long puzzled scientists. The explanation, findresearchers at Keio University, lies in the unusual shape of cells on the skin’s surface.
A te am l e d by A k i h ar u Kub o and
Masayuki Amagai at Keio University
School of Medicine found that epidermal
cells, which make up our external coating,adopt the shape of a tetrakaidecahedron, a

14-sided geometrical structure consistingof 6 rectangular and 8 hexagonal sides1.
“Such beautiful shapes are rarely observedin animal cells,” says Kubo. “The discovery
has changed the concept of the epidermis,”— on a basic biological level, and forunderstanding what goes wrong when theskin’s barrier is breached, as happens with
inflammatory diseases such as eczema.
The epidermis — the body’s largest andfastest-growing organ — consists of a thickouter layer of dead cells that are constantly
shedding. Below this sits a multilayered sheet

The 14-sided tetrakaidecahedron shape of epidermal cells (seen here from different angles) explains
how the skin maintains a physical barrier against disease.

8

of living epidermal cells, sealed together likesewing thread by protein complexes known
as tight junctions in a particular upper layer.
The cells eventually die, and get replaced bynewer cells from lower down in the epidermis. The Keio team wanted to know how thisreplacement happens without disrupting thephysical seal of the tight junctions.
The researchers used a sophisticatedimaging technique called confocal microscopy to examine the process in mice ears. A
snapshot showed that the cells resembled aflattened version of a tetrakaidecahedron,a shape proposed 130 years ago by British
physicist, Lord Kelvin, as optimal for
packaging equal-sized objects with the least
amount of surface area between them.
Kelvin conceived the space-filling shapewhen thinking about how bubbles fit together to form foam, a concept that can also
be applied to skin cells.
The researchers used mathematicalmodels to show that the mix of rectangularand hexagonal sides allow tight junctions
to form with no gaps between adjacentcells. Further imaging revealed that during
cell turnover the junctions form between
three different cells to allow a new one
Jitsugaku | May 2017

Reproduced from Ref. 1 and licensed under CC BY 4.0 (creativecommons.org/licenses/by/4.0/legalcode) © 2016 M. Yokouchi et al .

Scientists discover the unusual geometry that holds mammalian skin together,even while sheddingResearch highlights

to swap in and an old one to move out,
while maintaining a continuous barrier inthe mouse skin, and presumably also inhuman skin.
As Kubo sees it, the process involves abalancing act between cell formation andold cell shedding at the tight junctions —all made possible by the 14-sided shape ofthe epidermal cells. Tip the balance andthe skin barrier is weakened, leading to eczema, or too many new cells are produced,
resulting in psoriasis.

Beta-blockers not betterfor heart surgery patientsJapan-wide study shows a widely used heart drug
does not improve bypass resultsA© sudok1/iStock/Getty Images Plus

class of drugs traditionally used toprotect the heart from disease may
have no effect on cardiovascularsurgical outcomes, according to a
study by Keio University researchers1.
The drugs, known as beta-blockers,
are among the most widely prescribed
medications for controlling high bloodpressure, and were recognized as being“cardioprotective” under surgical conditions,says Shun Kohsaka, from Keio University’s

Department of Cardiology. This is because
the drug causes the heart to beat slower andto contract with less force, Kohsaka says.
“When heart rates are lower the oxygen
consumption within the heart is kept low,”says Kohsaka. Theoretically, this would allow
the heart to tolerate a longer period understress if any problems occur during surgery.
However, he says, in recent years there
has been growing debate around the useof beta-blockers for bypass operations,

The use of beta-blockers to slow down the heart rate during bypass surgery has no clinical benefit.

research-highlights.keio.ac.jp

Reference
1.

Yokouchi, M., Atsugi, T., van Logtestijn, M.,
Tanaka, R. J., Kajimura, M., Suematsu, M.,
Furuse, M., Amagai, M. & Kubo, A. Epidermal cell turnover across tight junctions
based on Kelvin’s tetrakaidecahedron cell
shape. eLife 5, e19593 (2016).

which involve routing blood throughhealthy arteries.
Recent studies have suggested b eta-blockers have little effect on short-term,
post-operative mortality and in some cases
were shown to push the heart rate or bloodpressure too low.
To investigate this, Kohsaka and colleagues analyzed 34,980 cases of coronary
bypass surgery undertaken in Japan between January 2008 and December 2011.
The data, from the Japan Cardiovascular
Surgical Database, involved 333 centers,
accounting for almost 74 per cent of sites
performing open-heart bypass surgeries
in the country. The average age of patientswas 68 years, with women comprising onefifth of the patients.
B eta-blockers were used in 10,496
patients — around 30 per cent of cases.
Patients receiving the drugs were slightly
younger, but more likely to have other risk
factors such as diabetes.
The researchers used rigorous statistical modeling to compare outcomes forpatients undergoing the surger y withand without beta-blockers. This modeling was then extended to isolate subgroups that included low- and high-riskpatients and those known to have left
ventricular dysfunction.
The study found no major benefit inbeta-blocker use under any of the analyses
they performed — confirming recent findings of studies in the West.
Kohs a ka s ays b e caus e E ast Asians
are known to be genetically sensitive
to beta-blockers, any effect should be
more marked in his cohort. “Within
beta-blocker-sensitive patients, we would
9Research highlights
prescribe, it does not seem to show any
benefit, retrospectively.”
Kohsaka is now looking at using the same
approach to investigate the use of statinsand aspirin in cardiac patients.

Brain regions controlling
emotion pass frommothers to daughters
Women are more likely to inherit brain structureslinked to depression from their mothers thantheir fathersA

brain-imaging study by neuroscientists at Keio University Schoolof Medicine begins to explain theclose association between depression in mothers and teenage daughters1.
Scans revealed that the size of the brain
area controlling mood and emotion correlated more between mothers and daughtersthan between mothers and sons, or between
fathers and children of either gender.
If a parent has a family member with amood disorder, there is approximately a40 per cent chance that his or her offspring
will develop that psychiatric condition, andthe risk is even greater for mothers passing
on their family’s mental illness to daughters.
As such, the insights gleaned through brain

imaging can help answer critical questions
about maternal effects on brain development and female susceptibility to developing depression and other female-biased
psychiatric disorders, says Bun Yamagata,
the study’s lead author, who is now an
assistant professor at Keio University’s
Department of Neuropsychiatry.
While working as a postdoctoral fellow
at Stanford University in the United States,
Yamagata collaborated with Fumiko Hoeft,
who holds a joint appointment at Keio
University, to study the heritability of brain
circuitry. They recruited 35 healthy families
from California and placed the parents
and their biological children in a magnetic
resonance imaging machine.

Reference
1.

Kohsaka, S. et al. Effects of preoperative
β-blocker use on clinical outcomes after
coronary artery bypass grafting: A reportfrom the Japanese cardiovascular surgery
database. Anesthesiology 55, 45–55 (2016).

Their analysis showed that the volume ofgray matter in the brain’s amygdala, hippocampus and other parts of the so-called corticolimbic circuit, which plays a critical rolein mood disorders like depression, correlated most strongly in mother–daughter pairs
than in other parent–offspring relationships.
The reason remains unclear, but Yamagata
speculates that genetic, prenatal and postnatal
environmental factors and their interactions
may underlie the intergenerational patterns.
To tease out those contributors, Hoeft
and her colleagues are now repeating theexperiment with mothers who used donor
eggs, families that used other women to
carry their genetic offspring to term, and, as
controls, mothers whose eggs were fertilizedusing assisted reproductive technology. The
research, Hoeft says, “will establish a newand complementary paradigm for noninvasively studying genetic and environmental
influences of the human brain.”
Meanwhile, Yamagata is running similar brain-scanning experiments at Keio
University with families in which theparents have been clinically diagnosed withdepression. He hopes the study will offer
further justification for early interventions
in female mental health.
Understanding how psychiatric diseases persist from one generation to theother can help to develop novel therapeutics
and prevention paradigms that target
high-risk individuals such as women,says Yamagata.
Reference
1.

Mother–daughter similarities in the brain are most pronounced in regions involved in controlling
emotion: the amygdala (red), gyrus rectus (blue), orbitofrontal cortex (green), parahippocampus gyrus(yellow), and anterior cingulate cortex (pink).

10

Yamagata, B., Murayama, K., Black, J.
M., Hancock, R., Mimura, M., Yang, T. T.,
Reiss, A. L. & Hoeft, F. Female-specific intergenerational transmission patterns of thehuman corticolimbic circuitry. Journal of
Neuroscience 36,1254–1260 (2016).

Jitsugaku | May 2017

Reproduced, with permission, from Ref. 1 © 2016 B. Yamagata et al.

assume beta-blockers work very well, but
in this study we do not see any benefits,”
says Kohsaka.
“No matter which ethnic group you
are in, or what type of beta-blockers youFeature article

Preserving more than words© 2016 Keio University

A vast collection of rare books at Keio University is attracting
worldwide interest through a new online courseSurrounded by floor-to-ceiling bookshelves filled withancient scrolls, original manuscripts and rare artworks, Takahiro Sasaki, a professor at Keio University’s
Shido Bunko (Institute of Oriental Classics), reflects
on his career. “When I studied medieval Japanese literature here
at Keio University, I was struck by the sheer beauty of books.
That was my first step into the world of bibliography,” he says.
Housing 175,000 works, mainly Japanese classical texts, aswell as pieces from China, Korea, and Vietnam, and a collectionof rare Western books, Shido Bunko’s library was amassed largely through items donated to the institute after World War II.
The world gained digital access to its collection through an
online course guided by Sasaki. The course, Japanese Culture
Through Rare Books, launched in collaboration with the UK’ssocial learning platform FutureLearn in July 2016, explored therole of books in Japan’s culture and history.
Books as time capsules“Books are not just a way of preserving words and images,”says Sasaki. “They are time capsules; their binding method,
format and cover style can tell us a great deal about authorship and where they were made. We can learn about thecultural background, paper-making methods, fashions andtechnologies that led to their creation.”“For example, we have the single extant scroll-format copyof the first volume of Shinsen Tsukuba shū, written in the
15th century by imperial decree,” says Sasaki of the anthologyof Japanese collaborative poetry known as renga (see image).
“Through research, I have found that the copyist of this work
was not the master poet Sōboku as previously thought, but
Anegakōji Mototsuna, a feudal lord who may have drafted thepreliminary copy of the text.”
Sasaki’s detective work to unravel such mysteries using techniques such as handwriting analysis and comparative studies oftextual lines is detailed in his book, The Bibliographical Studyof Classical Japanese Texts, published in Japanese in June 2016.
The book contains examples taken from popular works such as
The Tale of Genji, The Tale of the Heike and The Pillow Book.
Opening up to the world
Unfurling a scroll dating back to 740 — the oldest known in
the university’s collection — Sasaki explains that Buddhist
research-highlights.keio.ac.jp

The single extant scroll-format copy of Shinsen Tsukuba shū (first volume) housed at
Keio University’s Shido Bunko (Institute of Oriental Classics)

texts in the form of sutras came to Japan from China andKorea during the Nara period (710–794).
“Among all formats, including the ‘multi-section-binding’and ‘pouch-binding’ styles used for classical texts, my research
has shown that the scroll format symbolises the highest rank,
meaning that the scroll is at the top of the cultural hierarchy
in terms of both the content and readership,” says Sasaki.
The “multi-section-binding” format (tetsuyōsō) refers tosingle-folded pages sewn together along the fold and the“pouch-binding” style (fukuro-toji) refers to double-leaved
pages forming a pouch as they are bound along the spine.
The scroll format subsequently influenced the placement of
titles on bound books. For example, a vertical title on the lefthand side of a book cover often indicates that the book originated as a scroll, while a title placed in the center suggeststhat the book is a work of fiction, not derived from a scroll.
Japanese literature and the art of bookmaking flourishedin the Heian (794–1185) and medieval (1185–1600) periods; this synergy of creativity is reflected in the diverse
bookbinding techniques developed during this time and,for example, in the innovative use of minerals, such as mica
powder to create luminous patterns.
“Today, we can see the influence of these features inJapanese stationery, which is famed for its intricate designs,”
says Sasaki. “Manga and anime also have their roots in theseclassical Japanese texts.”
Sasaki observes that there is growing interest in Japaneserare books overseas. “We’ve had tremendous interest in our
online course from around the world,” he says. “I hope thecourse will deepen people’s knowledge of Japanese culture
and history,” says Sasaki. “Books are an excellent gateway tounderstanding Japan.”
11

Feature articles

Mind overmachineChronic stroke sufferers
boost the brain’s ability
to heal itself throughbrain–machine interfaces

Chronic stroke patientscan regain lost
movement by training
their brain to control arobotic exoskeleton.

12

Jitsugaku | May 2017

Feature articles

J

unichi Ushiba works in the science-fictional world of brain–
machine interfaces, but he doesn’t like the term ‘cyborg’.
“ ‘Cyborg’ sounds like ‘technology’s invasion of humanbeings’,” says Ushiba, from Keio University’s Laboratory
for Rehabilitation Neuroscience. He’s more interested in howtechnology can be used in a more benign way to promote thebrain’s self-healing abilities in people whose neurological function
has been compromised by neuromuscular disease. The results
have been impressive; by connecting stroke patients’ brains tocomputers, Ushiba is helping damaged neural regions come alive.

© 2016 Junichi Ushiba, Keio University

Wiring up
An engineer by training, Ushiba became interested in the interface
between engineering and neurology in 2009 when a student cameto him and suggested the idea of a brain–machine interface thatused noninvasive electroencephalogram (EEG) technology, involving electrodes on the surface of the skin. This approach was firstdeveloped in the 1980s to help people with ‘locked-in’ syndrome
to communicate.
Having studied rehabilitation, Ushiba realized there was a lack oftreatment options for people whose disease had affected their ability
to control their arms, and who therefore couldn’t manually interact
with a machine or computer.
“I realized that helping the damaged brain to rewire itself using
brain–machine interfaces could become an essential and uniquetherapy to such patients,” Ushiba says. He thought that using thebrain to direct actions on a computer or machine might stimulate
rewiring and healing in the damaged parts of the brain that normally control those same physical movements.
So he and his research team began working with people withmuscular dystrophy; a group of inherited diseases characterised by
gradual muscle wastage. The aim was to see if they could control amachine with the power of their mind.
Moving thoughts
The first question was whether brainwaves recorded throughthe skin would be an accurate measure of activity in the parts ofthe brain associated with muscle control. Ushiba and his teamconducted experiments in which they used EEG to look at brain
and spinal cord activity in healthy volunteers who were asked toimagine moving their wrist1, 2. This showed that just imagining the
movement of a limb was enough to excite the neurons in the brain
and spinal cord that would normally trigger this movement.
The next step was to see what effect this approach might havein people paralysed by stroke. By this time, Ushiba’s work was
garnering international attention, and he began working withresearch-highlights.keio.ac.jp

overseas collaborators — including neuroscientists Surjo Soekadar
from Germany and Hartwig Siebner from Denmark — to develop
the next generation of brain–machine interfaces. The international partnership has since seen one of Ushiba’s master’s students,
Shuka Shibusawa, working in Soekadar’s lab to continue thecollaboration.
The team conducted an experiment in which they used real-time
brain imaging to see what happened when stroke patients tried tomove a paralysed finger.
After one hour of finger extension training, every day, for a month,
Ushiba and colleagues observed increased brain activity in the damaged parts of the brain that normally would control this movement3.
The results were testament to the brain’s remarkable plasticity— its ability to ‘rewire’ around damage — and showed how abrain–machine interface might facilitate this process.
Stroke therapy
But, the researchers aren’t stopping there. If the neural activity
associated with imagining a physical movement can be recorded,
can it also be used to activate that movement?
He and his collaborators are now working to use the EEG-based
brain–machine interface in humans to control a robotic exoskeleton. Animal studies by other research groups already suggest thatthe approach not only enables robotic-assisted movement, but the
movement feeds back into the brain to further promote functional
reorganisation around damaged areas.
“We believe that our brain–machine interfaces would be far
more effective compared to simple robotic movement support,”
Ushiba says, referring to passive exoskeleton-style robotics that
simply translate physical movement to robotic movement.
The team have already published numerous case studies ofbrain–machine interface work in people suffering chronic stroke,and found that around 70 per cent of patients show improvements
in lost motor function. It offers hope to people for whom there
currently are few prospects for improvement.
References1.

Takemi, M., Masakado, Y., Liu, M. & Ushiba, J. Sensorimotor event-related desynchronization represents the excitability of human spinal
motoneurons. Neuroscience 297, 58–67 (2015).

2.

Takemi, M., Masakado, Y., Liu, M. & Ushiba, J. Event-related desynchronization reflects downregulation of intracortical inhibition in humanprimary motor cortex. Journal of Neurophysiology 110, 1158–1166 (2013).

3.

Ono, T., Tomita, Y., Inose, M., Ota, T., Kimura, A., Liu, M. & Ushiba, J.
Multimodal sensory feedback associated with motor attempts alters
BOLD responses to paralyzed hand movement in chronic stroke patients. Brain Topography 28, 340–351 (2015).

13

Feature articles
In March 2011, adevastating earthquake
hit Japan’s eastern coast,
destroying livelihoods,
as seen in this aerial
shot of Ishinomaki city,and changing people’s
perception of risk.

Measuring the tremors ofan earthquake-savvy public

Understanding how people perceive risk during natural disasters could save lives
14

Jitsugaku | May 2017© 2016 Satoko Oki, Keio University© Michael S. Yamashita/National Geographic/Getty Images

Feature article

Everyone in Japan knows what to do when the Earth begins toshake — the small island-nation sits above one of the world’s
most seismically active regions. While this familiarity withearthquakes helped save many lives in the 2011 Tohoku
earthquake, it also caused many to underestimate the danger of being
hit by a tsunami. An estimated 19,000 people died in the Tohoku
disaster, more than 14,000 from drowning.
Satoko Oki, a geophysicist at Keio University’s Faculty ofEnvironment and Information Studies, has studied the Japanesepublic’s response to the earthquake and come up with some unexpected observations about how the brain processes risk. Her research
will help to improve communication and education in an earthquake-savvy community.
Paradox of perception
Oki was a teenager when in 1995 a devastating earthquake hit
Kobe city, killing more than 6,000 people. She spent hours glued tothe television news coverage of the disaster unfolding. It was thenshe decided to become a seismologist, but not just any seismologist. Oki wanted to engage the public in her work.
In 1981, Japan introduced more stringent standards for newbuildings to be constructed to withstand ground motion of magnitude 7 or higher. People living in coastal areas were also advised
to evacuate to higher ground to escape an impending tsunami. “We
don’t know when the ‘big one’ will occur, but we already know
how to survive,” says Oki.
Oki wanted to know what height of tsunami the general publicthought presented a serious threat. In 2010, about a year before the
Tohoku quake, she conducted a survey of more than 2,000 people,
providing answer choices from ‘don’t know’ to ‘more than 10 centimeters’ to ‘more than 5 meters’.
To help explain t he resu lts, Oki s oug ht t he advice ofKazuya Nakayachi, a psychology researcher at Doshisha University
in Kyoto. Before they had an opportunity to analyze the data, however, the magnitude 9 earthquake hit.
About a month after the quake, Oki and Nakayachi surveyed
1,036 participants and compared their answers to those of 733
respondents in the same prefectures from the previous survey. Okiassumed that the participants, out of fear of reliving the harrowing
experience, would be ready to evacuate for smaller tsunamis.
Nakayachi instead, “assumed that their risk perception would
decrease,” recalls Oki. The survey data validated Nakayachi’s hypothesis (see image), which was based on a psychological model
known as the anchoring effect1.
The anchoring effect describes how people judge data in relation
to a previously known value, and either inflate or diminish it. In thecase of the tsunami survivors, having just witnessed a 40-meter-highwave, many believed a 3-meter-high wave, which is still capable ofripping a house apart, to be ‘no big deal’.

research-highlights.keio.ac.jp

Tsunami alert! When would you evacuate?
10m

92%

5m

90%

3m

71%
Before

85%
73%
46%

1m

Tohoku Earthquake 11 March 2011

? 7% Don’t know when they would evacuate

After? 7% Don’t know when they would evacuate

Japanese perceived waves under 10 meters high to be less risky after
experiencing the magnitude-9 earthquake and 40-meter high tsunami that
hit Tohoku on 11 March 2011.

Unfortunately, people love reporting record-breaking events— from the fastest 100-meter sprint to the largest collection ofgnomes. Oki cautions that for natural disasters, to somewhat mitigate
this anchoring effect, records should be accompanied with a baseline,
such as a 1-meter-high tsunami — “which is still dangerous.”
Finite pool of worry
The Tohoku earthquake also caused one of the world’s worst nuclear
accidents at the Fukushima Daiichi power plant. Oki and Nakayachi
went on to investigate whether the high level of public anxiety
around earthquakes and radioactive contamination following
Tohoku affected the way people felt about other unrelated hazards2.
They compared survey results from 2008 and 2012 for changes inpublic anxiety about 51 hazards ranging from nanotechnology tointernational conflict.
Overall anxiety about these hazards decreased significantly, ina manner not commensurate with the larger loss of life associatedwith them. The lowered risk perception for other hazards in thewake of a severe natural disaster could dilute harm-reduction
measures, warn Oki and Nakayachi.
In April 2016 Japan was hit with another powerful series of shakes
in southern Kumamoto. Oki is keeping a close eye on the public
communication. “It is not enough to conduct research into earthquake science, we also need to develop our communication skills toimprove public awareness and promote preparation,” she says.
References
1.

Oki, S & Nakayachi, K. Paradoxical effects of the record-high tsunamis
caused by the 2011 Tohoku earthquake on public judgments of danger.
International Journal of Disaster Risk Reduction 2, 37–45 (2012).

2.

Nakayachi, K., Yokoyama, H. M. & Oki, S. Public anxiety after the 2011
Tohoku earthquake: Fluctuations in hazard perception after catastrophe. Journal of Risk Research 18, 156–169 (2015).

15

Feature articles

Western roots in Japanese manga

Delving into Japanese subcultures reveals surprising literary links with worksof Western literature

Other worlds
Ogushi started reading manga at a young age, and soon beganburrowing into translated works of Western literature. — stories by Edgar Allan Poe, Gaston Leroux, Arthur Conan Doyle,and other classics such as Louisa May Alcott’s Little Women.
“Those books opened the door for me to ‘the other world’,”says Ogushi. “I love both manga and literature, though I neverthought I’d combine the two genres in my research.”
While Ogushi was writing Hybrid Romance, her study ofcultural identity and women’s roles in American literature
published in Japanese in 2002, she “began incubating ideas
about gender, race, and genre studies,” which would becomea “launchpad for exploring the links between manga andWestern influences in greater depth.”“Take the historical romance Candy Candy, for instance — a

19th century Western literature has influenced many popular Japanese manga comic books.

16

hugely popular Shojo manga series published in the 1970s,”
says Ogushi, explaining that the novelist Keiko Nagita wrote
the text, which was illustrated by the renowned manga artist
Yumiko Igarashi. “Both of these women later revealed that they
were conscious of describing Western settings held to be ‘otherworldly’ at the time. So although young readers might not havecaught on, Nagita and Igarashi knowingly recreated the story of
Daddy-Long-Legs by the American writer, Jean Webster (1876–1916), and alluded to the world of Lucy Maud Montgomery(1874–1942), the Canadian author of Anne of Green Gables.”Ogushi points out further parallels between the March sisters
in Little Women and characters in Chieko Hara’s Three Swings,
as well as the more recent influences of Western films on manga
creations by Akimi Yoshida (California Story), Taeko Watanabe(Family), and Minako Narita (Alien Street and Cipher).
In many cases, the “re-imaginings” of Western settings canbe interpreted as homages or pastiches, says Ogushi. “Banana
Fish by Akimi Yoshida is another example of a respectful riff on
the original, A Perfect Day for Bananafish by J. D. Salinger.”
Many fictional lives
In addition to these individual influences cited by manga artists, Ogushi contends that Shojo manga as a genre has a longer,
more tangled history with Western literature. She argues thatthe roots of Shojo manga can be traced back to Shojo novelsof the 1910s and 1920s, a portion of which were based on
abridged versions of Western domestic fiction, or narrative
literature, largely written by and for women in the 19th century.
Works by Harriet Elizabeth Beecher Stowe, Susan Warner,
Lydia Maria Child, and others were highly influential during
this era, selling more books than male Western authors. Ogushi
continues to conduct comparative literature analyses to build amore comprehensive picture of Western influences on Japanese
fiction pre- and post-World War II.
In October 2016, Ogushi and her colleagues launched an
online course on Japanese Subcultures, in collaboration with theeducation platform FutureLearn. “This course is open to anyone
interested in learning more about Japan’s multifaceted culture.
Many foreign students at Keio University tell us that mangaor subcultures were their first step to getting to know Japan,”she says. “As I always tell my students: you only live once, but
through books, you can live as many times as you want.”
Jitsugaku | May 2017

© 2016 Hisayo Ogushi, Keio UniversityAt the closing ceremony of the Rio Olympics, Prime
Minister Shinzo Abe famously dressed up as Super
Mario. He was teleported to the stage at the end ofan animated trailer promoting the Tokyo Olympics
in 2020, which featured Hello Kitty, Pac-Man, and Doraemon— some of Japan’s best-known exports from its manga (comic
books), anime (animations), and gaming culture. The global popularity of these characters forms a major part of the government’s
Cool Japan initiative designed to boost the creative industries.
Beneath the variously kawaii (cute) or deadpan masks ofthese characters there are long histories, and in some cases,
unexamined literary connections, according to Hisayo Ogushi,
professor of literature at Keio University’s Faculty of Letters.
“The influence of Western literature, particularly works by
19th century women writers, on Shojo manga, or manga forgirls, is particularly striking,” she says.

A global research hub

Inside Keio

Keio University Global Research Institute launches an international mission to
help society through interdisciplinary researchK

eio University Global ResearchInstitute (KGRI) was founded in
November 2016 to address thechallenges facing Japan and the restof the world in an era of political, social, andenvironmental transformation.
Established in a year of significant globalchange, the institute aims to contribute to
the modern world through interdisciplinary collaborations between Keio University
and global partners in industry, academia,
and government.
By encouraging researchers from diverse
disciplines and cultures to share their workand perspectives, the center will foster newconnections between people and link theirideas. The institute represents an acceleration of Keio University’s globalization andwill further its already valuable contributions to society.

© 2017 Keio University

Learning from Japan
Keio, Japan’s oldest private institution ofhigher learning, was among 13 top-tieracademic institutions chosen in 2014 by theJapanese government to be part of the Top
Global University Project, a funding program
designed to enhance the international competitiveness of Japan’s leading schools.

As part of the initiative, Keio is committed
to enhancing the sustainability of global
society through jitsugaku (science), as a natural continuation of the philosophy of Keio’s
founder, Yukichi Fukuzawa. Keio University
president, Atsushi Seike, identified three key
areas of research on which it would focus:
longevity, security, and creativity.
These comprehensive research initiatives
are pertinent to the current situation inwhich Japan finds itself in the 21st century.
With a rapidly aging population and declining birthrate, longevity is at the forefrontof Japan’s agenda. The nuclear accident inFukushima is evidence of the danger of increasing risks to environmental, economic,
and regional security. And Japan faces arising demand for innovation to maintainglobal competitiveness.
“The Top Global University Project has
been at the center of Keio University’s
strategy over the last three years,” says
Jiro Kokuryo, vice-president for international
affairs. Among the many changes it has
introduced have been institutional reforms toextend Keio’s reach through cross-appointments, assignments of international staff intenure-track positions, and expansion of the
English-language syllabus.

“I hope KGRI will become a trigger for change,” said Keigo Komamura, Keio University vice-president anddirector of the new center, Keio University Global Research Institute, at an inaugural symposium.

www.keio.ac.jp

The KGRI represents the next stage of thisstrategy, providing platforms to promote,foster, and support current research projects.
“The proliferation of efforts has made usaware of the need for a central program tointegrate the various programs and maximize
output. KGRI is our response to these needs.
I hope it will contribute to providing effective
solutions to the issues encountered by society.”
Giant steps
KGRI will have three major missions: actualizing research through funding, making
research more visible through effective
publicity, and exploring new forms of interdisciplinary research.
Keigo Komamura, Keio University
vice-president and director of KGRI, explains that the institute will have a loose,decentralized structure that will promote
free-flowing exchanges between researchers.
It will be an open platform, going beyond
traditional working styles to connect
academia with business, government, andinternational initiatives.
“The institute is destined to be a growing
and unfinished project and that’s why it has
no fixed form.”
Komamura particularly welcomes “idletalk” between researchers because it canlead to great discoveries. “I hope KGRI will
become a trigger for change,” he says.
At the inaugural KGRI symposium in
December 2016, two commemorative lectures
provided a glimpse of the kinds of researchthat KGRI will encompass.
“Economic integration and uncertainty
define the world,” said Huang Jing, directorof the Centre on Asia and Globalisation at
the Lee Kuan Yew School of Public Policy,
National University of Singapore, who
described a changing economic, social, and17

Longevity
Initiative to realize
a society where
people live better,longer lives

Integrative
Approaches

Security

Creativity

Initiative to assurea safer, moresustainable society

Initiative to bolster
innovation in
educationand research

Keio University President Atsushi Seike introduced
a bold global research initiative to focus on thethree areas of longevity, security, and creativity.

18

“We are focused on people who share the same vision as us but who come from a different culture,” said
Thibaut David of Grenoble Innovation for Advanced New Technologies. “The goal is really to be stronger.”different culture,” David said. “The goal isreally to be stronger.”
Keio’s three global initiatives
The world has much to learn from how
Japan deals with the global challenges being
tackled by KGRI’s three research initiatives.
Considering aged-studies, more than a quarter of Japan’s population is 65 years or older
and other countries are quickly joining the‘super-aged’ bandwagon. Finland, Germany,
Italy, Bulgaria, Portugal, Sweden, and Greece
all have an elderly population of 20% or higher, lifting the global average of people in thisbracket to 8%.
“Aging is not a unique issue to Japan— it’s an issue for the entire world,” says
Hideyuki Okano, professor and dean of the
Keio University School of Medicine, wholeads KGRI’s longevity initiative. “We aim for
initiatives to realize a society where people
live better and longer lives.”
In one example, Keio researchers are gaining ground in tackling the growing incidence
of dementia in Japan. The social cost of thedisease has been estimated at ¥14.5 trillion
per year, or 3% of GDP, a ratio that is expected to increase as the population ages. Early
diagnosis and intervention can reduce those
figures, and Keio researchers are exploring
the role of nicotinamide adenine dinucleotide(NAD), a naturally produced anti-aging molecule. A precursor substance has been used
in a clinical study to examine its safety andeffectiveness in humans.
Another important part of Keio’s focus
on aging is the Center for Supercentenarian
Medical Research, which brings researchersand clinicians together to better meetthe needs of elderly patients. The centercollects and analyses data from multiple
surveys of centenarians to develop preventative care measures.
In the area of security, Keio covers abroad range of domestic and international
issues including military tensions, climatechange, and natural disasters. These include
an analysis of the mass media’s coverage ofJapan in the aftermath of the Fukushima
nuclear disaster, particularly its discussion ofrisk related to nuclear power technologies.
“I believe that this security initiative projectwill contribute not only to academic research, but also to policy and practice,” says
law professor Yutaka Oishi, leader of the
security initiative.
The creativity initiative, led by Tojiro
Aoyama, includes projects such as multilingual search tools for social scientists that canbe used to access data accumulated in various
countries and languages, as well as vaccine
adjuvants that use near-infrared laser light toprompt a more robust immune response.
Another project in the realm of creativity is
the adaptation of brain-scanning technology
to measure electrical activity in the brain
associated with mental states like enjoyment,interest, stress, concentration, and calm. The
Kansei Analyzer has been commercialized fortesting people’s responses to new products.
By fostering this kind of interdisciplinary
research, KGRI will bind the many threads
of investigation at Keio into a whole, says
Komamura. “KGRI will be a kind of tapestry,”
he says, “into which we will interweave many
research projects.”
Jitsugaku | May 2017

© 2017 Keio University

political landscape fueling global insecurity
in the 21st century.
“We need to do global research to find out
why we are having these problems,” he said.
“We are human beings and we see facts fromdifferent perspectives and we have different
opinions about the same truth. That’s why
we need communication and thoroughinternational, global research projects to help
us to understand each other better. We haveto build networks of researchers on platforms
provided by institutions such as KGRI.”The need for international dialogue on
research was echoed by Thibaut David ofGrenoble Innovation for Advanced New
Technologies (GIANT), one of the principal
research centers in France. David, a scientific program coordinator at the French
Alternative Energies and Atomic Energy
Commission (CEA), gave a briefing about
GIANT, a center in the French Alps thatgroups roughly 30,000 people from academia,
industry, and research labs.
David emphasized the relationship between Keio University, CEA and the French
National Center for Scientific Research,which signed a five-year collaborationagreement in 2014. Keio and GIANT haveengaged in student and researcher exchanges
in such fields as microfluidics, the Internetof Things, cyber-physical systems, andnanotechnologies.
“We are focused on people who sharethe same vision as us but who come from a© 2017 Keio University

Inside Keio

Research highlights

In 2015, the CMS
detector at the Large
Hadron Collider
spotted evidence ofa mysteriously heavy
particle that could be
related to dark matter.

Making light of a dark matter© 2017 CERN, for the benefit of the CMS Collaboration

The see-sawing behavior of dark-matter particles might have jolted
experiments at the Large Hadron ColliderUnexpected signals in experiments
at the Large Hadron Collider(LHC) could have been causedby heavy and light versions ofa potential dark-matter particle known
as the axion, propose researchers at
Keio University1.
Studies indicate that the Universe contains
about six times more mass than can be seen
with normal telescopes. Researchers once
believed that this transparent or ‘dark’
matter was made mostly from abundantresearch-highlights.keio.ac.jp

subatomic particles known as neutrinos, but
recent cosmic observations disproved their
hypothesis. Instead, researchers are now
focusing on finding the axion, a theoreticalparticle predicted 40 years ago as a way tosolve problems in the standard model ofparticle physics.
Similar to a photon, but with definite
mass, axions should exist in sufficientquantities to account for dark matteri n t h e Un ive rs e. Phy s i c i st s are m e thodically searching for these particles

by scanning the microwave spectrum
for weak resonance signals, and looking for the creation of a new photon— a key indicator that an axion was
captured. But spotting extremely minisculeaxion resonances amid a constant background of cosmic microwave radiation
left over from the Big Bang requires extraordinary luck.
To better their odds, researchers aresmashing light beams together in themost powerful accelerator ever built
19Research highlights

a new state to exist,” says Tetsutaro Higaki
from the Department of Physics at Keio
University. “But if it was real, we thought it
had to be related to dark matter.”
Higaki and his colleagues from Japanand South Korea theorized that the excess
resonance belonged to a different type ofaxion. Through a model known as a see-saw
mechanism, they predicted that heavy axions
could align and generate the lightweight axions expected from particle physics througha mixing of quantum states. This theory

Female flies have soft
spots for male genitalia

The reproductive tracts of female fruit flies have
evolved to minimize damage caused by matingP

ity the poor female fruit fly. Whenshe mates, the male inserts his
pointy genital organ into her reproductive tract, where it opens
like an anchoring device, inflicting what are
known as copulatory wounds.
However, a new study by Yoshitaka
Kamimura shows that female flies have

Male West African fruit
flies (Drosophila erecta)
have pointed genitalia(pictured), whichfemales have evolved toaccommodate.

20

developed an adaptation that protects
them from this traumatic penetration1. The
female genitalia have evolved soft pouches
that ensure the resulting damage does notinterfere with reproductive success.
“This sexual conflict over mating is likely
to be the major evolutionary force underlying the observed genital coevolution,” says

concurs with models of the Universe’s expansion, and explains why axions have been
so tricky to find — scientists may have been
looking in the wrong energy region.
“The heavy axions might be observed
as new excesses when the LHC can get tohigher energy scales,” notes Higaki. 
Reference1.

Higaki, T., Jeong, K. S., Kitajima, N. &Takahashi, F. The QCD axion from aligned
axions and diphoton excess.
Physics Letters B 755, 13–16 (2016).

Kamimura, an entomologist and evolutionary biologist at Keio University. Whilemost scholars of sexual conflicts in the
animal kingdom have focused on male adaptations, Kamimura’s study demonstrates
that the evolution of female genitalia canbe just as complex.
Kamimura had previously found thatthe females of several species of fruit flies
and other insects have copulatory wounds
after mating. However, in the West African
fruit fly, Drosophila erecta, it seemed thefemale genital tract had evolved to limit
these injuries, but it wasn’t clear how.
Did their soft pouches serve a protectivefunction? Or was it the nearby hardened
shields that mitigated the harmful effects
of mating?
To better understand the evolutionar y forces shaping fema le genit a lia,
Kamimura artificially damaged eachstructure and examined how it affected
reproductive output. With each female
fly, he anesthetized the insect and gently
pushed aside the tips of the abdomen
to reveal the internal structures of the
reproductive tract. He then punctured
the genital tract in one of three sites: thepouch, the shield, or the plate above theovipositor tube through which the female
lays her eggs. “The pouches were especially difficult to manipulate because they
are colorless, tiny, and inconspicuous,”
Kamimura says.
Jitsugaku | May 2017

© 2016 Yoshitaka Kamimura, Keio University

in the hope that scattering particles can illuminate previously inaccessible parts of the
microwave spectrum. In late 2015, an LHC
team uncovered evidence of something
resembling an axion, but different in key
ways — the resonance signal had an excess
of energy — decaying into, not one, but two
photons — and had a mass much heavier
than predicted theoretically.
“When we saw this signal, we honestly
had no idea whether it was genuine because there weren’t any good reasons forResearch highlights

Kamimura didn’t use special equipment— only forceps, pins, scalpels, glass slides,
sticky tape, and a microscope. “What I
needed,” he says, “was just practice, practice, and practice.”
The flies generally survived the surgery
but subsequent reproductive successdepended on the site of the damage.
Injury to the vaginal shield resulted in

fewer eggs being successfully laid, and aharmed ovipositor plate led to lower rates
of successful insemination. Wounding
the pouch had little effect on matingand egg-laying success, suggesting thatthe soft structures evolved to help direct
the spiny male appendages to locations
where sex-induced injuries do not reduce
female fecundity.

A bit of chaos benefits
light-driven devices

Random features in nanoscale photonic cavities canhelp miniaturize devices that control optical data

R

Computing and shuttling data with lightinstead of electrons can hugely boost the
speed and energy efficiency of signal processing. Such applications require strong
interactions between photons and silicon
crystals to produce nonlinear effects. One
way to focus light waves at atomic targets
is with photonic waveguides: ordered
arrays of circular dimples, hundreds offreq.ω

Designed

W1.05

W0.98

W1.05

Fabricatedfreq.ω

Reproduced, with permission, from Ref. 1 © 2016 Optical Society of America

esearchers usually try to avoid
structural flaws when constructing photonic devices that manipulate, amplify, and switch signals
from light beams. A team from Japan,
however, has reported a high-speed photonic system that uses random fabrication
errors to localize light for more compact
optical devices1.

W1.05

W0.98

W1.05

Photonic waveguides fabricated using a speedy nanoscale patterning technique known as
photolithography have more errors than a perfectly designed structure would, but can also tap intochaotic light-trapping capabilities.

research-highlights.keio.ac.jp

“Developing hardened structures is notalways the optimal way to counter maleharassment,” says Kamimura.
Reference
1.

Kamimura, Y. Significance of constraints
on genital coevolution: Why do female
Drosophila appear to cooperate with malesby accepting harmful matings? Evolution 70,
1674–1683 (2016).

nanometers wide, carved into a siliconsurface, one by one, through a techniquecalled electron-beam lithography.
For the past decade, Takasumi Tanabefrom Keio University and colleagues
have been developing waveguides withstrong light-confinement capabilities. Oneof the team’s most efficient designs sandwiches one waveguide, compressed to 98%
of its normal spacing (W0.98), between twoothers at 105% spacing (W1.05). This setup
causes photons at a specific ‘cutoff frequency’ to propagate very slowly throughthe waveguide, interacting with manysilicon atoms along the way.
To better integrate their W1.05–W0.98–
W1.05 device with electronic silicon circuits, the researchers investigated whether
it could be produced using photolithography — a speedy way of forming nanoscalepatterns using masks and etching solutions. These experiments produced dimples
with larger fabrication errors than hoped
for, but also modified the character of the
propagating light so it became dominatedby random scattering effects (see image).
Tanabe explains that when randomness
increases in a photonic structure, scattering can cause light to localize and form
‘nanocavities’ that offer high confinement.
This localization could be used to makephotonic devices much smaller, but only
if the randomness can be controlled bysome method.
To accomplish this, the researchers varied the width of the W0.98 portion of their
waveguide nanocavities until localized21

Research highlightsthat modulates electro-optic signals at
high-speed gigahertz rates.
“Our device has a much smaller footprint than conventional modulators andis compatible with photolithographic
fabrication,” says Tanabe. “By studying
this random behavior in more detail,
we might be able to develop different

Beaks of canny crows
adapted to tool use

Bill structure assists New Caledonian crows in using
twig hooks to catch grubsAn international team of researchers discovered the unusual beakshape of the New Caledoniancrow (Corvus moneduloides) is anadaptation to the smart bird’s use of tools forcatching insect prey1.
The beak, with its short, straight upper
bill and upturned lower bill, enables the

Securely holding a stick tool in its bill, a New
Caledonian crow fishes out larvae hidden in
decaying wood.

22

species to grip and precisely manipulate thestick and leaf tools that it makes and uses
to hook larvae out of wood. This is the firsttime scientists have discovered evidence
that the physical shape of a non-humanspecies has evolved and changed for better
tool manipulation.
“If you look at the bill structure of the
New Caledonian crow it is clear to the eyethat you have a strange bill structure that isquite different from other crows,” says one ofthe paper’s lead authors, Ei-Ichi Izawa of the
Department of Psychology at Keio University.
Izawa, a biological psychologist, hadpreviously completed the first crow ‘brain
atlas’ — a detailed brain analysis and map ofa Japanese jungle crow (Corvus macrorhynchos). He also studied the behavior of thesebold, city-smart crows.
In 2012, he met ecologist Gavin Huntfrom the University of Auckland at aconference in Tokyo, and the two scientists
discussed ways to analyze the distinctive
beak structure of the more reticent New
Caledonian crow. These forest-dwelling
crows are endemic to certain islands in New

de v ices such as a l l-opt ic a l sw itches
or logic gates.”
Reference
1.

Ooka, Y., Daud, N. A. B., Tetsumoto, T. &Tanabe, T. Compact resonant electro-optic
modulator using randomness of a photonic
crystal waveguide. Optics Express 24,
11199 (2016).

Caledonia and, although their population is
declining, are still common.
Hunt had discovered that wild New
Caledonian crows made two types of tools,
which they used to fish out plump longhorn
beetle grubs from tree trunks. The canny
birds fashioned hooks from twigs and ripped
saw-toothed probes from pandanus leaves
that they found in their natural habitat.
Izawa says: “My Japanese colleague
Naomichi Ogihara suggested that the morphology of the bill enhanced and improved
the use of tools.” The team used computed
tomography and a statistical techniqueknown as three-dimensional landmark
analysis to compare and measure how thebeak structure of the New Caledoniancrow differed from that of nine related
corvids, and a woodpecker.
They found the New Caledonian crow’s
upper bill was deeper and shorter thanthat of the related crow species, and had astraight cutting edge. The thickened lower
bill curves slightly upwards, giving the crowa secure grip on its tools. Izawa says: “Thisshape protects the bill from being bent by
the strong forces exerted when probing forfood and also allows the bird a clearer view
when using tools to fish out prey.”
Now Izawa wants to pinpoint how long
ago the gene expression related to the ‘strange
upturned bill’ occurred.
Reference
1.

Matsui, H. et al. Adaptive bill morphology
for enhanced tool manipulation in
New Caledonian crows. Scientific Reports 6,22776 (2016).

Jitsugaku | May 2017

© Gavin Huntresonances due to randomness appeared
close to the cutoff frequency. The design
confined randomized light to the central
region of the waveguide, and yielded
sufficient optical power for practical applications. As proof, the team integrated therandom photonic system into a semiconductor diode circuit to produce a device

Research highlights

Beauty is in the prefrontal
cortex of the beholder

E

Electrical brain
stimulation can alter ourappreciation of art.

© edoardogobattoni.net/Moment/Getty

Noninvasive electrical brain stimulation can alter our appreciation of art
lectrically stimulating certain pleasure-sensing regions of the brain
can change a person’s subjective
experience of beauty, researchers at
Keio University have discovered1.
In a s t u d y o f 4 7 f e m a l e Jap a n e s estudents, res earchers found par ticipants whose medial prefrontal cortex
was inhibited with an electrical current
were significantly less likely to findresearch-highlights.keio.ac.jp

beauty in a series of 20th centur yabstract artworks. However, the stimulation had no effect on their experienceof ugliness, supporting the idea thatbeauty and ugliness are not opposite
ends of the same scale but independent
subjective experiences.
“This can help us understand the conflicting experience elicited by recent works
of modern art, in which there is beauty andugliness together in a single art work,” says
Hideaki Kawabata from Keio’s Departmentof Psychology, who led the study.
In previous studies using brain imaging
machines, Kawabata and his colleagues
showed that the medial prefrontal cortex
is activated when a person sees a face,painting or even mathematical formulathey consider to be beautiful. “This brain
area also responds when we obser ve
23Research highlights

Simulation solves Venus
atmosphere mystery

Waves of air create cold regions around the poles of
our nearest planetary neighborAdetailed simulation of theVenusian atmosphere created bya team of researchers in Japan
explains, for the first time, someof its mysterious features1.
The winds that swirl around the poles ofplanets are called polar vortices. On Earth, thepolar vortex is colder than the air at mid-latitudes. But Venus has a relatively warm polar
vortex surrounded by a ‘cold collar’, a bandof cooler air at around 60 degrees latitude.
Moreover, the clouds above Venus’s southpole are thicker than in its cold collar, and the
air there is rich in carbon monoxide. Many
studies have observed these features, but none
have been able to explain how they form.
Norihiko Sugimoto of Keio University’s
Research and Education Center for Natural
Sciences and colleagues have adapted amodel of Earth’s atmosphere to reproduce
these features on Venus and reveal the underlying causes. While similar in size to Earth,

192

188

204

Reference
1.

24

Nakamura, K. & Kawabata, H. Transcranial
direct current stimulation over the medial
prefrontal cortex and left primary motor
cortex (mPFC-lPMC) affects subjective
beauty but not ugliness. Frontiers in Human Neuroscience 9, 654 (2015).

Venus has a noxious atmosphere of densecarbon dioxide and sulfuric acid clouds.
The model showed that the cold collar wasformed partly by the flow of air from equator
to poles — known as meridional circulation — but was intensified by the thermaltide, a large wave of air driven by heat fromthe Sun. The thermal tide is most significant
at cloud level, between altitudes of 50 and
70 kilometers, where most of the solar flux
on Venus is absorbed. It can generate windsof 360 kilometers per hour at the cloud tops.
In the simulations, these atmosphericcirculations caused a cold collar to appear
around 60 degrees latitude at an altitude of
68 kilometers; its air was about -77 degrees
Celsius, some 10–20 degrees cooler thanat the north pole (see image). And at analtitude of 75 kilometers, the polar air
temperature varied from -81 to -57 degrees
Celsius, up to 40 degrees warmer than at
30 degrees latitude. Crucially, the simulation

210

216
[K]

Around the top of
Venus’s cloud layer, a‘cold collar’ of air (blue)
surrounds the warmer
north pole (green andyellow). (Meridional
circulation shown as red
arrows; zonal circulation
shown as white arrows.)

Jitsugaku | May 2017

© 2016 H. Ando et al .

good, moral or social behaviors in others,”
Kawabata adds.
Ugliness, in contrast, lit up the left
motor cortex of the brain, a region whose
primary function is to plan and executemovement — suggesting it primes neuralcircuits to “escape from aversive stimuli or
situations, or flick away incoming aversive
objects,” Kawabata says.
Kawabata and his team investigatedthe human experience of beauty andugliness in more detail using a brain
stimulation technique called transcranial
direct current stimulation (tDCS). tDCS
involves placing electrodes at certain
positions on the scalp, to either enhanceor suppress brain activity in areas beneaththe electrode.
Although enhancing activity in the
medial prefrontal cortex had no effect onparticipants’ experience of beauty or ugliness, suppressing activity in the brain region made them less likely to find abstract
paintings beautiful.
The results surprised Kawabata because
they suggested that the medial prefrontal
cortex is not just responding to the feelingof beauty — it actually has a role in causing
the feeling.
In contrast, stimulating or inhibiting
the medial prefrontal cortex had no effecton the number of paintings participantsconsidered ugly, confirming that uglinessis not the opposite of beauty, but mustarise as a separate cognitive mechanism ina different part of the brain.
The team plans to test whether, by
adjusting the placement of electrodes, it
is possible to enhance people’s perceptionof beauty. Kawabata also raised the ethicaldimension of being able to manipulate
a person’s subjective experiences using
brain stimulation.

Research highlights

only matched observations when it featured
the effects of the thermal tide. “We’ve reproduced these features for the first time in a
general circulation model,” says Sugimoto.
“This makes it the best model of Venus’s
atmosphere so far.”
The air currents and temperature patterns in the simulation also suggest how

the south pole might accumulate morecarbon monoxide and thicker clouds
through photochemical reactions.
Japan’s Venus Climate Orbiter ‘Akatsuki’
is c ur rent ly circling Venus, and t heteam plans to use the probe’s high-resolution observations to improve theirsimulation. They also hope to use theirmodel to propose future observations
for Akatsuki.
Reference
1.

Ando, H., Sugimoto, N., Takagi, M., Kashimura, H., Imamura, T. & Matsuda, Y. The puzzling Venusian polar atmospheric structure
reproduced by a general circulation model.
Nature Communications 7, 10398 (2016).

Plastic-munching bacterium foundT

New discovery could lead to a safer solution to plastic pollution© 2016 Kohei Oda, Kyoto Institute of Technology

he discovery of a bacteriumthat feeds on polyethylene
terephthalate (PET), by a teamof Japanese scientists, has been
hailed as a potential international breakthrough in dealing with the major pollution
caused by the tough plastic1.
The bacterium, named Idoenella sakaiensis, pitted the surface of a PET film withholes within just 60 hours. In six weeks, it

1 µm
The bacterium Idoenella sakaiensis feeds onplastic bottles for energy and carbon.

research-highlights.keio.ac.jp

almost completely degraded the plastic. “Thisis the first PET-degrading bacterium found,”says Kenji Miyamoto, an associate professor
in the Department of Biosciences andInformatics at Keio University and one of
the study’s authors. The team plans to buildon the discovery “to develop a new andnature-friendly system” of recycling PET.
More than 55 million tons of PET is
produced each year to make products
such as soda bottles, clothing and even car
bumpers. First manufactured 70 years ago
from petroleum products, PET’s crystalline
structure is difficult to break down. With
only 14 per cent of plastic recycled, most of
it ends up contaminating the environment,
especially rivers and oceans.
The team, led by Kohei Oda of the Kyoto
Institute of Technology, went in search ofa microorganism that could degrade PET
so it could be recycled without posing anenvironmental burden.
They collected 250 samples of contaminated soil, waste water and sludge
from a PET bottle recycling factory inOsaka. Each sample was screened for
microorganisms that could grow on thepolymer. To make it easier for the bacteria
to consume the polymer, they used anamorphous form of PET film, heat treatedat 260 degrees Celsius to break down its
crystalline structure.

In one sample, a consortium of microbes
degraded the PET film and catabolized
75 per cent of the carbon into carbon dioxide. The researchers isolated the PET-eating
bacterium from the sample.
“We were very excited,” says Miyamoto.
Fur ther investigations found thatI. sakaiensis had evolved to use PET as its
major source of energy and carbon.
E le c t ron mi c ro s c op e photog r aphs
showed clusters of bacterial cells, resembling tiny grubs, connected to the PET filmand each other by thread-like appendages(see image).
Through DNA analysis the researchers
discovered that the bacterium uses two
enzymes — PETase and MHETase —to break down the plastic into its basic
building blocks.
In follow-up research, Miyamoto says
the team intends to determine the three-dimensional structure of the two enzymes “inorder to know their reaction mechanism”.
The enzymes could potentially be manufactured and used to convert heat-treated
PET waste into environmentally benign
and useful materials.
Reference
1.

Yoshida, S. et al. A bacterium that degrades
and assimilates poly(ethylene terephthalate). Science 351, 1196–1199 (2016).

25

Research highlights

Wandering catalyst activates carbon atoms to form
carbon–carbon bonds

I

nspired by a reaction that has becomea mainstay of polymer synthesis, Keio
University researchers have discovered
a novel way to construct small organic
molecules. Their method uses a ‘chain-walking’ catalyst to activate otherwise unreactive
parts of simple molecules, catalyzing theformation of new carbon–carbon bonds1.
The conventional formation of new
carbon–carbon bonds — which turn simple
starting molecules into complex structures,such as therapeutic drugs — is to first installa chemical ‘handle’. For example, a chlorine
atom might be used to pre-activate a particular carbon atom toward bond formation.
Adding and manipulating these handles canmake the synthesis of complex molecules
slow and inefficient, so there is much interest
in finding ways to directly install new bondsat unreactive carbon atoms.
Chain walking could be just such areaction, realized Takuya Kochi fromthe Department of Chemistry at Keio
University. Chain-walking chemistry was
pioneered in the 1990s, when polymer
chemists discovered a palladium catalyst
that would attach to the end of a chain ofcarbon atoms, then ‘walk’ along the polymer chain before adding the next building
block to the chain. “It is not a conventional way to form a carbon–carbon bond,”says Kochi.
Polymer chemists use bulky substituentsaround the palladium atom to slow acompeting reaction, alkene exchange, inwhich the palladium drops off the growing
polymer chain. “We felt that if we justremoved the bulky substituent, we could
switch the rates,” says Kochi, favoringalkene exchange over polymerization —the desired pathway when making small
molecules rather than polymers.
The researchers tested their slimmeddown catalyst on a variety of starting“It’s not a conventional
way to form a carbon–
carbon bond.”
Using their reaction, the team has beenable to synthesize a structure called prostane, the underlying carbon framework ofa family of natural products. They are now
investigating the reaction to identify whichmolecules are particularly suited to chain
walking. “The chemistry is still in its initial
phase,” says Kochi.
Reference
1.

Hamasaki, T., Aoyama, Y., Kawasaki, J.,
Kakiuchi, F. & Kochi, T. Chain walking as a
strategy for carbon–carbon bond formation at unreactive sites in organic synthesis: Catalytic cycloisomerization of various
1,n-dienes. Journal of the American Chemical
Society 137, 16163 (2015).

Like a tightrope walker
on a high wire, achain-walking catalyst
traverses a chain ofcarbon atoms before
activating the middleof the chain towardbond formation.

26

Jitsugaku | May 2017

© Giancarlo Banfi/EyeEm/Getty

Chain-walking chemistry
installs new carbon bonds

molec ules, e ach of w hich cont ained
two parallel ‘arms’ consisting of carbon
atoms. They showed the catalyst would
attach to the end of one arm, then walkfrom atom to atom until it was opposite
a carbon–carbon double bond on theother arm. It would join the two arms ofthe molecule at that point — activating
the otherwise unreactive carbon it had
w a l k e d t o — t o f o r m t h e n e w c a rbon–carbon single bond.

Research highlights

New peptide-based
diagnostics could help
diagnose influenza.

Catching up with the influenza virus

T© ROGER HARRIS/Science Photo Library/Getty

New diagnostic tests could quickly reveal a flu infection in its early stages

wo new detection methods for the
influenza virus could help preventthe next global pandemic.
Seasonal influenza is responsible
for up to 500,000 deaths around the world,
every year, and pandemic strains of the virus
have periodically killed many more. Current
methods to diagnose and track flu outbreaks
are cumbersome, expensive or both.
A simpler technique for identifying patients in the early stages of infection could
help get anti-influenza therapies faster tothose who need them, and so limit theinfection of others.

research-highlights.keio.ac.jp

A team led by Toshinori Sato from Keio
University’s Department of Biosciences andInformatics exploited the fact that influenza
invades the human respiratory tract andbloodstream by focusing on a sugar molecule
found on the surface of our cells called sialic
acid. Through a special kind of binding
between sialic acid and a flu protein called
hemagglutinin, viral particles can enter thehuman body, replicate and make us sick.
Sato and his colleagues previously
identified a short chain of amino acids thatmimics sialic acid, which they used as a decoy to bind viral hemagglutinin and prevent

cell infection in the lab. In their most recent
work, they took the same short peptide
chain and developed two diagnostic assays
for revealing the presence of influenza in athroat swab or other form of patient sample.
For the first test1, Sato’s team created amembrane that combined the peptide witha fatty molecule called a phospholipid. Thispreparation was fixed to a surface where it
selectively attached to hemagglutinin whenincubated with a flu-containing sample.
Once all the flu particles had been collected,
the researchers could then count them using
traditional chemical and genetic techniques.
27

Research highlights

diagnostics offer several advantages overexisting ones in terms of manufacturing,storage and engineering. But, perhaps thebiggest benefit comes from the peptides
mimicking a part of the flu virus essential
for its survival. So, whereas other tests need
to be designed anew whenever a novel flu
strain arises, according to Sato, “we expectthat our strategy will be applicable to thedetection of new influenza viruses that willappear in the near future.”

Dimming the lights on
cancer cells

Fluorescent probes selectively taken up by tumorous
tissue could be used for early disease detection

A

Stimuli-responsive fluorescent polymers light up
to reveal the temperature inside cells.

stimuli-responsive
fluorescentpolymer that is readily taken
up by living cells could becomea useful diagnostic tool for
identifying diseased cells, Keio University
scientists suggest. The research team developed fluorescent polymers whose light output
dims in response to warmer temperaturesand more acidic pH — conditions typical ofpathological tissue in patients with diseases
ranging from cancer to Alzheimer’s disease.
The polymers’ responsive properties
could eventually be used to selectively deliver drugs to diseased cells.
At the heart of the polymer, developed28

by Hideko Kanazawa and her team at Keio
University’s Department of Pharmacy, is amolecule called Poly(N-isopropylacrylamide),or PNIPAAm. This polymer is well known for
significantly changing its structure in water
above a critical temperature.
At low temperatures, a strong interaction
between water molecules and the polar nitrogen-rich amido groups in the PNIPAAm
polymer means the polymer spreads out
into an expanded coil formation. But,
warming the solution disrupts the water–
polymer interaction, until the critical temperature of 32℃ is reached and the polymer
suddenly contracts, forming a compact
globular structure.
Kanazawa and her team created four new
forms of PNIPAAm polymer that incorporate different fluorescent side-chains.
Previous work showed these fluorescentgroups are pH-responsive, dimming underacidic conditions. But the team showed
that, once combined with the PNIPAAm
polymer, they also became responsive toReferences
1.

Matsubara, T., Shibata, R. & Sato, T. Bindingof hemagglutinin and influenza virus to a
peptide-conjugated lipid membrane.
Frontiers in Microbiology 7, 468 (2016).

2.

Matsubara, T., Ujie, M., Yamamoto, T.,
Akahori, M., Einaga, Y. & Sato, T.
Highly sensitive detection of
influenzavirus by boron-doped diamondelectrode terminated with sialic
acid-mimic peptide. Proceedings of
the National Academy of Sciences USA 113,
8981–8984 (2016).

temperature. Below the polymer’s criticaltemperature the side-chains fluoresce
brightly. But as soon as the polymer collapses, the fluorescence is switched off1.
This responsive behavior remains active
inside living cells, Kanazawa showed (seeimage). The researchers attached a non-polar
lipid additive called DOPE to the polymer
to help draw it through the non-polar cell
membrane and into the living cell. They were
surprised to find just how effective the strategy proved. “DOPE caused a strong preference
for cellular uptake, allowing the polymers to
be rapidly internalized without the requirement for a delivery system,” Kanazawa says.
The team is already working on newversions of the fluorescent polymer withenhanced functionality, Kanazawa adds. For
example, it has developed versions of thepolymer that, under the mildly acidic pH
around diseased cells, switch from a polar to a
non-polar state. This polarity switch dramatically boosts the rate at which the fluorescentprobe is taken up by diseased cells comparedto healthy ones. “This polymer may offer the
potential for development as a diagnosis toolfor early tumor detection,” Kanazawa says.
“Furthermore, it could be used as a tumor-selective intracellular drug delivery system.”
Reference
1.

Yamada, A., Hiruta, Y., Wang, J., Ayano, E. &Kanazawa, K. Design of environmentally
responsive fluorescent polymer probes forcellular imaging. Biomacromolecules 16,
2356–2362 (2015).

Jitsugaku | May 2017

© 2016 Hideko Kanazawa, Keio University

The other test2 also started with the sialic-acid-mimic peptide, but in this case theresearchers attached it to a highly sensitiveelectrode made of a diamond enhanced withthe mineral boron. Any time a flu particle attached to the peptide, Sato and his colleagues
could then detect its presence though electrochemical changes in the diamond sensor,
without the need for additional assays.
By avoiding the use of complex biologicalmolecules, Sato says that his peptide-based

The Keio Medical Science Prizeobjective

The 2016 Keio Medical
Science Prize Laureates“

I am greatly
honored to receive
The Keio Medical
Science Prize. For
more than 30 years
I have worked on
the retrieval of DNA
from long deadorganisms. It has now
become possible to go
back in time and study the genomes of extinct
hominins, past human populations, ancientpathogens and extinct animals. Many talented collaborators both in my lab and elsewhere
have helped make this dream come true. I
thank them all.

“

Svante Pääbo“

It is my greathonor to receive The
Keio Medical Science
Prize 2016, which
has been awarded
to many excellent
medical scientists. I
encounteredthePD-1 molecule andfound that PD-1
serves as a brake in the immune system.
Based on the findings in animal models, thePD-1 blockade cancer therapy became available 22 years after its discovery. I deeply appreciate the active investment in basic researchin Japan about 20 years ago, which made thisinnovative application possible.

“

Tasuku Honjo

The Keio Medical Science Prize is an international prize that recongizes theoutstanding and creative achievements of researchers in the fields of medicine
and life sciences, in particular those contributing to scientific developments inmedicine. It aims to promote worldwide advances in these fields to encourage
the expansion of research 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