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Issue 3 実学 | Science | サイヤンス May 2017 JITSUGAKU Showcasing the best research from Keio University

100 years of excellence Medical innovation since 1917

Stroke of genius Junk food Physics rewritten Healing the brain with robots Bacterium found that digests plastic 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 the development of medical care in Japan.

ON THE COVER

1920 KEIO UNIVERSITY HOSPITAL OPENS he opening ceremony for the Keio University Hospital was held on November 6, 1920 and the first general Tmeeting of the Keio Medical Society was held on November 8 of the same year. Keio Igaku, the Journal of the Keio Medical Society was first published in 1921. The Building for Preventive Medicine & Public Health (Institute of Preventive Medicine) was completed in 1929, thanks to donations from the Rockefeller Foundation. Contents

実学 | Science | サイヤンス JITSUGAKU

3 Editorial Hundred years of medical excellence

Inside Keio Page 4 A prize for science visionaries 4

Research highlights 6 Star-crossed models of white matter disease 6 Neural support cells are implicated in childhood diseases of the brain’s fatty high-speed transmission lines

7 Building a colorectal cancer library Biobank of colorectal cancer ‘organoids’ reveals cancer’s secrets

8 Sealing the deal on leak-proof cells Scientists discover the unusual geometry that holds mammalian Page 6 skin together, even while shedding

9 Beta-blockers not better for heart surgery patients Japan-wide study shows a widely used heart drug does not improve bypass results

10 Brain regions controlling emotion pass from mothers to daughters Women are more likely to inherit brain structures linked to Page 8 depression from their mothers than their fathers

11Feature articles Preserving more than words 12 11 Mind over machine 14 Measuring the tremors of an earthquake-savvy public Longevity 16 Page 16 Initiative to realize Western roots in Japanese manga a society where people live better, longer lives

Integrative Approaches Inside Keio Page 17 A global research hub 17

Security Creativity research-highlights.keio.ac.jp Initiative to assure Initiative to bolster a safer, more innovation in sustainable society education and research Contents

Research highlights 19 Making light of a dark matter 19 The see-sawing behavior of dark-matter particles might have jolted experiments at the Large Hadron Collider

20 Female flies have soft spots for male genitalia The reproductive tracts of female fruit flies have evolved to minimize damage caused by mating

21 A bit of chaos benefits light-driven devices Random features in nanoscale photonic cavities can help miniaturize devices that Page 19 control optical data

22 Beaks of canny crows adapted to tool use Bill structure assists New Caledonian crows in using twig hooks to catch grubs

23 Beauty is in the prefrontal cortex of the beholder Noninvasive electrical brain stimulation can alter our appreciation of art Page 23 24 Simulation solves Venus atmosphere mystery Waves of air create cold regions around the poles of our nearest planetary neighbor

25 Plastic-munching bacterium found New discovery could lead to a safer solution to plastic pollution

26 Chain-walking chemistry installs new carbon bonds Wandering catalyst activates carbon atoms to form carbon–carbon bonds

27 Catching up with the influenza virus New diagnostic tests could quickly reveal a flu infection in its early stages

28 Dimming the lights on cancer cells Page 26 Fluorescent probes selectively taken up by tumorous tissue could be used for early disease detection

実学 | Science | サイヤンス Produced by: which offers a taste of the important Headquarters for Research Coordination research and scientific developments from JITSUGAKU and Administration, Keio University Keio University. 2-15-45 Mita, Minato-ku, Keio Research Highlights is published Tokyo 108-8345, Japan for Keio University by the Partnership and Custom Media unit of Nature Research, @ 2017 Keio University. Further information part of Springer Nature. All Rights Reserved. Keio University is Japan’s oldest insti- www.keio.ac.jp This publication may be reproduced in its tute of higher education, founded in research-highlights.keio.ac.jp original form for personal use only. Mod- 1858 by educator and intellectual leader ification or commercial use without prior Yukichi Fukuzawa. permission from the copyright holder Jitsugaku is a print publication of the is prohibited. online platform Keio Research Highlights,

Jitsugaku | September 2015 Editorial

実学 | Science | サイヤンス JITSUGAKU

Hundred years of medical excellence Keio celebrates a century of education, research, and clinical service in the medical and life sciences

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 Tits founding fathers: visionary leader and educator, Yukichi Fukuzawa, and respected microbiologist, Shibasaburo Kitasato. Fukuzawa was a strong advocate for social change informed by reason and education, which Kitasato, who served as the School’s first dean, realized through an equal commitment to basic and clinical medicine. The School of Medicine inspires young students to become pio- neers in the world of medicine, and backs scientific developments that 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 Issue 3, May 2017 global prominence as a prestigious reward for excellence and innovation, 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 peo- WHAT IS JITSUGAKU? ple live safer, longer, and more creative lives. The Keio University Jitsugaku is a way of learning Global Research Institute will coordinate multidisciplinary about the world pursued by research aimed at addressing the challenges facing Japan and the Keio University’s founder rest of the world in an era of political, social, and environmental Yukichi Fukuzawa through upheaval (see page 17). the application of reason, The articles in this third issue of Jitsugaku reflect Keio’s ongoing observation, and verification. It is science in the true sense of efforts in this direction, from revealing the links between manga the word, and a powerful tool and western literature, to discovering how crows’ beaks adapted to in Keio University’s never-end- tool use, and discovering plastic-eating bacteria. We hope that you ing search for practical solu- will join us on our journey into the next hundred years. tions to real-life problems.

research-highlights.keio.ac.jp 3 Inside Keio

A prize for science visionaries The Keio Medical Science Prize recognizes scientific developments The 21st Keio Medical Science Prize went to Japanese immunologist Tasuku that have led to paradigm shifts in Honjo (center right) and Swedish evolutionary biologist Svante Pääbo (center left). Keio University President Atsushi Seike (right) and professor and dean of medical and life sciences the Keio University School of Medicine, Hideyuki Okano (left), congratulated the laureates at an awards ceremony in Tokyo.

very year since 1996, Keio University Science Fund, which also provides grants The Keio University School of Medicine has honored the world’s most out- for research and international exchange. It was established in 1917, with microbiologist standing medical researchers with recognizes outstanding researchers of any Shibasaburo Kitasato serving as its first The Keio Medical Science Prize, a nationality, nominated and selected through dean. Kitasato was a strong defender of the globally recognized award that reflects the a rigorous evaluation process. Laureates egalitarian ideals of science for society. He university’s commitment to excellence and today receive a certificate of merit, a medal, fostered not just doctors, but the next gener- innovation in education, research and med- and a monetary award of 10 million yen ation of ‘physician scientists’ committed to Eicine. Remarkably, the prize has anticipated (equivalent to US$88,000). pursuing knowledge for the public good. the Nobel Prize on multiple occasions, and Over the past two decades, the prize has Keio’s mission “is to be a constant source seven winners of the Keio Prize have gone gained prominence as the only one of its of honorable character and a paragon of on to become Nobel Laureates. kind bestowed by a Japanese university intellect and morals for the entire nation,” The history of the Keio Prize dates to the focusing on medical and life sciences. It Fukuzawa said in 1896. He aspired for early 1990s, when a Keio alumnus called receives a large number of nominations every member of Keio “to apply this spirit Mitsunada Sakaguchi presented a gift to the from all over the world and has recognized to elucidate the essence of family, society, university that aimed to spur research in the researchers from Japan, the United States, and nation. They will not only articulate this life sciences and stir the aspirations of young Australia, Sweden, and France, covering a essence in words, but also demonstrate it medical scientists. wide range of research, from the discovery of in their actions, and by so doing make Keio Sakaguchi had graduated from the presti- infectious proteins to cellular self-digestion. a leader of society.” These words resonate gious Keio University School of Medicine in today in the high standards set for laureates 1940. Half a century later, he had not forgotten Global pioneer of The Keio Medical Science Prize. his alma mater and in 1994, his donation of Keio University, Japan’s oldest private insti- five billion Japanese yen was used to establish tute of higher learning, was established in Significant contributions the Keio University Medical Science Fund. His 1858 by educator and leading intellectual Selection of those laureates — one Japanese donation, equivalent to US$50 million, was Yukichi Fukuzawa, who championed reason, and one non-Japanese each year — is a followed several years later by an additional observation and verification in science. painstaking task. Every winter, the Keio two billion yen. Sakaguchi wished for the Today, it ranks among the top ten universities Prize committee gathers to begin a year-long money to be used to commend outstanding in the world for the number of degrees it has process that considers recommendations researchers, encourage medical research and conferred to chief executives, according to from all over the world. Candidates are its creative progress at Keio through grants, the Times Higher Education. Its well-connect- critically assessed for their accomplishments and promote worldwide medical advances. ed network of alumni include three former through a rigorous, four-stage vetting The Keio Medical Science Prize is a key prime ministers, the first Japanese woman to process. By the autumn, the winners project of the Keio University Medical go to space, and many Olympic medalists. are announced.

4 Jitsugaku | May 2017 Inside Keio

The result of those deliberations is a telomeres, have been found view of the value of prize that is unique in recognizing “not just to play an important role basic research. “I am very world-firsts, as is often the case with the in cellular aging and the honored by the prize and Nobel Prizes, but also cumulative research immortality of cancer cells. extraordinarily humbled to be that has an impact on human health,” says A decade after receiving the among such outstanding re- Hideyuki Okano, professor and dean of the Keio Prize, Blackburn was cipients,” he said. “Curiosity was Keio University School of Medicine and awarded a Nobel in 2009. the starting point of my career as chairman of the prize selection committee. Most recently, the Nobel a medical researcher. Fortunately, This distinction is an important one, he says. Prize in Physiology or Medicine this has led to results that may be Significant contributions to medical science 2016 went to Japanese mo- beneficial to many people.” can take many different forms. lecular biologist Yoshinori “I am deeply honored to Keio laureates are selected for having pre- Ohsumi, one year after he receive the prize,” said Pääbo cipitated a paradigm shift in the life sciences. received the Keio Prize. in his acceptance speech. “I © 2017 Keio University © 2017 Keio Their original research must have contrib- Ohsumi determined the share this award with many uted to medical advances. Prizewinners are process by which cells de- people in my laboratory revered not only for what they have already grade and recycle their own and elsewhere.” revealed about the world, but also for the contents, known as autophagy. The 2016 nomination process many more discoveries to come. As such, He described the Keio medal as “a involved a total of 3,142 academics the committee favors younger researchers great honor”. and researchers from Japan and overseas, who are likely to maintain an active involve- representing 40 countries. More than 100 ment in their work long after receiving the Cancer targets and Neanderthals nominations were put forward and assessed accolade — a criterion that distinguishes the On 1 December 2016, Keio inducted its by members of the selection committee to- Keio Prize from the Nobel. newest laureates at a grand event complete gether with a large panel of experts from ex- with a student string orchestra at Kitasato ternal institutions and Keio University. “The Nobel promise Memorial Hall, Keio University School selection, the achievement, I find it very From the beginning, the Keio Prize proved of Medicine. Japanese immunologist rewarding,” says Okano, who has already its acuity. The first two laureates in 1996 were Tasuku Honjo, who discovered a promising begun the exhaustive process of choosing American neurologist Stanley Prusiner and drug in the fight against cancer, and Swedish the 2017 laureates. Japanese neuroscientist Shigetada Nakanishi. evolutionary biologist Svante Pääbo, who Prusiner had discovered prions, a type of in- is responsible for sequencing the entire A lasting legacy fectious protein that causes many neurode- genome of our distant ancestors, the In many ways, The Keio Medical Science generative diseases such as scrapie in sheep Neanderthals, were the recipients. Prize encapsulates the founding principles and mad cow disease in cows. One year “Both professors, Honjo and Pääbo, are of Keio’s School of Medicine, which strives later, in 1997, he received the Nobel Prize in outstanding researchers who exemplify the to be a pioneer in the world of clinical and Physiology or Medicine for uncovering this criteria of the prize: advancing medical and medical studies. In 2017, the school will “new biological principle of infection”. life sciences, cultivating new paradigms and turn 100, and it has invited former prize For his part, Nakanishi developed a continuing to be active in research,” says laureates to give commemorative lectures at ground-breaking technique for determining Okano, who welcomed the audience of 300, the centennial celebrations. the structure, and eventually the function, of including many high-profile guests. Keio By honoring researchers who embody neural receptor proteins. In the years since University President Atsushi Seike congratu- Keio’s ideals in their work, The Keio Medical winning the award, the tools he developed lated Pääbo and Honjo on their accomplish- Science Prize acts as a driving force for have brought into view a deeper under- ments before conferring them with certificates ambitious young scientists. Students at standing of the inner workings of the brain, and medals decorated with the Keio colors, Keio’s School of Medicine are welcome at from learning to memory and movement. blue and red. “This year’s awards celebrate a the annual award ceremonies, and given One in every five laureates has since gone truly wide scope of research, with one having an opportunity to see researchers who are on to receive a Nobel Prize. an impact on lives in the future and the other active in the global frontlines. In 1999 Keio recognized Australian- reaching far back in time,” he said. “We hope that the prize will inspire young American biologist Elizabeth Blackburn for Both laureates gave commemorative students in particular,” says Okano. “It is her discovery of telomerase, the enzyme lectures after receiving their awards. Honjo our hope that Keio Medical Science Prize responsible for capping the ends of chro- described The Keio Medical Science Prize as Laureates serve as role models in terms of how mosomes. The protective caps, known as a “visionary” award that takes a long-term they approach and conduct their research.”

www.keio.ac.jp 5 Research highlights

Improved models of the brain’s communication network, known as white matter, could explain how diseases develop early in life.

Star-crossed models of white matter disease Neural support cells implicated in childhood diseases of the brain’s fatty high-speed transmission lines

apanese researchers have gained new neural projections wrapped in fatty megalencephalic leukoencephalopathy insights into childhood brain diseas- tissue that acts as insulation to speed up with subcortical cysts (MLC). es by manipulating gene expression transmission of electrical signals between Alexander disease and MLC both in laboratory mice1. The work, led brain regions. develop in infants and both are caused by Kenji Tanaka at Keio University’s School Destruction or defective develop- by mutations in genes expressed in star- of Medicine, offers a new view of the tissue ment of white matter leads to diseases shaped brain cells called astrocytes. In that constitutes almost half the human brain. called leukodystrophies, which include Alexander disease, the gene GFAP seems White matter is the brain’s commu- two disorders that Tanaka’s work fo- to be involved, and MLC1 is implicated in

J LIBRARY/Getty PHOTO © ALFRED PASIEKA/SCIENCE nication network. It consists of long cused on — Alexander disease and MLC. Healthy astrocytes are known to help

6 Jitsugaku | May 2017 Research highlights

maintain white matter, but how the genetic mutations in these cells cause white matter degeneration is unclear. One obstacle to solving the mystery was that mouse versions of these diseases either did not exhibit the characteristics of human Building a colorectal leukodystrophy, or the disease only developed in old age. “We needed a new model in which the onset is in the developmental period to cancer library mimic the human disease,” explains Tanaka. His team developed new mouse models Biobank of colorectal cancer ‘organoids’ of astrocyte-related leukodystrophy using a reveals cancer’s secrets technique they had previously developed to manipulate gene expression, called Flexible Accelerated STOP Tetracycline Operator hree-dimensional tumors grown patients with colorectal cancer, including (tetO)-knockin (FAST). The FAST system from cells of colorectal cancer pa- a number of rare subtypes. These samples enabled the researchers to create mice in tients are being used by Japanese were cultured with factors that might which Mlc1 was deleted and mice in which researchers to explore how benign activate or repress particular signaling Mlc1 was overexpressed. tumors transform into malignant metastat- pathways known to affect cell growth. Deletion of Mlc1 caused leukodystrophy ic cancer that claims nearly 700,000 lives Each tumor sample thrived under a unique in old, but not young, mice. By contrast, around the world each year. ‘niche factor’ microenvironment. mice with overexpressed Mlc1 developed TTheir library of ‘organoids’ offers a unique The result was a library of 55 colorectal white-matter abnormalities early in life, opportunity to observe colorectal cancers as cancer organoids, each with the same similar to the infantile onset of MLC in they would behave inside the human body. molecular signature as its in vivo counter- humans. Further experiments showed “Until recently, cell lines and rodents have part. They also replicated the same cellular that overexpression of Mlc1 in astrocytes been the only living tools for cancer research, structure when transplanted into an animal disrupted the energy-dependent balance of but these models may not fully reflect the model (see image)1. sodium and potassium inside and outside characteristics of the clinical cancers. This The biobank has already provided some the cells, leading to astrocyte swelling and has caused a bottleneck in translation from valuable insights into colorectal cancer white matter damage. basic science to clinics,” says Toshiro Sato growth and metastasis. For example, While the implications for humans are not of the Department of Gastroenterology and because the team tailored the niche yet clear, Tanaka has some ideas. “Disruption Hepatology at Keio University School of factors to each tumor, they were able of energy balance or the balance of sodium Medicine, who led the study. to see which niche factors the tumors and potassium might cause human leukodys- Colorectal cancer organoids are clusters of needed for growth, and which ones they trophy, and correction of these imbalances cells that form a mini-tumor, with the same didn’t require. could improve the disease.” structural features as the original tumor. While healthy intestinal stem cells are The team plans to further investigate To build the library, Sato and colleagues dependent on certain niche signals to grow, the role of astrocytes in the development collected cells from 52 tumors in 43 the researchers noted that tumors appear and maintenance of white matter. They are also using the FAST technique to study the role of proteins that support neural growth and survival in resilience and susceptibility to stress in models of neuropsychiatric diseases.

Reference

1. Sugio, S., Tohyama, K., Oku, S., 100 μm Fujiyoshi, K., Yoshimura, T. et al. Astrocyte-mediated infantile-onset leukoencephalopathy mouse model. Three-dimensional tumors grown on a dish and transplanted into animal models (right) develop similar Reprinted from Ref. 1, Copyright 2016, with permission from Elsevier. 1, Copyright 2016, with permission from Ref. from Reprinted Glia 65, 150–168 (2016). cellular structures as the original colorectal cancer cells taken from patient tumors (left).

research-highlights.keio.ac.jp 7 Research highlights Research highlights

to have negated some of these growth process did not appear to influence the This suggests some other mechanism, un- restrictions through genetic mutations. transition from early cancer to advanced related to genetic mutation is causing cancers “We referred to this phenomenon as metastatic cancer. to spread; a mechanism that we are yet to niche-independent growth,” says Sato. The study showed that while samples identify and target with treatment. “By profiling the niche factor require- from the original tumor and from its metas- ments of each tumor organoid, we found tases were almost identical genetically, the Reference that the transition from a benign adenoma to metastatic organoids were still much more 1. Fujii, M. et al. A colorectal tumor organoid library demonstrates progressive loss of cancer, frequently accompanies this loss of likely to metastasize when transplanted into niche factor requirements during tumori- niche-dependency.” Interestingly, this same the animal model. genesis. Cell Stem Cell 18, 827–838 (2016).

Sealing the deal on leak-proof cells Scientists discover the unusual geometry that holds mammalian skin together, even while shedding

he human body sheds an estimated 14-sided geometrical structure consisting of living epidermal cells, sealed together like .

200 million skin cells every hour, of 6 rectangular and 8 hexagonal sides1. sewing thread by protein complexes known al et but doesn’t leak. How the body “Such beautiful shapes are rarely observed as tight junctions in a particular upper layer. maintains this protective barrier, in animal cells,” says Kubo. “The discovery The cells eventually die, and get replaced by despite such extensive cellular turnover has has changed the concept of the epidermis,” newer cells from lower down in the epider- long puzzled scientists. The explanation, find — on a basic biological level, and for mis. The Keio team wanted to know how this researchers at Keio University, lies in the un- understanding what goes wrong when the replacement happens without disrupting the Tusual shape of cells on the skin’s surface. skin’s barrier is breached, as happens with physical seal of the tight junctions. A team led by Akiharu Kubo and inflammatory diseases such as eczema. The researchers used a sophisticated Masayuki Amagai at Keio University The epidermis — the body’s largest and imaging technique called confocal micros- School of Medicine found that epidermal fastest-growing organ — consists of a thick copy to examine the process in mice ears. A cells, which make up our external coating, outer layer of dead cells that are constantly snapshot showed that the cells resembled a adopt the shape of a tetrakaidecahedron, a shedding. Below this sits a multilayered sheet flattened 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 shape when thinking about how bubbles fit together to form foam, a concept that can also be applied to skin cells. The researchers used mathematical models to show that the mix of rectangular and hexagonal sides allow tight junctions to form with no gaps between adjacent cells. Further imaging revealed that during cell turnover the junctions form between The 14-sided tetrakaidecahedron shape of epidermal cells (seen here from different angles) explains three different cells to allow a new one © 2016 M. Yokouchi 4.0 (creativecommons.org/licenses/by/4.0/legalcode) BY under CC 1 and licensed Ref. from Reproduced how the skin maintains a physical barrier against disease.

8 Jitsugaku | May 2017 Research highlights Research highlights

to swap in and an old one to move out, old cell shedding at the tight junctions — Reference

while maintaining a continuous barrier in all made possible by the 14-sided shape of 1. Yokouchi, M., Atsugi, T., van Logtestijn, M., the mouse skin, and presumably also in the epidermal cells. Tip the balance and Tanaka, R. J., Kajimura, M., Suematsu, M., human skin. the skin barrier is weakened, leading to ec- Furuse, M., Amagai, M. & Kubo, A. Epider- mal cell turnover across tight junctions As Kubo sees it, the process involves a zema, or too many new cells are produced, based on Kelvin’s tetrakaidecahedron cell balancing act between cell formation and resulting in psoriasis. shape. eLife 5, e19593 (2016).

which involve routing blood through healthy arteries. Recent studies have suggested be- Beta-blockers not better ta-blockers have little effect on short-term, post-operative mortality and in some cases were shown to push the heart rate or blood for heart surgery patients pressure too low. Japan-wide study shows a widely used heart drug To investigate this, Kohsaka and colleagues analyzed 34,980 cases of coronary does not improve bypass results bypass surgery undertaken in Japan between January 2008 and December 2011. class of drugs traditionally used to Department of Cardiology. This is because The data, from the Japan Cardiovascular protect the heart from disease may the drug causes the heart to beat slower and Surgical Database, involved 333 centers, have no effect on cardiovascular to contract with less force, Kohsaka says. accounting for almost 74 per cent of sites surgical outcomes, according to a “When heart rates are lower the oxygen performing open-heart bypass surgeries study by Keio University researchers1. consumption within the heart is kept low,” in the country. The average age of patients The drugs, known as beta-blockers, says Kohsaka. Theoretically, this would allow was 68 years, with women comprising one- are among the most widely prescribed the heart to tolerate a longer period under fifth of the patients. Amedications for controlling high blood stress if any problems occur during surgery. Beta-blockers were used in 10,496 pressure, and were recognized as being However, he says, in recent years there patients — around 30 per cent of cases. “cardioprotective” under surgical conditions, has been growing debate around the use Patients receiving the drugs were slightly says Shun Kohsaka, from Keio University’s of beta-blockers for bypass operations, younger, but more likely to have other risk factors such as diabetes. The researchers used rigorous statistical modeling to compare outcomes for patients undergoing the surgery with and without beta-blockers. This modeling was then extended to isolate sub- groups that included low- and high-risk patients and those known to have left ventricular dysfunction. The study found no major benefit in beta-blocker use under any of the analyses they performed — confirming recent findings of studies in the West. Kohsaka says because East Asians are known to be genetically sensitive to beta-blockers, any effect should be more marked in his cohort. “Within

© sudok1/iStock/Getty Images Plus Images © sudok1/iStock/Getty beta-blocker-sensitive patients, we would The use of beta-blockers to slow down the heart rate during bypass surgery has no clinical benefit.

research-highlights.keio.ac.jp 9 Research highlights Research highlights

assume beta-blockers work very well, but prescribe, it does not seem to show any Reference in this study we do not see any benefits,” benefit, retrospectively.” 1. Kohsaka, S. et al. Effects of preoperative says Kohsaka. Kohsaka is now looking at using the same β-blocker use on clinical outcomes after coronary artery bypass grafting: A report “No matter which ethnic group you approach to investigate the use of statins from the Japanese cardiovascular surgery are in, or what type of beta-blockers you and aspirin in cardiac patients. database. Anesthesiology 55, 45–55 (2016).

Their analysis showed that the volume of gray matter in the brain’s amygdala, hippo- campus and other parts of the so-called cor- Brain regions controlling ticolimbic circuit, which plays a critical role in mood disorders like depression, correlat- ed most strongly in mother–daughter pairs emotion pass from than in other parent–offspring relationships. The reason remains unclear, but Yamagata mothers to daughters speculates that genetic, prenatal and postnatal environmental factors and their interactions Women are more likely to inherit brain structures may underlie the intergenerational patterns. linked to depression from their mothers than To tease out those contributors, Hoeft and her colleagues are now repeating the their fathers experiment with mothers who used donor eggs, families that used other women to brain-imaging study by neurosci- imaging can help answer critical questions carry their genetic offspring to term, and, as entists at Keio University School about maternal effects on brain develop- controls, mothers whose eggs were fertilized of Medicine begins to explain the ment and female susceptibility to devel- using assisted reproductive technology. The close association between depres- oping depression and other female-biased research, Hoeft says, “will establish a new sion in mothers and teenage daughters1. psychiatric disorders, says Bun Yamagata, and complementary paradigm for noninva- Scans revealed that the size of the brain the study’s lead author, who is now an sively studying genetic and environmental area controlling mood and emotion correlat- assistant professor at Keio University’s influences of the human brain.” Aed more between mothers and daughters Department of Neuropsychiatry. Meanwhile, Yamagata is running sim- than between mothers and sons, or between While working as a postdoctoral fellow ilar brain-scanning experiments at Keio fathers and children of either gender. at Stanford University in the United States, University with families in which the If a parent has a family member with a Yamagata collaborated with Fumiko Hoeft, parents have been clinically diagnosed with mood disorder, there is approximately a who holds a joint appointment at Keio depression. He hopes the study will offer

40 per cent chance that his or her offspring University, to study the heritability of brain further justification for early interventions .

will develop that psychiatric condition, and circuitry. They recruited 35 healthy families in female mental health. al et the risk is even greater for mothers passing from California and placed the parents Understanding how psychiatric dis- on their family’s mental illness to daughters. and their biological children in a magnetic eases persist from one generation to the As such, the insights gleaned through brain resonance imaging machine. other can help to develop novel therapeutics and prevention paradigms that target high-risk individuals such as women, says Yamagata.

Reference

1. 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 the Mother–daughter similarities in the brain are most pronounced in regions involved in controlling human corticolimbic circuitry. Journal of emotion: the amygdala (red), gyrus rectus (blue), orbitofrontal cortex (green), parahippocampus gyrus

10 Jitsugaku | May 2017 Feature article

Preserving more than words A vast collection of rare books at Keio University is attracting worldwide interest through a new online course

urrounded by floor-to-ceiling bookshelves filled with ancient 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.

© 2016 Keio University © 2016 Keio That was my first step into the world of bibliography,” he says. Housing 175,000 works, mainly Japanese classical texts, as S The single extant scroll-format copy of Shinsen Tsukuba shū (first volume) housed at well as pieces from China, Korea, and Vietnam, and a collection Keio University’s Shido Bunko (Institute of Oriental Classics) of rare Western books, Shido Bunko’s library was amassed largely through items donated to the institute after World War II. texts in the form of sutras came to Japan from China and The world gained digital access to its collection through an Korea during the Nara period (710–794). online course guided by Sasaki. The course, Japanese Culture “Among all formats, including the ‘multi-section-binding’ Through Rare Books, launched in collaboration with the UK’s and ‘pouch-binding’ styles used for classical texts, my research social learning platform FutureLearn in July 2016, explored the has shown that the scroll format symbolises the highest rank, role of books in Japan’s culture and history. meaning that the scroll is at the top of the cultural hierarchy in terms of both the content and readership,” says Sasaki. Books as time capsules The “multi-section-binding” format (tetsuyōsō) refers to “Books are not just a way of preserving words and images,” single-folded pages sewn together along the fold and the says Sasaki. “They are time capsules; their binding method, “pouch-binding” style (fukuro-toji) refers to double-leaved format and cover style can tell us a great deal about author- pages forming a pouch as they are bound along the spine. ship and where they were made. We can learn about the The scroll format subsequently influenced the placement of cultural background, paper-making methods, fashions and titles on bound books. For example, a vertical title on the left- technologies that led to their creation.” hand side of a book cover often indicates that the book orig- “For example, we have the single extant scroll-format copy inated as a scroll, while a title placed in the center suggests of the first volume of Shinsen Tsukuba shū, written in the that the book is a work of fiction, not derived from a scroll. 15th century by imperial decree,” says Sasaki of the anthology Japanese literature and the art of bookmaking flourished of Japanese collaborative poetry known as renga (see image). in the Heian (794–1185) and medieval (1185–1600) pe- “Through research, I have found that the copyist of this work riods; this synergy of creativity is reflected in the diverse was not the master poet Sōboku as previously thought, but bookbinding techniques developed during this time and, Anegakōji Mototsuna, a feudal lord who may have drafted the for example, in the innovative use of minerals, such as mica preliminary copy of the text.” powder to create luminous patterns. Sasaki’s detective work to unravel such mysteries using tech- “Today, we can see the influence of these features in niques such as handwriting analysis and comparative studies of Japanese stationery, which is famed for its intricate designs,” textual lines is detailed in his book, The Bibliographical Study says Sasaki. “Manga and anime also have their roots in these of Classical Japanese Texts, published in Japanese in June 2016. classical Japanese texts.” The book contains examples taken from popular works such as Sasaki observes that there is growing interest in Japanese The Tale of Genji, The Tale of the Heike and The Pillow Book. rare books overseas. “We’ve had tremendous interest in our online course from around the world,” he says. “I hope the Opening up to the world course will deepen people’s knowledge of Japanese culture Unfurling a scroll dating back to 740 — the oldest known in and history,” says Sasaki. “Books are an excellent gateway to the university’s collection — Sasaki explains that Buddhist understanding Japan.”

research-highlights.keio.ac.jp 11 Feature articles

Mind over machine Chronic stroke sufferers boost the brain’s ability to heal itself through brain–machine interfaces

Chronic stroke patients can regain lost movement by training their brain to control a robotic exoskeleton.

12 Jitsugaku | May 2017 Feature articles

unichi Ushiba works in the science-fictional world of brain– overseas collaborators — including neuroscientists Surjo Soekadar machine interfaces, but he doesn’t like the term ‘cyborg’. from Germany and Hartwig Siebner from Denmark — to develop “ ‘Cyborg’ sounds like ‘technology’s invasion of human the next generation of brain–machine interfaces. The internation- beings’,” says Ushiba, from Keio University’s Laboratory al partnership has since seen one of Ushiba’s master’s students, for Rehabilitation Neuroscience. He’s more interested in how Shuka Shibusawa, working in Soekadar’s lab to continue the technology can be used in a more benign way to promote the collaboration. brain’s self-healing abilities in people whose neurological function The team conducted an experiment in which they used real-time Jhas been compromised by neuromuscular disease. The results brain imaging to see what happened when stroke patients tried to have been impressive; by connecting stroke patients’ brains to move a paralysed finger. computers, Ushiba is helping damaged neural regions come alive. After one hour of finger extension training, every day, for a month, Ushiba and colleagues observed increased brain activity in the dam- Wiring up aged parts of the brain that normally would control this movement3. An engineer by training, Ushiba became interested in the interface The results were testament to the brain’s remarkable plasticity between engineering and neurology in 2009 when a student came — its ability to ‘rewire’ around damage — and showed how a to him and suggested the idea of a brain–machine interface that brain–machine interface might facilitate this process. used noninvasive electroencephalogram (EEG) technology, involv- ing electrodes on the surface of the skin. This approach was first Stroke therapy developed in the 1980s to help people with ‘locked-in’ syndrome But, the researchers aren’t stopping there. If the neural activity to communicate. associated with imagining a physical movement can be recorded, Having studied rehabilitation, Ushiba realized there was a lack of can it also be used to activate that movement? treatment options for people whose disease had affected their ability He and his collaborators are now working to use the EEG-based to control their arms, and who therefore couldn’t manually interact brain–machine interface in humans to control a robotic exoskele- with a machine or computer. ton. Animal studies by other research groups already suggest that “I realized that helping the damaged brain to rewire itself using the approach not only enables robotic-assisted movement, but the brain–machine interfaces could become an essential and unique movement feeds back into the brain to further promote functional therapy to such patients,” Ushiba says. He thought that using the reorganisation around damaged areas. brain to direct actions on a computer or machine might stimulate “We believe that our brain–machine interfaces would be far rewiring and healing in the damaged parts of the brain that nor- more effective compared to simple robotic movement support,” mally control those same physical movements. Ushiba says, referring to passive exoskeleton-style robotics that So he and his research team began working with people with simply translate physical movement to robotic movement. muscular dystrophy; a group of inherited diseases characterised by The team have already published numerous case studies of gradual muscle wastage. The aim was to see if they could control a brain–machine interface work in people suffering chronic stroke, machine with the power of their mind. and found that around 70 per cent of patients show improvements in lost motor function. It offers hope to people for whom there Moving thoughts currently are few prospects for improvement. The first question was whether brainwaves recorded through the skin would be an accurate measure of activity in the parts of References

the brain associated with muscle control. Ushiba and his team 1. Takemi, M., Masakado, Y., Liu, M. & Ushiba, J. Sensorimotor event-re- conducted experiments in which they used EEG to look at brain lated desynchronization represents the excitability of human spinal and spinal cord activity in healthy volunteers who were asked to motoneurons. Neuroscience 297, 58–67 (2015). imagine moving their wrist1, 2. This showed that just imagining the 2. Takemi, M., Masakado, Y., Liu, M. & Ushiba, J. Event-related desynchro- movement of a limb was enough to excite the neurons in the brain nization reflects downregulation of intracortical inhibition in human primary motor cortex. Journal of Neurophysiology 110, 1158–1166 (2013). and spinal cord that would normally trigger this movement. The next step was to see what effect this approach might have 3. Ono, T., Tomita, Y., Inose, M., Ota, T., Kimura, A., Liu, M. & Ushiba, J. Multimodal sensory feedback associated with motor attempts alters in people paralysed by stroke. By this time, Ushiba’s work was BOLD responses to paralyzed hand movement in chronic stroke patients. Brain Topography 28, 340–351 (2015).

research-highlights.keio.ac.jp 13 Feature articles

In March 2011, a devastating 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 of an earthquake-savvy public Understanding how people perceive risk during natural disasters could save lives 14 Jitsugaku | May 2017 Feature article

veryone in Japan knows what to do when the Earth begins to Tsunami alert! When would you evacuate?

shake — the small island-nation sits above one of the world’s 10m most seismically active regions. While this familiarity with earthquakes 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 92% 85% disaster, more than 14,000 from drowning. 5m Satoko Oki, a geophysicist at Keio University’s Faculty of E 90% 73% Environment and Information Studies, has studied the Japanese 3m public’s response to the earthquake and come up with some unex- 71% 46% pected observations about how the brain processes risk. Her research 1m will help to improve communication and education in an earth- Before Tohoku Earthquake 11 March 2011 After quake-savvy community. ? 7% Don’t know when they would evacuate ? 7% Don’t know when they would evacuate © 2016 Satoko Oki, Keio University Oki, Keio © 2016 Satoko

Paradox of perception Japanese perceived waves under 10 meters high to be less risky after Oki was a teenager when in 1995 a devastating earthquake hit experiencing the magnitude-9 earthquake and 40-meter high tsunami that hit Tohoku on 11 March 2011. Kobe city, killing more than 6,000 people. She spent hours glued to the television news coverage of the disaster unfolding. It was then Unfortunately, people love reporting record-breaking events she decided to become a seismologist, but not just any seismolo- — from the fastest 100-meter sprint to the largest collection of gist. Oki wanted to engage the public in her work. gnomes. Oki cautions that for natural disasters, to somewhat mitigate In 1981, Japan introduced more stringent standards for new this anchoring effect, records should be accompanied with a baseline, buildings to be constructed to withstand ground motion of mag- such as a 1-meter-high tsunami — “which is still dangerous.” nitude 7 or higher. People living in coastal areas were also advised to evacuate to higher ground to escape an impending tsunami. “We Finite pool of worry don’t know when the ‘big one’ will occur, but we already know The Tohoku earthquake also caused one of the world’s worst nuclear how to survive,” says Oki. accidents at the Fukushima Daiichi power plant. Oki and Nakayachi Oki wanted to know what height of tsunami the general public went on to investigate whether the high level of public anxiety thought presented a serious threat. In 2010, about a year before the around earthquakes and radioactive contamination following Tohoku quake, she conducted a survey of more than 2,000 people, Tohoku affected the way people felt about other unrelated hazards2. providing answer choices from ‘don’t know’ to ‘more than 10 centi- They compared survey results from 2008 and 2012 for changes in meters’ to ‘more than 5 meters’. public anxiety about 51 hazards ranging from nanotechnology to To help explain the results, Oki sought the advice of international conflict. Kazuya Nakayachi, a psychology researcher at Doshisha University Overall anxiety about these hazards decreased significantly, in in Kyoto. Before they had an opportunity to analyze the data, how- a manner not commensurate with the larger loss of life associated ever, the magnitude 9 earthquake hit. with them. The lowered risk perception for other hazards in the About a month after the quake, Oki and Nakayachi surveyed wake of a severe natural disaster could dilute harm-reduction 1,036 participants and compared their answers to those of 733 measures, warn Oki and Nakayachi. respondents in the same prefectures from the previous survey. Oki In April 2016 Japan was hit with another powerful series of shakes assumed that the participants, out of fear of reliving the harrowing in southern Kumamoto. Oki is keeping a close eye on the public experience, would be ready to evacuate for smaller tsunamis. communication. “It is not enough to conduct research into earth- Nakayachi instead, “assumed that their risk perception would quake science, we also need to develop our communication skills to decrease,” recalls Oki. The survey data validated Nakayachi’s hy- improve public awareness and promote preparation,” she says. pothesis (see image), which was based on a psychological model known as the anchoring effect1. References The anchoring effect describes how people judge data in relation 1. Oki, S & Nakayachi, K. Paradoxical effects of the record-high tsunamis to a previously known value, and either inflate or diminish it. In the caused by the 2011 Tohoku earthquake on public judgments of danger. International Journal of Disaster Risk Reduction 2, 37–45 (2012). case of the tsunami survivors, having just witnessed a 40-meter-high 2. Nakayachi, K., Yokoyama, H. M. & Oki, S. Public anxiety after the 2011 wave, many believed a 3-meter-high wave, which is still capable of Tohoku earthquake: Fluctuations in hazard perception after catastro-

research-highlights.keio.ac.jp 15 Feature articles

Western roots in Japanese manga Delving into Japanese subcultures reveals surprising literary links with works of Western literature

t the closing ceremony of the Rio Olympics, Prime hugely popular Shojo manga series published in the 1970s,” Minister Shinzo Abe famously dressed up as Super says Ogushi, explaining that the novelist Keiko Nagita wrote Mario. He was teleported to the stage at the end of the text, which was illustrated by the renowned manga artist an animated trailer promoting the Tokyo Olympics Yumiko Igarashi. “Both of these women later revealed that they in 2020, which featured Hello Kitty, Pac-Man, and Doraemon were conscious of describing Western settings held to be ‘other- — some of Japan’s best-known exports from its manga (comic worldly’ at the time. So although young readers might not have books), anime (animations), and gaming culture. The global pop- caught on, Nagita and Igarashi knowingly recreated the story of Aularity of these characters forms a major part of the government’s Daddy-Long-Legs by the American writer, Jean Webster (1876– Cool Japan initiative designed to boost the creative industries. 1916), and alluded to the world of Lucy Maud Montgomery Beneath the variously kawaii (cute) or deadpan masks of (1874–1942), the Canadian author of Anne of Green Gables.” these characters there are long histories, and in some cases, Ogushi points out further parallels between the March sisters unexamined literary connections, according to Hisayo Ogushi, in Little Women and characters in Chieko Hara’s Three Swings, professor of literature at Keio University’s Faculty of Letters. as well as the more recent influences of Western films on manga “The influence of Western literature, particularly works by creations by Akimi Yoshida (California Story), Taeko Watanabe 19th century women writers, on Shojo manga, or manga for (Family), and Minako Narita (Alien Street and Cipher). girls, is particularly striking,” she says. In many cases, the “re-imaginings” of Western settings can be interpreted as homages or pastiches, says Ogushi. “Banana Other worlds Fish by Akimi Yoshida is another example of a respectful riff on Ogushi started reading manga at a young age, and soon began the original, A Perfect Day for Bananafish by J. D. Salinger.” burrowing into translated works of Western literature. — sto- ries by Edgar Allan Poe, Gaston Leroux, Arthur Conan Doyle, Many fictional lives and other classics such as Louisa May Alcott’s Little Women. In addition to these individual influences cited by manga art- “Those books opened the door for me to ‘the other world’,” ists, Ogushi contends that Shojo manga as a genre has a longer, says Ogushi. “I love both manga and literature, though I never more tangled history with Western literature. She argues that thought I’d combine the two genres in my research.” the roots of Shojo manga can be traced back to Shojo novels While Ogushi was writing Hybrid Romance, her study of of the 1910s and 1920s, a portion of which were based on cultural identity and women’s roles in American literature abridged versions of Western domestic fiction, or narrative published in Japanese in 2002, she “began incubating ideas literature, largely written by and for women in the 19th century. about gender, race, and genre studies,” which would become Works by Harriet Elizabeth Beecher Stowe, Susan Warner, a “launchpad for exploring the links between manga and Lydia Maria Child, and others were highly influential during Western influences in greater depth.” this era, selling more books than male Western authors. Ogushi “Take the historical romance Candy Candy, for instance — a continues to conduct comparative literature analyses to build a more 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 the education 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 manga or subcultures were their first step to getting to know Japan,” she says. “As I always tell my students: you only live once, but

16 Jitsugaku | May 2017 Inside Keio

A global research hub Keio University Global Research Institute launches an international mission to help society through interdisciplinary research

eio University Global Research As part of the initiative, Keio is committed The KGRI represents the next stage of this Institute (KGRI) was founded in to enhancing the sustainability of global strategy, providing platforms to promote, November 2016 to address the society through jitsugaku (science), as a nat- foster, and support current research projects. challenges facing Japan and the rest ural continuation of the philosophy of Keio’s “The proliferation of efforts has made us of the world in an era of political, social, and founder, Yukichi Fukuzawa. Keio University aware of the need for a central program to environmental transformation. president, Atsushi Seike, identified three key integrate the various programs and maximize Established in a year of significant global areas of research on which it would focus: output. KGRI is our response to these needs. Kchange, the institute aims to contribute to longevity, security, and creativity. I hope it will contribute to providing effective the modern world through interdisciplin- These comprehensive research initiatives solutions to the issues encountered by society.” ary collaborations between Keio University are pertinent to the current situation in and global partners in industry, academia, which Japan finds itself in the 21st century. Giant steps and government. With a rapidly aging population and declin- KGRI will have three major missions: actu- By encouraging researchers from diverse ing birthrate, longevity is at the forefront alizing research through funding, making disciplines and cultures to share their work of Japan’s agenda. The nuclear accident in research more visible through effective and perspectives, the center will foster new Fukushima is evidence of the danger of in- publicity, and exploring new forms of inter- connections between people and link their creasing risks to environmental, economic, disciplinary research. ideas. The institute represents an accelera- and regional security. And Japan faces a Keigo Komamura, Keio University tion of Keio University’s globalization and rising demand for innovation to maintain vice-president and director of KGRI, ex- will further its already valuable contribu- global competitiveness. plains that the institute will have a loose, tions to society. “The Top Global University Project has decentralized structure that will promote been at the center of Keio University’s free-flowing exchanges between researchers. Learning from Japan strategy over the last three years,” says It will be an open platform, going beyond Keio, Japan’s oldest private institution of Jiro Kokuryo, vice-president for international traditional working styles to connect higher learning, was among 13 top-tier affairs. Among the many changes it has academia with business, government, and academic institutions chosen in 2014 by the introduced have been institutional reforms to international initiatives. Japanese government to be part of the Top extend Keio’s reach through cross-appoint- “The institute is destined to be a growing Global University Project, a funding program ments, assignments of international staff in and unfinished project and that’s why it has designed to enhance the international com- tenure-track positions, and expansion of the no fixed form.” petitiveness of Japan’s leading schools. English-language syllabus. Komamura particularly welcomes “idle talk” between researchers because it can lead 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 research that KGRI will encompass. “Economic integration and uncertainty define the world,” said Huang Jing, director of the Centre on Asia and Globalisation at the Lee Kuan Yew School of Public Policy, National University of Singapore, who “I hope KGRI will become a trigger for change,” said Keigo Komamura, Keio University vice-president and © 2017 Keio University © 2017 Keio described a changing economic, social, and director of the new center, Keio University Global Research Institute, at an inaugural symposium.

www.keio.ac.jp 17 Inside Keio

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 from different perspectives and we have different opinions about the same truth. That’s why we need communication and thorough international, global research projects to help us to understand each other better. We have to build networks of researchers on platforms University © 2017 Keio provided by institutions such as KGRI.” “We are focused on people who share the same vision as us but who come from a different culture,” said The need for international dialogue on Thibaut David of Grenoble Innovation for Advanced New Technologies. “The goal is really to be stronger.” research was echoed by Thibaut David of different culture,” David said. “The goal is and clinicians together to better meet Grenoble Innovation for Advanced New really to be stronger.” the needs of elderly patients. The center Technologies (GIANT), one of the principal collects and analyses data from multiple research centers in France. David, a sci- Keio’s three global initiatives surveys of centenarians to develop preven- entific program coordinator at the French The world has much to learn from how tative care measures. Alternative Energies and Atomic Energy Japan deals with the global challenges being In the area of security, Keio covers a Commission (CEA), gave a briefing about tackled by KGRI’s three research initiatives. broad range of domestic and international GIANT, a center in the French Alps that Considering aged-studies, more than a quar- issues including military tensions, climate groups roughly 30,000 people from academia, ter of Japan’s population is 65 years or older change, and natural disasters. These include industry, and research labs. and other countries are quickly joining the an analysis of the mass media’s coverage of David emphasized the relationship be- ‘super-aged’ bandwagon. Finland, Germany, Japan in the aftermath of the Fukushima tween Keio University, CEA and the French Italy, Bulgaria, Portugal, Sweden, and Greece nuclear disaster, particularly its discussion of National Center for Scientific Research, all have an elderly population of 20% or high- risk related to nuclear power technologies. which signed a five-year collaboration er, lifting the global average of people in this “I believe that this security initiative project agreement in 2014. Keio and GIANT have bracket to 8%. will contribute not only to academic re- engaged in student and researcher exchanges “Aging is not a unique issue to Japan search, but also to policy and practice,” says in such fields as microfluidics, the Internet — it’s an issue for the entire world,” says law professor Yutaka Oishi, leader of the of Things, cyber-physical systems, and Hideyuki Okano, professor and dean of the security initiative. nanotechnologies. Keio University School of Medicine, who The creativity initiative, led by Tojiro “We are focused on people who share leads KGRI’s longevity initiative. “We aim for Aoyama, includes projects such as multilin- the same vision as us but who come from a initiatives to realize a society where people gual search tools for social scientists that can live better and longer lives.” be used to access data accumulated in various Longevity In one example, Keio researchers are gain- countries and languages, as well as vaccine Initiative to realize a society where ing ground in tackling the growing incidence adjuvants that use near-infrared laser light to people live better, longer lives of dementia in Japan. The social cost of the prompt a more robust immune response. disease has been estimated at ¥14.5 trillion Another project in the realm of creativity is per year, or 3% of GDP, a ratio that is expect- the adaptation of brain-scanning technology Integrative ed to increase as the population ages. Early to measure electrical activity in the brain Approaches diagnosis and intervention can reduce those associated with mental states like enjoyment, figures, and Keio researchers are exploring interest, stress, concentration, and calm. The the role of nicotinamide adenine dinucleotide Kansei Analyzer has been commercialized for (NAD), a naturally produced anti-aging mol- testing people’s responses to new products. Security Creativity ecule. A precursor substance has been used By fostering this kind of interdisciplinary Initiative to assure Initiative to bolster a safer, more innovation in in a clinical study to examine its safety and research, KGRI will bind the many threads sustainable society education and research effectiveness in humans. of investigation at Keio into a whole, says Another important part of Keio’s focus Komamura. “KGRI will be a kind of tapestry,” Keio University President Atsushi Seike introduced on aging is the Center for Supercentenarian he says, “into which we will interweave many a bold global research initiative to focus on the Medical Research, which brings researchers research projects.” University © 2017 Keio three areas of longevity, security, and creativity.

18 Jitsugaku | May 2017 Research highlights

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

Making light of a dark matter The see-sawing behavior of dark-matter particles might have jolted experiments at the Large Hadron Collider

nexpected signals in experiments subatomic particles known as neutrinos, but by scanning the microwave spectrum at the Large Hadron Collider recent cosmic observations disproved their for weak resonance signals, and look- (LHC) could have been caused hypothesis. Instead, researchers are now ing for the creation of a new photon by heavy and light versions of focusing on finding the axion, a theoretical — a key indicator that an axion was a potential dark-matter particle known particle predicted 40 years ago as a way to captured. But spotting extremely miniscule as the axion, propose researchers at solve problems in the standard model of axion resonances amid a constant back- Keio University1. particle physics. ground of cosmic microwave radiation UStudies indicate that the Universe contains Similar to a photon, but with definite left over from the Big Bang requires ex- about six times more mass than can be seen mass, axions should exist in sufficient traordinary luck. with normal telescopes. Researchers once quantities to account for dark matter To better their odds, researchers are believed that this transparent or ‘dark’ in the Universe. Physicists are me- smashing light beams together in the

research-highlights.keio.ac.jp 19 Research highlights Research highlights

in the hope that scattering particles can illu- a new state to exist,” says Tetsutaro Higaki concurs with models of the Universe’s ex- minate previously inaccessible parts of the from the Department of Physics at Keio pansion, and explains why axions have been microwave spectrum. In late 2015, an LHC University. “But if it was real, we thought it so tricky to find — scientists may have been team uncovered evidence of something had to be related to dark matter.” looking in the wrong energy region. resembling an axion, but different in key Higaki and his colleagues from Japan “The heavy axions might be observed ways — the resonance signal had an excess and South Korea theorized that the excess as new excesses when the LHC can get to of energy — decaying into, not one, but two resonance belonged to a different type of higher energy scales,” notes Higaki. photons — and had a mass much heavier axion. Through a model known as a see-saw than predicted theoretically. mechanism, they predicted that heavy axions Reference “When we saw this signal, we honestly could align and generate the lightweight ax- 1. Higaki, T., Jeong, K. S., Kitajima, N. & Takahashi, F. The QCD axion from aligned had no idea whether it was genuine be- ions expected from particle physics through axions and diphoton excess. cause there weren’t any good reasons for a mixing of quantum states. This theory Physics Letters B 755, 13–16 (2016).

Kamimura, an entomologist and evolutionary biologist at Keio University. While most scholars of sexual conflicts in the Female flies have soft animal kingdom have focused on male ad- aptations, Kamimura’s study demonstrates that the evolution of female genitalia can spots for male genitalia be just as complex. The reproductive tracts of female fruit flies have Kamimura had previously found that the females of several species of fruit flies evolved to minimize damage caused by mating and other insects have copulatory wounds after mating. However, in the West African ity the poor female fruit fly. When developed an adaptation that protects fruit fly, Drosophila erecta, it seemed the she mates, the male inserts his them from this traumatic penetration1. The female genital tract had evolved to limit pointy genital organ into her re- female genitalia have evolved soft pouches these injuries, but it wasn’t clear how. productive tract, where it opens that ensure the resulting damage does not Did their soft pouches serve a protective like an anchoring device, inflicting what are interfere with reproductive success. function? Or was it the nearby hardened known as copulatory wounds. “This sexual conflict over mating is likely shields that mitigated the harmful effects However, a new study by Yoshitaka to be the major evolutionary force underly- of mating? PKamimura shows that female flies have ing the observed genital coevolution,” says To better understand the evolutionary forces shaping female genitalia, Kamimura artificially damaged each structure 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: the pouch, the shield, or the plate above the Male West African fruit ovipositor tube through which the female flies Drosophila( erecta) have pointed genitalia lays her eggs. “The pouches were espe- (pictured), which cially difficult to manipulate because they females have evolved to are colorless, tiny, and inconspicuous,” accommodate.

20 Jitsugaku | May 2017 Research highlights Research highlights

Kamimura didn’t use special equipment fewer eggs being successfully laid, and a “Developing hardened structures is not — only forceps, pins, scalpels, glass slides, harmed ovipositor plate led to lower rates always the optimal way to counter male sticky tape, and a microscope. “What I of successful insemination. Wounding harassment,” says Kamimura. needed,” he says, “was just practice, prac- the pouch had little effect on mating tice, and practice.” and egg-laying success, suggesting that Reference The flies generally survived the surgery the soft structures evolved to help direct 1. Kamimura, Y. Significance of constraints but subsequent reproductive success the spiny male appendages to locations on genital coevolution: Why do female Drosophila appear to cooperate with males depended on the site of the damage. where sex-induced injuries do not reduce by accepting harmful matings? Evolution 70, Injury to the vaginal shield resulted in female fecundity. 1674–1683 (2016).

nanometers wide, carved into a silicon surface, one by one, through a technique called electron-beam lithography. A bit of chaos benefits For the past decade, Takasumi Tanabe from Keio University and colleagues have been developing waveguides with light-driven devices strong light-confinement capabilities. One Random features in nanoscale photonic cavities can of the team’s most efficient designs sand- wiches one waveguide, compressed to 98% help miniaturize devices that control optical data of its normal spacing (W0.98), between two others at 105% spacing (W1.05). This setup esearchers usually try to avoid Computing and shuttling data with light causes photons at a specific ‘cutoff fre- structural flaws when construct- instead of electrons can hugely boost the quency’ to propagate very slowly through ing photonic devices that manip- speed and energy efficiency of signal pro- the waveguide, interacting with many ulate, amplify, and switch signals cessing. Such applications require strong silicon atoms along the way. from light beams. A team from Japan, interactions between photons and silicon To better integrate their W1.05–W0.98– however, has reported a high-speed pho- crystals to produce nonlinear effects. One W1.05 device with electronic silicon cir- tonic system that uses random fabrication way to focus light waves at atomic targets cuits, the researchers investigated whether Rerrors to localize light for more compact is with photonic waveguides: ordered it could be produced using photolithogra- optical devices1. arrays of circular dimples, hundreds of phy — a speedy way of forming nanoscale patterns using masks and etching solu- Designed tions. These experiments produced dimples with larger fabrication errors than hoped for, but also modified the character of the propagating light so it became dominated freq. ω by random scattering effects (see image). W1.05 W0.98 W1.05 Tanabe explains that when randomness Fabricated increases in a photonic structure, scattering can cause light to localize and form ‘nanocavities’ that offer high confinement. This localization could be used to make

freq. ω photonic devices much smaller, but only if the randomness can be controlled by W1.05 W0.98 W1.05 some method. To accomplish this, the researchers var- Photonic waveguides fabricated using a speedy nanoscale patterning technique known as ied the width of the W0.98 portion of their photolithography have more errors than a perfectly designed structure would, but can also tap into Reproduced, with permission, from Ref. 1 © 2016 Optical Society of America Society 1 © 2016 Optical Ref. with permission, from Reproduced, chaotic light-trapping capabilities. waveguide nanocavities until localized

research-highlights.keio.ac.jp 21 Research highlights Research highlights

resonances due to randomness appeared that modulates electro-optic signals at devices such as all-optical switches close to the cutoff frequency. The design high-speed gigahertz rates. or logic gates.” confined randomized light to the central “Our device has a much smaller foot- region of the waveguide, and yielded print than conventional modulators and Reference sufficient optical power for practical appli- is compatible with photolithographic 1. Ooka, Y., Daud, N. A. B., Tetsumoto, T. & cations. As proof, the team integrated the fabrication,” says Tanabe. “By studying Tanabe, T. Compact resonant electro-optic modulator using randomness of a photonic random photonic system into a semicon- this random behavior in more detail, crystal waveguide. Optics Express 24, ductor diode circuit to produce a device we might be able to develop different 11199 (2016).

Caledonia and, although their population is declining, are still common. Hunt had discovered that wild New Beaks of canny crows Caledonian crows made two types of tools, which they used to fish out plump longhorn beetle grubs from tree trunks. The canny adapted to tool use birds fashioned hooks from twigs and ripped Bill structure assists New Caledonian crows in using saw-toothed probes from pandanus leaves that they found in their natural habitat. twig hooks to catch grubs Izawa says: “My Japanese colleague Naomichi Ogihara suggested that the mor- n international team of research- species to grip and precisely manipulate the phology of the bill enhanced and improved ers discovered the unusual beak stick and leaf tools that it makes and uses the use of tools.” The team used computed shape of the New Caledonian to hook larvae out of wood. This is the first tomography and a statistical technique crow (Corvus moneduloides) is an time scientists have discovered evidence known as three-dimensional landmark adaptation to the smart bird’s use of tools for that the physical shape of a non-human analysis to compare and measure how the catching insect prey1. species has evolved and changed for better beak structure of the New Caledonian The beak, with its short, straight upper tool manipulation. crow differed from that of nine related Abill and upturned lower bill, enables the “If you look at the bill structure of the corvids, and a woodpecker. New Caledonian crow it is clear to the eye They found the New Caledonian crow’s that you have a strange bill structure that is upper bill was deeper and shorter than quite different from other crows,” says one of that of the related crow species, and had a the paper’s lead authors, Ei-Ichi Izawa of the straight cutting edge. The thickened lower Department of Psychology at Keio University. bill curves slightly upwards, giving the crow Izawa, a biological psychologist, had a secure grip on its tools. Izawa says: “This previously completed the first crow ‘brain shape protects the bill from being bent by atlas’ — a detailed brain analysis and map of the strong forces exerted when probing for a Japanese jungle crow (Corvus macrorhyn- food and also allows the bird a clearer view chos). He also studied the behavior of these when using tools to fish out prey.” bold, city-smart crows. Now Izawa wants to pinpoint how long In 2012, he met ecologist Gavin Hunt ago the gene expression related to the ‘strange from the University of Auckland at a upturned bill’ occurred. conference in Tokyo, and the two scientists discussed ways to analyze the distinctive Reference beak structure of the more reticent New 1. Matsui, H. et al. Adaptive bill morphology Securely holding a stick tool in its bill, a New for enhanced tool manipulation in Caledonian crow. These forest-dwelling New Caledonian crows. Scientific Reports 6, Caledonian crow fishes out larvae hidden in crows are endemic to certain islands in New 22776 (2016). © Gavin Hunt decaying wood.

22 Jitsugaku | May 2017 Research highlights Research highlights

Electrical brain stimulation can alter our appreciation of art.

Beauty is in the prefrontal cortex of the beholder Noninvasive electrical brain stimulation can alter our appreciation of art

lectrically stimulating certain plea- beauty in a series of 20th century ugliness together in a single art work,” says sure-sensing regions of the brain abstract artworks. However, the stimu- Hideaki Kawabata from Keio’s Department can change a person’s subjective lation had no effect on their experience of Psychology, who led the study. experience of beauty, researchers at of ugliness, supporting the idea that In previous studies using brain imaging Keio University have discovered1. beauty and ugliness are not opposite machines, Kawabata and his colleagues In a study of 47 female Japanese ends of the same scale but independent showed that the medial prefrontal cortex students, researchers found partici- subjective experiences. is activated when a person sees a face, Epants whose medial prefrontal cortex “This can help us understand the con- painting or even mathematical formula was inhibited with an electrical current flicting experience elicited by recent works they consider to be beautiful. “This brain

research-highlights.keio.ac.jp 23 Research highlights Research highlights

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 execute movement — suggesting it primes neural Simulation solves Venus circuits to “escape from aversive stimuli or situations, or flick away incoming aversive objects,” Kawabata says. atmosphere mystery Kawabata and his team investigated the human experience of beauty and Waves of air create cold regions around the poles of ugliness in more detail using a brain our nearest planetary neighbor stimulation technique called transcranial direct current stimulation (tDCS). tDCS involves placing electrodes at certain detailed simulation of the Venus has a noxious atmosphere of dense positions on the scalp, to either enhance Venusian atmosphere created by carbon dioxide and sulfuric acid clouds. or suppress brain activity in areas beneath a team of researchers in Japan The model showed that the cold collar was the electrode. explains, for the first time, some formed partly by the flow of air from equator Although enhancing activity in the of its mysterious features1. to poles — known as meridional circula- medial prefrontal cortex had no effect on The winds that swirl around the poles of tion — but was intensified by the thermal participants’ experience of beauty or ugli- planets are called polar vortices. On Earth, the tide, a large wave of air driven by heat from ness, suppressing activity in the brain re- Apolar vortex is colder than the air at mid-lat- the Sun. The thermal tide is most significant gion made them less likely to find abstract itudes. But Venus has a relatively warm polar at cloud level, between altitudes of 50 and paintings beautiful. vortex surrounded by a ‘cold collar’, a band 70 kilometers, where most of the solar flux The results surprised Kawabata because of cooler air at around 60 degrees latitude. on Venus is absorbed. It can generate winds they suggested that the medial prefrontal Moreover, the clouds above Venus’s south of 360 kilometers per hour at the cloud tops. cortex is not just responding to the feeling pole are thicker than in its cold collar, and the In the simulations, these atmospheric of beauty — it actually has a role in causing air there is rich in carbon monoxide. Many circulations caused a cold collar to appear the feeling. studies have observed these features, but none around 60 degrees latitude at an altitude of In contrast, stimulating or inhibiting have been able to explain how they form. 68 kilometers; its air was about -77 degrees the medial prefrontal cortex had no effect Norihiko Sugimoto of Keio University’s Celsius, some 10–20 degrees cooler than on the number of paintings participants Research and Education Center for Natural at the north pole (see image). And at an considered ugly, confirming that ugliness Sciences and colleagues have adapted a altitude of 75 kilometers, the polar air is not the opposite of beauty, but must model of Earth’s atmosphere to reproduce temperature varied from -81 to -57 degrees arise as a separate cognitive mechanism in these features on Venus and reveal the under- Celsius, up to 40 degrees warmer than at a different part of the brain. lying causes. While similar in size to Earth, 30 degrees latitude. Crucially, the simulation The team plans to test whether, by adjusting the placement of electrodes, it is possible to enhance people’s perception 192 of beauty. Kawabata also raised the ethical dimension of being able to manipulate 188 a person’s subjective experiences using brain stimulation. 204 Around the top of Venus’s cloud layer, a Reference ‘cold collar’ of air (blue)

210 . 1. Nakamura, K. & Kawabata, H. Transcranial surrounds the warmer direct current stimulation over the medial north pole (green and al et prefrontal cortex and left primary motor yellow). (Meridional cortex (mPFC-lPMC) affects subjective 216 circulation shown as red arrows; zonal circulation beauty but not ugliness. Frontiers in Hu- [K] shown as white arrows.) man Neuroscience 9, 654 (2015). © 2016 H. Ando

24 Jitsugaku | May 2017 Research highlights Research highlights

only matched observations when it featured the south pole might accumulate more model to propose future observations the effects of the thermal tide. “We’ve repro- carbon monoxide and thicker clouds for Akatsuki. duced these features for the first time in a through photochemical reactions. general circulation model,” says Sugimoto. Japan’s Venus Climate Orbiter ‘Akatsuki’ Reference “This makes it the best model of Venus’s is currently circling Venus, and the 1. Ando, H., Sugimoto, N., Takagi, M., Kashimu- atmosphere so far.” team plans to use the probe’s high-res- ra, H., Imamura, T. & Matsuda, Y. The puz- zling Venusian polar atmospheric structure The air currents and temperature pat- olution observations to improve their reproduced by a general circulation model. terns in the simulation also suggest how simulation. They also hope to use their Nature Communications 7, 10398 (2016).

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

he discovery of a bacterium almost completely degraded the plastic. “This In one sample, a consortium of microbes that feeds on polyethylene is the first PET-degrading bacterium found,” degraded the PET film and catabolized terephthalate (PET), by a team says Kenji Miyamoto, an associate professor 75 per cent of the carbon into carbon diox- of Japanese scientists, has been in the Department of Biosciences and ide. The researchers isolated the PET-eating hailed as a potential international break- Informatics at Keio University and one of bacterium from the sample. through in dealing with the major pollution the study’s authors. The team plans to build “We were very excited,” says Miyamoto. caused by the tough plastic1. on the discovery “to develop a new and Further investigations found that TThe bacterium, named Idoenella sakaien- nature-friendly system” of recycling PET. I. sakaiensis had evolved to use PET as its sis, pitted the surface of a PET film with More than 55 million tons of PET is major source of energy and carbon. holes within just 60 hours. In six weeks, it produced each year to make products Electron microscope photographs such as soda bottles, clothing and even car showed clusters of bacterial cells, resem- bumpers. First manufactured 70 years ago bling tiny grubs, connected to the PET film from petroleum products, PET’s crystalline and each other by thread-like appendages structure is difficult to break down. With (see image). only 14 per cent of plastic recycled, most of Through DNA analysis the researchers it ends up contaminating the environment, discovered that the bacterium uses two especially rivers and oceans. enzymes — PETase and MHETase — The team, led by Kohei Oda of the Kyoto to break down the plastic into its basic Institute of Technology, went in search of building blocks. a microorganism that could degrade PET In follow-up research, Miyamoto says so it could be recycled without posing an the team intends to determine the three-di- environmental burden. mensional structure of the two enzymes “in They collected 250 samples of con- order to know their reaction mechanism”. taminated soil, waste water and sludge The enzymes could potentially be manu- from a PET bottle recycling factory in factured and used to convert heat-treated Osaka. Each sample was screened for PET waste into environmentally benign microorganisms that could grow on the and useful materials. polymer. To make it easier for the bacteria 1 µm to consume the polymer, they used an Reference

amorphous form of PET film, heat treated 1. Yoshida, S. et al. A bacterium that degrades at 260 degrees Celsius to break down its and assimilates poly(ethylene terephtha- The bacterium Idoenella sakaiensis feeds on © 2016 Kohei Oda, Kyoto Institute of Technology Institute Oda, Kyoto © 2016 Kohei crystalline structure. late). Science 351, 1196–1199 (2016). plastic bottles for energy and carbon.

research-highlights.keio.ac.jp 25 Research highlights Research highlights

molecules, each of which contained two parallel ‘arms’ consisting of carbon atoms. They showed the catalyst would Chain-walking chemistry attach to the end of one arm, then walk from atom to atom until it was opposite a carbon–carbon double bond on the installs new carbon bonds other arm. It would join the two arms of Wandering catalyst activates carbon atoms to form the molecule at that point — activating the otherwise unreactive carbon it had carbon–carbon bonds walked to — to form the new carbon–carbon single bond. nspired by a reaction that has become the Department of Chemistry at Keio a mainstay of polymer synthesis, Keio University. Chain-walking chemistry was University researchers have discovered pioneered in the 1990s, when polymer “It’s not a conventional a novel way to construct small organic chemists discovered a palladium catalyst way to form a carbon– molecules. Their method uses a ‘chain-walk- that would attach to the end of a chain of carbon bond.” ing’ catalyst to activate otherwise unreactive carbon atoms, then ‘walk’ along the poly- parts of simple molecules, catalyzing the mer chain before adding the next building Iformation of new carbon–carbon bonds1. block to the chain. “It is not a convention- Using their reaction, the team has been The conventional formation of new al way to form a carbon–carbon bond,” able to synthesize a structure called pros- carbon–carbon bonds — which turn simple says Kochi. tane, the underlying carbon framework of starting molecules into complex structures, Polymer chemists use bulky substituents a family of natural products. They are now such as therapeutic drugs — is to first install around the palladium atom to slow a investigating the reaction to identify which a chemical ‘handle’. For example, a chlorine competing reaction, alkene exchange, in molecules are particularly suited to chain atom might be used to pre-activate a partic- which the palladium drops off the growing walking. “The chemistry is still in its initial ular carbon atom toward bond formation. polymer chain. “We felt that if we just phase,” says Kochi. Adding and manipulating these handles can removed the bulky substituent, we could make the synthesis of complex molecules switch the rates,” says Kochi, favoring Reference slow and inefficient, so there is much interest alkene exchange over polymerization — 1. Hamasaki, T., Aoyama, Y., Kawasaki, J., in finding ways to directly install new bonds the desired pathway when making small Kakiuchi, F. & Kochi, T. Chain walking as a strategy for carbon–carbon bond forma- at unreactive carbon atoms. molecules rather than polymers. tion at unreactive sites in organic synthesis: Catalytic cycloisomerization of various Chain walking could be just such a The researchers tested their slimmed- 1,n-dienes. Journal of the American Chemical reaction, realized Takuya Kochi from down catalyst on a variety of starting Society 137, 16163 (2015).

Like a tightrope walker on a high wire, a chain-walking catalyst traverses a chain of carbon atoms before activating the middle of the chain toward bond formation. © Giancarlo Banfi/EyeEm/Getty © Giancarlo

26 Jitsugaku | May 2017 Research highlights Research highlights

New peptide-based diagnostics could help diagnose influenza.

Catching up with the influenza virus New diagnostic tests could quickly reveal a flu infection in its early stages

wo new detection methods for the A team led by Toshinori Sato from Keio cell infection in the lab. In their most recent influenza virus could help prevent University’s Department of Biosciences and work, they took the same short peptide the next global pandemic. Informatics exploited the fact that influenza chain and developed two diagnostic assays Seasonal influenza is responsible invades the human respiratory tract and for revealing the presence of influenza in a for up to 500,000 deaths around the world, bloodstream by focusing on a sugar molecule throat swab or other form of patient sample. every year, and pandemic strains of the virus found on the surface of our cells called sialic For the first test1, Sato’s team created a have periodically killed many more. Current acid. Through a special kind of binding membrane that combined the peptide with Tmethods to diagnose and track flu outbreaks between sialic acid and a flu protein called a fatty molecule called a phospholipid. This are cumbersome, expensive or both. hemagglutinin, viral particles can enter the preparation was fixed to a surface where it A simpler technique for identifying pa- human body, replicate and make us sick. selectively attached to hemagglutinin when tients in the early stages of infection could Sato and his colleagues previously incubated with a flu-containing sample. help get anti-influenza therapies faster to identified a short chain of amino acids that Once all the flu particles had been collected, those who need them, and so limit the mimics sialic acid, which they used as a de- the researchers could then count them using

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The other test2 also started with the sial- diagnostics offer several advantages over References ic-acid-mimic peptide, but in this case the existing ones in terms of manufacturing, 1. Matsubara, T., Shibata, R. & Sato, T. Binding researchers attached it to a highly sensitive storage and engineering. But, perhaps the of hemagglutinin and influenza virus to a electrode made of a diamond enhanced with biggest benefit comes from the peptides peptide-conjugated lipid membrane. Frontiers in Microbiology 7, 468 (2016). the mineral boron. Any time a flu particle at- mimicking a part of the flu virus essential 2. Matsubara, T., Ujie, M., Yamamoto, T., tached to the peptide, Sato and his colleagues for its survival. So, whereas other tests need Akahori, M., Einaga, Y. & Sato, T. could then detect its presence though elec- to be designed anew whenever a novel flu Highly sensitive detection of trochemical changes in the diamond sensor, strain arises, according to Sato, “we expect influenzavirus by boron-doped diamond electrode terminated with sialic without the need for additional assays. that our strategy will be applicable to the acid-mimic peptide. Proceedings of By avoiding the use of complex biological detection of new influenza viruses that will the National Academy of Sciences USA 113, molecules, Sato says that his peptide-based appear in the near future.” 8981–8984 (2016).

temperature. Below the polymer’s critical temperature the side-chains fluoresce brightly. But as soon as the polymer collaps- Dimming the lights on es, the fluorescence is switched off1. This responsive behavior remains active inside living cells, Kanazawa showed (see cancer cells image). The researchers attached a non-polar Fluorescent probes selectively taken up by tumorous lipid additive called DOPE to the polymer to help draw it through the non-polar cell tissue could be used for early disease detection membrane and into the living cell. They were surprised to find just how effective the strate- by Hideko Kanazawa and her team at Keio gy proved. “DOPE caused a strong preference University’s Department of Pharmacy, is a for cellular uptake, allowing the polymers to molecule called Poly(N-isopropylacrylamide), be rapidly internalized without the require- or PNIPAAm. This polymer is well known for ment for a delivery system,” Kanazawa says. significantly changing its structure in water The team is already working on new above a critical temperature. versions of the fluorescent polymer with At low temperatures, a strong interaction enhanced functionality, Kanazawa adds. For Stimuli-responsive fluorescent polymers light up between water molecules and the polar ni- example, it has developed versions of the to reveal the temperature inside cells. trogen-rich amido groups in the PNIPAAm polymer that, under the mildly acidic pH stimuli-responsive fluorescentpolymer means the polymer spreads out around diseased cells, switch from a polar to a polymer that is readily taken into an expanded coil formation. But, non-polar state. This polarity switch dramat- up by living cells could become warming the solution disrupts the water– ically boosts the rate at which the fluorescent a useful diagnostic tool for polymer interaction, until the critical tem- probe is taken up by diseased cells compared identifying diseased cells, Keio University perature of 32℃ is reached and the polymer to healthy ones. “This polymer may offer the scientists suggest. The research team devel- suddenly contracts, forming a compact potential for development as a diagnosis tool oped fluorescent polymers whose light output globular structure. for early tumor detection,” Kanazawa says. Adims in response to warmer temperatures Kanazawa and her team created four new “Furthermore, it could be used as a tumor-se- and more acidic pH — conditions typical of forms of PNIPAAm polymer that incor- lective intracellular drug delivery system.” pathological tissue in patients with diseases porate different fluorescent side-chains. ranging from cancer to Alzheimer’s disease. Previous work showed these fluorescent Reference The polymers’ responsive properties groups are pH-responsive, dimming under 1. Yamada, A., Hiruta, Y., Wang, J., Ayano, E. & could eventually be used to selectively deliv- acidic conditions. But the team showed Kanazawa, K. Design of environmentally responsive fluorescent polymer probes for er drugs to diseased cells. that, once combined with the PNIPAAm cellular imaging. Biomacromolecules 16,

28 Jitsugaku | May 2017 The Keio Medical Science Prize

objective The Keio Medical Science Prize is an international prize that recongizes the outstanding and creative achievements of researchers in the fields of medicine and life sciences, in particular those contributing to scientific developments in medicine. It aims to promote worldwide advances in these fields to encourage The 2016 Keio Medical the expansion of research networks throughout the world and to contribute to Science Prize Laureates the well-being of humankind.

I am greatly honored to receive prize “The Keio Medical Science Prize. For Laureates receive a certificate of merit, a medal, and a monetary award. The more than 30 years award ceremony and commemorative lectures are held at Keio University. I have worked on the retrieval of DNA from long dead nomination and selection organisms. It has now Nominees must have made an outstanding contribution in the fields of medicine become possible to go back in time and study the genomes of extinct or life sciences closely related to medicine, and must be currently active in their hominins, past human populations, ancient field of research. pathogens and extinct animals. Many talent- “ ed collaborators both in my lab and elsewhere have helped make this dream come true. I 1. An invitation is sent out to academics and researchers all over the world thank them all. each year, inviting them to nominate a candidate for the Prize. Svante Pääbo 2. The Keio Medical Science Prize Selection Committee reviews the nominations, selects laureates through a rigorous review process, and submits a It is my great recommendation to the Board. honor to receive The 3. The Board makes the final decision and the President of Keio University Keio Medical Science “ formally announces the laureate(s). Prize 2016, which has been awarded to many excellent medical scientists. I yearly schedule (Subject to change) encountered the • Call for nominations: late January PD-1 molecule and • Deadline for nominations: early March found that PD-1 • Prize announcement: mid-September serves as a brake in the immune system.

Based on the findings in animal models, the • Award ceremony: November or December at Keio University

PD-1 blockade cancer therapy became availa- ble 22 years after its discovery. I deeply appre- “ ciate the active investment in basic research in Japan about 20 years ago, which made this innovative application possible. www.ms-fund.keio.ac.jp/prize Tasuku Honjo