EARLY SCHIZOPHRENIA DETECTION Biomarker Found in Hair

SPRING 2020

SHOWCASING THE BEST OF JAPAN’S PREMIER RESEARCH ORGANIZATION • www.riken.jp/en

EARLY SCHIZOPHRENIA DETECTION Biomarker found in hair

WHAT'S THE MATTER? LIVING UNTIL 110 READING THE MIND OF AI Possible link between Abundance of immune Cancer prognosis two cosmic mysteries cell linked to longevity method revealed ▲ Web of dark matter A supercomputer simulation showing the distribution of dark matter in the local universe. RIKEN astrophysicists have performed the first laboratory experiments to see whether the interaction between dark matter and antimatter differs from that between dark matter and normal matter. If such a difference exists, it could explain two cosmological mysteries: why there is so little antimatter in the Universe and what is the true nature of dark matter (see page 18).

ADVISORY BOARD

RIKEN, Japan’s flagship publication is a selection For further information on the BIOLOGY ARTIFICIAL INTELLIGENCE research institute, conducts of the articles published research in this publication or • Kuniya Abe (BRC) • Hiroshi Nakagawa (AIP) basic and applied research in by RIKEN at: https://www. to arrange an interview with a • Makoto Hayashi (CSRS) • Satoshi Sekine (AIP) a wide range of fields riken.jp/en/news_pubs/ researcher, please contact: • Shigeo Hayashi (BDR) including physics, chemistry, research_news/ RIKEN International • Joshua Johansen (CBS) PHYSICS medical science, biology Please visit the website for Affairs Division • Atsuo Ogura (BRC) • Akira Furusaki (CEMS) and engineering. recent updates and related 2-1, Hirosawa, Wako, • Yasushi Okada (BDR) • Hiroaki Minamide (RAP) articles. Articles showcase Saitama, 351-0198, Japan • Hitoshi Okamoto (CBS) • Yasuo Nabekawa (RAP) Initially established RIKEN’s groundbreaking Tel: +81 48 462 1225 • Kensaku Sakamoto (BDR) • Shigehiro Nagataki (CPR) as a private research results and are written for a Fax: +81 48 463 3687 • Kazuhiro Sakurada (MIH) • Masaki Oura (RSC) foundation in Tokyo in 1917, non-specialist audience. [email protected] • Harukazu Suzuki (IMS) • Toru Tamagawa (RNC) RIKEN became a national • Toshitada Takemori (IMS) • Tomohiro Uesaka (RNC) research and development RIKEN Research is published ISSN 1883-3519 • Makoto Taketani (RCH) • Yasunori Yamazaki (CPR) institute in 2015. by RIKEN in collaboration www.riken.jp/en • Todd Taylor (IMS) with Nature Research • Koji Yonekura (RSC) COMPUTER / RIKEN Research is an online Custom Media, a part COMPUTATIONAL SCIENCE and print publication that of Springer Nature. CHEMISTRY • Ryutaro Himeno (ISC) highlights the best research • Hideki Abe (CSRS) • Toshiaki Iitaka (ISC) published by RIKEN. This • Keisuke Tajima (CEMS) • Takahito Nakajima (R-CCS)

• Katsunori Tanaka (CPR) • Hirofumi Tomita (R-CCS) © VOLKER SPRINGEL / MAX PLANCK INSTITUTE FOR ASTROPHYSICS / SCIENCE PHOTO LIBRARY TABLE OF CONTENTS

Editorial Research 3 Data sharing, 10 highlights commercial strategies and performance COVER STORY

10 Hair follicles could reveal People sign of schizophrenia p.13 11 Modeling a sense 4 Observing the of responsibility cosmic web 12 Brain waves vary Hideki Umehata with age of memory Special Postdoctoral Researcher 13 Thinking, fast and slow

Computer-assisted disaster recovery 14 Roots of weed’s parasitism run deep Bahareh Kalantar Postdoctoral 15 First responder Researcher to light revealed

16 Long-distance light sources

17 A vital gene in the mating game p.14

6 Briefs Sixteen RIKEN researchers in the top 1% of their fields by citations

New supercomputer dedicated to drug discovery

RIKEN Advisory Council 2019

Accelerating routes to innovation

Fugaku prototype is world’s greenest supercomputer

First anniversary of RIKEN’s Europe Office

Front row at periodic table event

SPRING 2020 1 TABLE OF CONTENTS

Research 18 highlights Perspectives 26 Building a roadmap to real world outcomes: With the launch of a new company, the deepening integration of industry COVER STORY and RIKEN researchers is poised to create a suite of new patent- 18 Killing two cosmic winning products, says Hidetoshi Kotera. mysteries with one hypothetical particle

19 Kondo cloud spotted for the first time

20 A new spin on spider webs

21 Detecting the metabolites of a single cell

22 Wearing your heart monitor on your sleeve

23 Coffee habit could be genetically brewed Feature COVER STORY New clues in AI cancer prognoses: Understanding artificial 24 Shining a new light 29 intelligence’s reasoning has taken it from merely a cancer on ethylene prognosis tool to a means to understand why cancers reoccur.

COVER STORY 25 The killer cells for a ripe old age

p.21 Infographic 32 Cream of the crop: The RIKEN Center for Sustainable Resource Science (CSRS) is led by a number of researchers listed among 2019’s top 1% in plant and animal science by citations.

p.23

2 RIKEN RESEARCH EDITORIAL

Data sharing, commercial strategies and performance

Hiroshi Matsumoto President, RIKEN

ast year was an important one for us, as that are common to research institutes around the we went through our process of evalu- world, such as making sure that we have the best ation by external panels, culminating performance indicators available, that we manage in the meeting of the RIKEN Advisory and share our data in the best possible way, and LCouncil (RAC) at the end of November. For that we conduct our translational research based three very intensive days, we met with the panel, on a clear strategy. They asked us to explore an headed by the eminent neuroscientist, Sir Colin institutional policy on open access, for example, an Blakemore. We gave the Council an overview issue that is being tackled by many of our partners of our current situation and goals, and received around the world. valuable advice from them. This system of We are now carefully considering their recom- receiving evaluations and recommendations by mendations and making changes accordingly, and distinguished experts from around the world is I very much hope that you will see the fruits of unique among Japanese institutes. It allows us to these changes appear in the pages of future issues COVER STORY: RIKEN researchers maintain top-level research in the intensely com- of RIKEN Research, both in terms of new initia- have found that the petitive world of scientific research. tives and in research findings that have relevance elevated expression I am happy to report that their evaluation was to the society we live in. We also look forward to of a gene called largely positive, with strong support for new ini- interacting with our partners around the world in MPST in human hair tiatives that we have made in recent years, such as addressing the many challenges facing the world of could be an indicator of schizophrenia. the Hakubi Fellows and Kato Sechi programs for scientific research today. See a summary on page 7 Page 10 attracting talented young scientists and enhancing for more details on the expert panel. diversity, and for the establishment of the new © 2020 NOBEAST- company, RIKEN Innovation, to help use our SOFIERCE / SCIENCE PHOTO LIBRARY research to the good of society. They also gave us recommendations for taking on some challenges

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SPRING 2020 3 PEOPLE

Observing the cosmic web Hideki Umehata Special Postdoctoral Researcher (SPDR) Star and Planet Formation Laboratory, RIKEN Cluster for Pioneering Research

Please describe your role and understand the formation process of distant universe is the most attractive current research. these monsters to help us understand to me, partly due to its magnificence I’m a Special Postdoctoral Researcher cosmic history. and vastness. And, personally, I also at RIKEN looking at galaxy formation just enjoy the fun of an astronomical and evolution in the early Universe. It What excites you the most about event. It would be great if we could see has become clear that more than your current research? a supernova in the Milky Way with our 12 billion years ago there were a number About four years ago, while visiting a naked eyes. of cosmic ‘monsters’-violent star- collaborator in the United Kingdom, I forming galaxies and rapidly growing analyzed an image taken by the Subaru super-massive black holes. I’m trying to Telescope in Japan and found the signatures of large extended gas filaments. These filaments (sometimes [Gas] filaments described as the cosmic web) had been assumed to exist in theory for had been assumed to many years, but no-one had directly exist in theory for many observed them before. We published years, but no-one had the finding in Science last October. directly observed them. What do you think has been the most interesting recent discovery in your field? How and when did you join In a broad context, the direct imaging of RIKEN? the black hole shadow of Messier 87 this I joined RIKEN about a year and a half year by the Event Horizon Telescope ago. The team leader of the laboratory project was very impressive. It I work in, Dr. Nami Sakai, is an expert provided us with strong evidence in using the ALMA Observatory tel- of super-massive black holes. escopes in Chile, which is my favorite This is intrinsically important to observatory and that’s why I decided to me since super-massive black join her team. holes are one of my target cosmic objects. How has being at RIKEN helped your research? How did you RIKEN hosts several astronomy labora- become interested in tories that cover theoretical fields, x-ray your current field of research, and our group studying the research? submillimeter/millimeter wavelengths of During my childhood, I the electromagnetic spectrum, through loved to gaze at the night which we can examine molecular clouds, sky. I was especially absorbed looking at the process of star formation in astronomy when I was a high- from earliest collapse to stellar birth, for school student after seeing the instance. This wide variety of groups Leonid shooting stars created by and high-level scientists helps stimulate debris left behind by the comet ideas to further develop my research. I Tempel–Tuttle in 2001. Now, even hope the opposite is also true. In fact, I after getting my PhD, I’m still would say that the environment here is captivated by the sky. Among the the best thing to me. I really enjoy day-

4 RIKEN RESEARCH PEOPLE

I met Japanese students or professors. As a result, I already knew I would like to Computer-assisted work in Japan. In 2017, when I learned there were openings for RIKEN postdocs, I noticed disaster recovery that Naonori Ueda (who is now my super- visor) is a widely recognised machine Bahareh Kalantar learning scientist. I felt it was a great Postdoctoral Researcher opportunity for me. Disaster Resilience Science Team, RIKEN Center for Advanced Do you enjoy working at RIKEN? Intelligence Project Working with Japanese researchers is amazing. They encouraged me to focus on one specific thing and to do Tell me a little bit about yourself? neural networks (CNNs) to map which it perfectly. That’s the way Japanese I grew up in Iran, in the city of Esfahan. I’m areas were damaged, slightly damaged scientists work. ■ now a postdoc in the Disaster Resilience or contained debris. Science Laboratory at the RIKEN Center In the future, we could also use Light Careers at RIKEN for Advanced Intelligence Project. The Detection and Ranging (LiDAR), which For further information, visit our Careers page: center is headquartered in central Tokyo, is a good tool for collecting data on Website: www.riken.jp/en/careers E-mail: [email protected] but my lab is located at the Keihanna building surface elevation. LiDAR uses campus, between Kyoto and Osaka. its own light, so we could collect data at any time of day and under water. How did you become interested in Unmanned aerial vehicles (UAVs) artificial intelligence? could also be used more extensively to When I was nine or ten, I used to play collect images in remote areas at a low chess against a computer. Most of the cost compared to satellite images. time I lost. I was curious how a computer Others at the lab are using AI to better could be smarter than a human. Today, predict when earthquakes will occur. when we Google something or use Google Translate that’s artificial intelli- Could you describe your work gence (AI) too. It really is all around us. on landslides? We are doing landslide susceptibility mapping, looking at conditioning factors AI could help quickly such as slope, aspect, curvature, the stream power index (SPI) and terrain reveal if an area [hit by ruggedness index (TRI). Using the an earthquake] has been history of landslides in the area, an inventory map is produced. These con- damaged and where ditioning factors and inventory map are help is needed. used in machine learning algorithms to map landslide susceptibility. The results could be adapted for land-use planners and decision makers to improve What is your research about? landslide risk-assessments. I apply machine learning to natural disasters, such as landslides, earth- What is your aim as a scientist? quakes and floods. Earthquakes in About one in three people is affected by particular destroy infrastructure in natural disasters. I would like to contrib- Japan, and AI could help quickly reveal ute to creating better disaster resilience, if an area has been damaged and where particularly in vulnerable developing and help is needed. undeveloped countries. Currently, I’m using aerial photo- graphs from before and after the main How did you come to RIKEN? shock to study the Kumamoto earth- I was studying at the Universiti Putra quakes of 2016. We plan to use a type of Malaysia (UPM), and we had exchange

SPRING 2020 5 BRIEFS

Sixteen RIKEN researchers in the top 1% of their fields by citations

Clarivate Analytics selected 16 researchers from RIKEN among their highly cited researchers in 2019, a listing of the world’s most influential scientists and social scientists, who, over the past 10 years, have shown considerable influence through highly cited published work. More than 6,000 scientists from 21 research fields were chosen to receive the citation, with 104 coming from Japan.

CLARIVATE ANALYTICS’ HIGHLY CITED RESEARCHERS AT RIKEN

CROSS-FIELD • Yoshihiro Iwasa, The University of Tokyo (UTokyo)/RIKEN • Takao Someya, UTokyo/RIKEN IMMUNOLOGY • Koji Atarashi*, RIKEN • Kenya Honda, Keio University/RIKEN The supercomputer MDGRAPE-4A conducts molecular dynamics simulations for drug discovery. It PHYSICS was developed at the RIKEN BDR. • Yoshinori Tokura*, RIKEN/UTokyo • Naoto Nagaosa*, RIKEN/UTokyo • Franco Nori*, RIKEN/ University of Michigan New supercomputer • Ryotaro Arita, UTokyo/RIKEN dedicated to drug discovery PLANT & ANIMAL SCIENCE • Kazuo Shinozaki*, RIKEN/ The RIKEN Osaka campus is now host to faster general-purpose supercomputers Nagoya University a new supercomputer, MDGRAPE-4A. due to its architecture. By modeling water • Ken Shirasu*, RIKEN Designed to conduct molecular dynamics molecules and the roughly 100,000 atoms • Yuji Kamiya*, RIKEN simulations for drug discovery, the that typically make up proteins, it can • Motoaki Seki*, RIKEN/ computer was developed by the Laboratory carry out a simulation of approximately 1.1 Yokohama City University for Computational Molecular Design at the microseconds of molecular dynamics in a • Lam-Son Phan Tran*, RIKEN RIKEN Center for Biosystems Dynamics day. This allows it, in a realistic timeframe, • Kazuki Saito, Chiba Research (BDR). to model the interactions between drugs University/RIKEN In an aqueous solution, proteins change and proteins in the body, which will help • Hitoshi Sakakibara, Nagoya conformation-the spatial arrangements develop more effective targeted therapies. University/RIKEN of atoms in a molecule as it rotates. In The MDGRAPE-4A computer will be NEUROSCIENCE & BEHAVIOR order to understand this, it’s necessary made available to academic and industry • Susumu Tonegawa, to calculate the force of each atom and researchers globally. In the future, BDR Massachusetts Institute the surrounding water molecules, and plans to incorporate new elements such of Technology/RIKEN to move the proteins inside a computer as artificial intelligence and hybrids of *Asterisks indicate researchers simulation. MDGRAPE-4A is designed general-purpose and specific circuits to whose primary affiliation is RIKEN. for this purpose. It has an overall power further improve the system. www.riken.jp/

6 RIKEN RESEARCH BRIEFS

RIKEN Advisory Council 2019 Chair Vice Chair

The 11th meeting of the RIKEN Advisory then presented a set of evaluations and rec- meeting of the full council, individual centers Council (RAC) was held in Tokyo in ommendations. The panel was chaired by Sir hold their own advisory councils, and their November 2019. Nineteen international experts Colin Blakemore from City University of Hong reports are considered by the RAC in their from different scientific fields came together to Kong. This system is a unique experiment discussions. www.riken.jp/en/news_pubs/ examine RIKEN’s initiatives and centers. They pioneered in Japan by RIKEN. Prior to the news/2020/20200122_1/index.html

FIELD OF COUNTRY NAME TITLE INSTITUTION RESEARCH AFFILIATION Chair Professor of Neuroscience and Senior Fellow Hong Kong Institute for Advanced Blakemore, Colin Neuroscience Hong Kong (Former Chief Executive, Medical Research Council, UK) Study, City University of Hong Kong

University of Milan Bracco, Angela Professor National Institute of Nuclear Nuclear Physics Italy Physics, Italy

Carpenter, Catalytic Professor and Vice President University of Rennes 1 France Jean-François Chemistry

King Abdullah University of Computer Science Chan, Tony F. President Saudi Arabia Science and Technology (KAUST) and Engineering

Aerospace Fujii, Kozo Professor Tokyo University of Science Japan Engineering

Solid States Fukuyama, Hidetoshi Advisor to President Tokyo University of Science Japan Science

Hall, Wendy Regius Professor (Former President of ACM) University of Southampton Computer Science United Kingdom

Hara-Nishimura, Ikuko Professor Konan University Plant Science Japan

National Institutes for Quatum Medicine, Hirano, Toshio President (Former President, Osaka University) and Radiological Science and Immunology, Japan Technology (QST) Genetics

Biochemisty, Howard, Jonathon Professor Yale University United States Biophysics

Physics Inan, Umran President Koc University Electromagnetic Turkey radiation

1. Proteros biostructures GmbH, 1. Former Deputy Chairman of the Board and Acting Germany Drug Discovery, CSO Metternich, Rainer E. 2. Hoffmann-La Roche, Medicinal Germany 2. Former Global Head of Small MoleculeReseach Switzerland Chemistry 3. Former Head of Basic Research and Site Head 3. Merck & Co., USA

SIP Sub Program Director (Former President, Tokyo Cross Ministral Strategic Innovation Materials Mishima, Yoshinao Japan Institute of Technology) Promotion Program (SIP) Engineering

1. Professor 1. Harvard University Murray, Cherry A. 2. Director, Biosphere 2 Applied Physics United States 2. University of Arizona (Former Director, USDOE Office of Science)

International Institute for Information Nagao, Makoto Academic Advisor (Former President, Kyoto University) Japan Advanced Studies Technology

Member of National Assembly of Republic of Korea National Assembly, Oh, Se-Jung Applied Physics South Korea (Former Professor of Physics, Seoul National University) Republic of Korea

Wellcome Trust - Medical Embryo Stem Smith, Austin Professor Research Council, Cambridge United Kingdom Cell Biology Stem Cell Institute

1. Hitachi, LTD. Mathematical 1. Corporate Chief Engineer Takeda, Haruo 2. Science, Technology and Engineering, Japan 2. Project Leader Innovation for SDGs, EAJ Innovation Studies

MOH Office for Healthcare Medicine: Renal Tan, Chorh Chuan Executive Director Singapore Transformation Physiology

SPRING 2020 7 BRIEFS

Accelerating routes CELEBRATIONS to innovation RIKEN’s first fully owned subsidiary, RIKEN Innovation, Co., Ltd., was established in September 2019. The company will work to improve communication with private industry, support collaborative projects and carry out work related to licensing technologies. This move was made possible by a new law passed in January 2019, which allows national research and development Brussels, Belgium institutes to establish subsidiaries. RIKEN Europe RIKEN Innovation will focus on four Office major areas: strategic management and transfer of intellectual property; support for start-ups working towards technology commercialization; support for large-scale collaborations, and co-creation with industry using RIKEN’s knowledge and research. Jean-Eric Paquet “The image of RIKEN is that we are an of the European institute focused on theoretical research,” Commission speaks said President Hiroshi Matsumoto. “But the at the event. reality is that many of our breakthroughs are being used by industry, and our papers are frequently cited in patent applications. “Thanks to the efforts of many people, a law was enacted giving us the ability to invest in an innovation company.” Read more on page 26. www.riken.jp/en/news_pubs/ news/2019/20191217_3/

Fugaku prototype First anniversary of is world’s greenest RIKEN’s Europe Office supercomputer On 2 December 2019, a symposium in for Integrative Medical Sciences, The prototype for Fugaku, which is being Brussels marked the first anniversary of Tadashi Yamamoto; deputy director of developed by RIKEN and Fujitsu as a the opening of RIKEN’s Europe Office. the RIKEN Center for Emergent Matter successor to the K computer, has recently More than 100 guests attended, including Science, Seigo Tarucha, and director of been awarded the top spot on the Green500 Takeshi Nakane, ambassador for Science the RIKEN Center for Computational list. This announcement demonstrates that and Technology of the Ministry of Science, Satoshi Matsuoka. the Fugaku prototype is the most energy- Foreign Affairs of Japan (MOFA), and The event also featured a panel efficient of the world’s 500 fastest computers Jean-Eric Paquet, Director General, DG discussion where policy specialists from as measured by the LINPACK benchmark. Research and Innovation for the European Japan and the European Union, including Based at Fujitsu’s plant in Numazu, Japan, Commission. In his welcoming address, Koshi Nitta, director of the International the prototype achieved a mark of 16.876 RIKEN Executive Director Shigeo Koyasu Science and Technology Affairs Division, gigaflops per watt of power. It also achieved said: “I hope today’s symposium will be a part of the Science and Technology a rating of 1.9995 petaflops on the LINPACK trigger for further fruitful collaborations Bureau at the Ministry of Education, benchmark. The Supercomputer Fugaku, with European partners and beyond.” Culture, Sports, Science and Technology which will likely go into full operation in 2021, Representatives from RIKEN spoke (MEXT), discussed trends in science and will be used in a variety of areas such as drug, about their respective centers and their technology policy in Europe and Japan natural disaster, and industrial simulations, partnerships with Europe, including as well as the expansion of cooperation and will become a platform for artificial intel- director of the RIKEN Center for between RIKEN and research performing ligence and big data applications. www.riken. Sustainable Resource Science, Kazuo organizations in Europe. www.riken.jp/ jp/en/news_pubs/news/2019/20191118_1/ Shinozaki; director of the RIKEN Center en/news_pubs/news/2019/20191204_2/ © 2020 RIKEN

8 RIKEN RESEARCH BRIEFS

Front row at periodic table event

The closing ceremony of the International Year of the Periodic Table of Chemical Elements (IYPT) was held in Tokyo on 5 December 2019. The year 2019 marked 150 years since Russian chemist Dmitri Mendeleev arranged the 60 then-known elements into a periodic table, showing a pattern in chemical properties and hinting at undiscovered elements. The IYPT was declared by the United Nations General Assembly and UNESCO and involved many events around the world. RIKEN has supported the IYPT and has been conducting educational outreach through public exhibitions and lectures. The closing ceremony began with a greeting from Kohei Tamao, a RIKEN Honorary Science Advisor and chairman of the Executive Committee for IYPT2019 in Japan. Welcome addresses were also given by Natalia Tarasova, past president of the International Union of Pure and Applied Kosuke Morita and Kouji Morimoto (top, front) represent nihonium. RIKEN President Hiroshi Matsumoto spoke. Chemistry, who was co-chair of the Inter- Union Management Committee IYPT2019; not only a driving force for chemistry and for Accelerator-Based Science. Fifteen Philippe Pypaert of the UNESCO Beijing various scientific fields, but also a door scientists who were involved in creating and Office; Grigory Trubnikov, First Deputy that invites young people to science. I discovering superheavy elements appeared Minister of Science and Higher Education would like to thank everyone in the world on stage to celebrate the completion of of the Russian Federation. who has contributed to this work for their the 7th row of the periodic table, from the RIKEN President Hiroshi Matsumoto great efforts.” 104th element rutherfordium to the 118th also spoke, saying: “RIKEN is very lucky to The highlight was a session on recent element oganesson. From RIKEN, on behalf have been able to contribute to the comple- international activities in the search for of the group who worked on element 113, tion of the seventh period of the Periodic superheavy elements, chaired by Hideto nihonium, were Kosuke Morita and Kouji

SPRING 2020 9 RESEARCH HIGHLIGHTS

A polarized light micrograph of a tangential section of human scalp showing sectioned hair follicles (round regions; dark ones still have hair intact). Levels of the enzyme Mpst in hair follicles could be a good biomarker for schizophrenia.

SCHIZOPHRENIA Hair follicles could reveal sign of schizophrenia Early diagnosis of a form of schizophrenia may be possible by measuring levels of a specific enzyme

subtype of schizophrenia hydrogen sulfide and schizo- people with schizophrenia and effective and have side effects, A is related to abnormally phrenia,” says team leader Takeo found that expression of MPST pharmaceutical companies high levels of hydrogen sulfide Yoshikawa. “Once we discovered mRNA was much higher than have stopped developing new in the brain, RIKEN researchers this, we had to figure out how it people without schizophrenia. drugs, Yoshikawa says. “A new have discovered1. This finding happens and if these findings in Even though the results were not paradigm is needed for the provides a new direction for mice would hold true for people perfect—indicating that sulfide development of novel drugs,” he exploring drug therapies and with schizophrenia.” stress does not account for all explains. “Our results provide a biomarker for this type of To ensure that Mpst was the cases of schizophrenia—MPST a new principle or paradigm schizophrenia. culprit, the researchers created levels in hair could be a good for designing drugs, and we Normally, we are not startled an Mpst-knockout version of the biomarker for schizophrenia are currently testing whether as much by a noise if it is low-PPI mice and found that they before other symptoms appear. inhibiting the synthesis of preceded by a smaller burst—a had a higher PPI than regular Because hydrogen sulfide can hydrogen sulfide can alleviate phenomenon called prepulse low-PPI mice. Thus, reducing the protect against inflammatory symptoms in mouse models inhibition (PPI). But people with amount of Mpst helped the mice stress, the team hypothesized of schizophrenia.” schizophrenia generally have a become more normal. that inflammatory stress during lower PPI than people without The researchers also found early development might be the the mental disorder. that MPST gene expression was root cause. “We found that anti- Reference Researchers at the RIKEN higher in postmortem brains oxidative markers—including 1. Ide, M., Ohnishi, T., Center for Brain Science found from people with schizophrenia the production of hydrogen Toyoshima, M., Balan, S., Maekawa, M., Shimamoto- that mice with low PPI expressed than in those from unaffected sulfide—that compensate Mitsuyama, C., Iwayama, the enzyme Mpst in their brains people. Mpst protein levels in against oxidative stress and Y., Ohba, H., Watanabe, more than mice with high PPI. these brains also correlated neuroinflammation during brain A., Ishii, T. et al. Excess This enzyme helps produce well with the severity of schizo- development were correlated hydrogen sulfide and hydrogen sulfide, and the team phrenic symptoms. with MPST levels in the brains polysulfides production underlies a schizophrenia found the low-PPI mice had The team then looked at MPST of people with schizophrenia,” pathophysiology. EMBO higher hydrogen sulfide levels. expression as a biomarker for says Yoshikawa. Molecular Medicine 11, “Nobody has ever thought schizophrenia. They examined Although current drugs for e10695 (2019). about a causal link between hair follicles from more than 150 schizophrenia are not very © STEVE LOWRY/SCIENCE PHOTO LIBRARY

10 RIKEN RESEARCH RESEARCH HIGHLIGHTS

COMPUTATIONAL NEUROSCIENCE Modeling a sense of responsibility A simulation measures perception of action and outcome

wo RIKEN neuroscientists T have developed a model that helps to explain the sense people have that their actions cause events1. They have also proposed experiments for testing the model. Our sense of agency is the feeling that we are responsible for our intended outcomes. As yet, scientists cannot explain how it arises in the brain. “Understanding our sense of agency is fundamental to knowing ourselves,” notes Taro Toyoizumi of the RIKEN Center for Brain Science (CBS), who devised the model together with CBS colleague Roberto Legaspi. It underpins the legal system, where people are held accountable for their deeds. It is also thought that people with schizophrenia and related disorders may wrongly think that their actions are caused by an external agent. In a classic test of agency carried out in 2002, subjects pressed a button and would hear a sound. The subjects reported Two RIKEN neuroscientists have developed a model that helps to explain the sense people have that their actions cause events. their estimates for the timings of their action and the sound. The flash of light, for instance— matched the results of the between action and outcome can results revealed that a person originated from the same place, classic experiment. be precisely controlled. If their who believed that their action underestimating their true The model suggests that the predictions are correct, then caused the sound would under- separation. person’s perception that the follow-up brain-imaging tests estimate the delay between the Legaspi and Toyoizumi outcome happened when they could be used to monitor what two events, whereas someone adapted this model to describe feel it should have occurred, happens when people believe who did not think they caused the mistaken time-interval underlies their sense of agency. they have caused an action, the outcome tended to overes- estimates seen in agency “If our model is correct, human compared to when they do not timate the time delay. But there experiments. They performed intention is not strictly needed to feel responsible. was no model to explain these computer simulations based feel a sense of agency,” explains perceptions. on their model to investigate Legaspi. “Reliable sensory inputs Toyoizumi had previously how people’s perception of arriving at the predicted timing Reference worked on a model to explain the the time delay between action may be sufficient.” 1. Legaspi, R. & Toyoizumi, T. A Bayesian psychophysics ventriloquism effect, in which and outcome is related to their The two researchers say that model of sense of agency. a person is likely to mistakenly belief about whether they or their model can be tested with Nature Communications think that two spatially something else caused the a fairly simple virtual-reality 10, 4250 (2019).

SPRING 2020 11 RESEARCH HIGHLIGHTS

NEUROSCIENCE Brain waves vary with age of memory The interaction between two brain regions differs for recent and distant memories

ecent and old memories R can be distinguished based on the different brain activity signatures they produce, neuroscientists at RIKEN have found1. This finding has important implications for research into brain damage and memory loss. Memory recall is considered to involve different neural circuits depending on when a memory was formed. Traditionally, scientists thought that memories are initially stored in the hippo campus and are transferred to the cortex over time. But there has been increasing evidence that the hippocampus is involved in the recall of old memories. Now, a team led by Thomas McHugh of the RIKEN Center for Brain Science has explored the connection between the hippocampus and the anterior cingulate cortex (ACC) in the prefrontal brain at the level of signals from individual neurons. Old and new memories in mice can be distinguished from the brain waves between a specific region in the hippocampus (red regions) and the anterior cingulate cortex. “This suggests were highly synchronized when brain recordings alone. “We originally formed. This suggests the hippocampus mice recalled the fear memory. could decode whether a mouse the hippocampus always plays a always plays a role The interactions of the two was recalling a recent or remote role in providing key details of brain areas changed over time, memory by looking at the cor- an old experience, at least in the in providing key with ACC and CA1 activity relations in ACC−CA1 interac- healthy brain.” details of an old becoming more correlated when tions,” says McHugh. Moreover, The team is now exploring experience.” an old or ‘remote’ memory was the researchers suggest that a how impairments in long-term recalled compared to the recent, small group of CA1 neurons memory that often accompany one-day memory. carries the information about aging and disease impact They recorded activity in both “While memory is consoli- memory age. activity in these brain circuits. brain areas before exposing mice dated over time in frontal areas, “While we have known to a foot shock and returned the we think in this case the ACC for 20 years that the ACC is mice to the same cage one day is facilitating the retrieval of important for recalling older Reference and one month later. If mice contextual details back from memories, how it contributes 1. Makino, Y., Polygalov, D., froze in the same context, it was the hippocampus,” says has remained a mystery,” says Bolanos, F., Benucci, A. & McHugh, T. J. Physiological a behavioral indication that they McHugh. McHugh. “We found that it signature of memory age in remembered the shock. The evolving pattern of signals plays an important role in the prefrontal-hippocampal The neuronal recordings over time allowed the research- organizing activity in the circuit. Cell Reports 29, revealed that the ACC and hip- ers to distinguish old and new hippocampus, the part of the 3835–3846 (2019).

pocampus, specifically area CA1, memories in mice from the brain in which the memory was © SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY

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Norepinephrine neurons in the mouse brain stem. RIKEN neuroscientists have transformed norepinephrine neurons in the locus coeruleus to be activated by light (yellow cells; red regions represent a wider set of brain stem cells).

mobilizes energy metabolism for norepinephrine release triggers memory consolidation,” explains these changes. NEUROSCIENCE Hajime Hirase of the RIKEN The short- and long-term Center for Brain Science (CBS). consequences of norepinephrine To see how these fast and release in the brain thus depend Thinking, fast and slow slow molecular responses are on the situation and behavior. In Memories could be formed by different chemical triggered naturally, mice were particular, memory formation given random air puffs to the seems to be supported by cAMP pathways depending on whether a mouse is face to evoke startle responses. level increases, whereas transient startled or in a state of heightened alert In this situation, cAMP levels or low-vigilance states involve did not go up at all, whereas the short-term elevation of calcium levels became elevated, calcium levels. momentary startle releases in a brain region called the locus as observed previously. “One of the effects of cAMP A a different signaling coeruleus (see image) to release In a second experiment, mice is to break down glycogen for molecule in the mouse brain norepinephrine by artificially were given a foot shock coupled quick energy in a fight-or-flight and generates a different type of stimulating them using laser light. with a sound to create a fear situation,” comments Hirase. memory from a sustained state Norepinephrine release memory. When they heard the “This boosting of energy of vigilance, RIKEN neuro launched two chains of sound again, the mice would metabolism could help con- scientists have found1. This molecular events: one involving freeze in anticipation of a shock. solidate memories over longer finding provides new insights calcium activity and the other This time, cAMP levels were time scales, while rapid calcium into how memories are formed cyclic adenosine monophosphate noticeably higher, while calcium boosts could lower the threshold and stored in the brain. (cAMP), an important signaling levels also rose but quickly for synaptic plasticity.” The release of the neuro- molecule. Calcium levels in tapered off. transmitter norepinephrine astrocytes quickly became “When mice are in this (also called noradrenaline) is elevated after norepinephrine sustained state of vigilance, a lot Reference important for modifying the release, whereas cAMP levels of norepinephrine is released, 1. Oe, Y., Wang, X., Patriarchi, connections between neurons exhibited a slower but more coupled with gradually building T., Konno, A., Ozawa, K., Yahagi, K., Hirai, H., responsible for forming and sustained increase. cAMP,” explains Yuki Oe, also Tian, L., McHugh, T. J. & consolidating memories. Brain “We think these fast and at CBS. “This reflects how the Hirase, H. Distinct temporal cells called astrocytes are crucial slow dynamics are significant astrocytes support the formation integration of noradrenaline mediators of these changes. because calcium elevation in of fear memory.” signaling by astrocytic second messengers The RIKEN team wanted to astrocytes promotes synaptic Mice that had been given during vigilance. Nature observe in real time what happens plasticity, or the ability of cells norepinephrine-blocking drugs Communications 11, in astrocytes when mice are to form new memory connec- did not exhibit calcium or 471 (2020).

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PLANT GENETICS Roots of weed’s parasitism run deep Sequencing the genome of a parasitic plant offers a glimpse of its evolution and points the way toward improved control

he genome of the parasitic two whole-genome duplication T plant Striga, commonly events in its evolution. More sig- known as witchweed, has been nificantly, they found evidence sequenced for the first time by that the Striga genome evolved RIKEN plant geneticists1. This in three phases, as suggested genetic analysis both offers by theories of parasitic plant insights into how parasitic plants evolution. evolved and a tool for improving First, Striga acquired genes the monitoring and control of to form its infectious root by the costly weed. repurposing genes normally A major agricultural pest, involved in the regulation of Striga (see image) causes billions lateral roots. of dollars of crop losses annually. Next, the parasite lost certain It taps into the roots of host functions in favor of getting plants, depriving them of water a resource from the host. For and nutrients. Herbicides and example, gene families related to mechanical removal can control photosynthesis shrunk in Striga the weed, but these methods are because it relies on carbon from costly and do not remove seeds its host. Striga also lost many in the soil. genes responsible for hormonal response to environmental stimuli such as water loss. These findings Third, the relationship became more specialized on specific open the door to hosts. Striga seeds and seedlings further genetic sense their host by detecting hormones known as strigolac- and genomic tones. The strigolactone-sensing analyses. gene family was dramatically The devastating parasitic plant Striga hermonthica. expanded in Striga, enabling the seedlings to recognize and transfers of large genomic to avoid agrochemicals, which To improve our understanding colonize on a wide range of fragments between species. This could provide a strategy to select of Striga’s evolution and biology, hosts. suggests that Striga can acquire cultivars and chemicals.” Ken Shirasu’s team at the RIKEN “The expansion of the strigol- genetic material from its hosts, Center for Sustainable Resource actone-sensing gene family was which may have affected its Science has sequenced the surprising,” says Shirasu. “We evolution. Reference genome of a Striga species that also found that many of these These findings open the door 1. Yoshida, S., Kim, S., Wafula, invaded the US in the 1950s. genes are expressed not in seeds to further genetic and genomic E. K., Tanskanen, J., Kim, Y.-M., Honaas, L., Yang, They also sequenced the tran- but in roots, meaning that some analyses. “With this genomic Z., Spallek, T., Conn, C. E., scriptome of the most devastat- of the gene family members are data, we can also currently Ichihashi, Y. et al. Genome ing Striga species. doing something other than monitor Striga spreading in sequence of Striga The team identified roughly controlling germination.” field at the genome level,” says asiatica provides insight into the evolution of plant 35,000 protein-coding genes Finally, comparison of the Shirasu. “This means that we parasitism. Current Biology in the genome, and their Striga genome with other can learn how Striga is adapting 29, 3041–3052 (2019). analysis revealed evidence of plant genomes revealed several to infect current cultivars or © 2020 Musembi Mutuku

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PHOTORECEPTOR PROTEINS First responder to light revealed The protein component of a light-sensitive molecule in bacteria reacts first to light

he sequence of changes that T light triggers in a bacterial photoreceptor starts with its protein scaffolding rather than the light-absorbing chromophore, an all-RIKEN team has shown1. This finding goes against conventional wisdom and sheds new insight on how photo receptors can convert light into chemical energy so efficiently. Many bacteria use special light-sensitive molecules known as photoreceptor proteins to turn light into chemical energy, which they use to initiate various biological functions. Scientists have long wanted to know how bacterial photo receptors are so efficient in converting light. “One of the fundamental questions is how these biomolecules realize such high-efficiency, low- energy photoreactions,” says Tahei Tahara. “This has been a long-standing question.” One motivation for uncovering the RIKEN researchers have found that light (long red line) first causes the shape of the protein (purple twirls) to change before mechanism of these photo the retinal chromophore (stick-like structure) in bacteriorhodopsin undergoes photoisomerization. receptors is that it could inform efforts to develop artificial protein plays an important role femtosecond stimulated While the team looked at versions of these molecules. in aiding the conversion of light Raman spectroscopy, which bacteriorhodopsin in this study, The most well-studied into chemical energy. can observe processes that they anticipate that the same bacterial photoreceptor, bacterio The conformational change occur faster than a picosecond effect could well occur in other rhodopsin, contains a retinal of the retinal chromophore was (1 picosecond = 10−12 seconds), rhodopsins. chromophore, which changes assumed to be the first response and extended it to the deep shape when it absorbs a photon of bacteriorhodopsin to light. ultraviolet region. This allowed of yellow light. This configura- But Tahara and his co-workers at them to look at the protein Reference tion change sets off a series of the RIKEN Molecular Spectro part of bacteriorhodopsin 1. Tahara, S., Kuramochi, structural changes in bacterio scopy Laboratory and the RIKEN (see image). H., Takeuchi, S. & rhodopsin that enables it to Center for Advanced Photonics This discovery came as a Tahara, T. Protein dynamics preceding pump protons. have now discovered that there is surprise to Tahara. “I didn’t photoisomerization of Interestingly, when the retinal a step that precedes it—the protein expect that the protein the retinal chromophore chromophore of bacterio that cradles the retinal chromo- would change shape before in bacteriorhodopsin rhodopsin is placed in solution, phore first alters its shape in chromophore isomerization, but revealed by deep-UV femtosecond stimulated its light-conversion efficiency response to light. This change in when I saw the experimental Raman spectroscopy. is three times lower than when the protein could help the retinal results I thought ‘Wow, it’s The Journal of Physical it is nestled within the protein chromophore use light efficiently. actually the case’,” he says. “It Chemistry Letters 10, structure of bacteriorhodopsin. The team took a spectroscopic was most surprising, and we 5422–5427 (2019).

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EXCIPLEX EMISSION Long- distance light sources Light emission has been generated by two molecules separated by an exceptionally long distance

ighly sensitive sensors and H photodetectors could result from RIKEN-led research that has shown that light-emitting complexes can form over far greater distances than ever suspected1. An exciplex is an excited-state complex formed between a molecule that donates electrons A long-distance and one that accepts electrons. interaction between Exciplexes are generally of electrons (red spheres) interest for their favorable and holes (blue spheres) separated by a spacer light-emission properties. In gives rise to exciplex emission particular, the excited state is (orange squiggles) that could be used in efficient organic readily able to undergo a process light-emitting diodes (OLEDs). that enhances the efficiency of organic light-emitting diodes (OLEDs). The two molecules usually have to be within a few nano the electron-donor molecule just as expected, confirming the The team is also considering meters of each other for an and the electron-acceptor formation of exciplexes. possible applications of their exciplex to form. However, by molecule are separated by a thick Although the mechanism surprising discovery, which placing the electron donor and spacer layer,” Pu explains. “The behind such long-distance may lie outside of the usual electron acceptor on either side of discovery was a big surprise— exciplex formation is not yet OLEDs. “We anticipate that a spacer layer, Yong-Jin Pu from the spacer was much thicker well understood, the spacer layer this totally new exciplex could the RIKEN Center for Emergent than the 10-nanometer spacers plays an important role, Pu says. lead to highly sensitive sensors Matter Science and his collabora- previously reported. The excep- The spacer forms an exciplex or photodetectors to external tors have created exciplexes when tional thickness goes far beyond state with the donor molecule stimulus,” Pu says. the donor and acceptor are up to previous preconceptions.” and also with the acceptor 70 nanometers apart. The team used four different molecule, the researchers The team started with a spacer electron-donor molecules to suspect (see image). “The spacer Reference layer 10 nanometers thick, and demonstrate that the light molecule behaves as an acceptor 1. Pu, Y.-J., Koyama, Y., Otsuki, D., Kim, M., Chubachi, then increased the thickness emission really was from to the donor molecule, and H., Seino, Y., Enomoto, in increments of 10 nano exciplex formation. “The type of simultaneously behaves as a K. & Aizawa, N. Exciplex meters. Remarkably, exciplex donor molecule must influence donor to the acceptor molecule,” emissions derived from light emission was still seen the emission wavelength of Pu says. “We’re now trying to exceptionally long-distance even when the spacer thickness the exciplex, due to the change understand the mechanism and donor and acceptor molecules. Chemical reached 70 nanometers. of energy difference between hidden physics of this long- Science 10, 9203–9208 “We tried to create a new and the donor and acceptor,” Pu distance exciplex formation and (2019). unique exciplex state, in which explains. The emissions varied its emission.” Matter Science Emergent for RIKEN Center 2019 ©

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NEUROSCIENCE A vital gene in the mating game Eliminating genes for a neuropeptide can cause abnormalities in the sexual receptivity of female fish

peptide expressed in the courtship display from males,” A brains of fish helps to Hiraki-Kajiyama says. “I would determine the different mating never have anticipated such behaviors of the two sexes, a change, so I was surprised RIKEN and University of Tokyo and very interested.” This scientists have found1. This might mean that the NPB advances our understanding of system enables females to the neurological processes that select a suitable mate by mating cause the sexes to behave differ- only with males that show ently in courtship. courtship display. For a long time, the sexual Since NPB is well conserved behavior of vertebrates, among vertebrates, including particularly mammals and Fluorescence micrographs of the brains of male (left) and female (right) medaka humans, it could affect sexual birds, has been considered fish. They show that neuropeptide B (green regions) is expressed in this nucleus behavior in other species. “NPB basically irreversible. The sex only in females. is also expressed in mammals steroids produced early in in brain regions thought to life generally determine their expression that depends on the expression of NPB might be the be homologous to the nuclei sexual behavior. sex of the fish. neurological difference between that have female-specific But there are exceptions. “A big motivation behind our the mating behaviors of male and NPB expression, so NPB may Fish belonging to the teleost work was to uncover the sex female medaka. be involved in female sexual order, for example, can undergo differences in the brain that lead To confirm this, the team receptivity in mammals,” notes physical and behavioral sex to sex differences in behavior,” knocked out the npb genes and Hiraki-Kajiyama. reversal in the wild. Researchers Hiraki-Kajiyama explains. their protein receptors and found have even reversed the mating The team examined gene that female sexual behavior was behaviors of such fish by expression differences in medaka altered when NPB was absent—a Reference manipulating their hormones. and found that a gene coding clear indicator that it is impli- 1. Hiraki-Kajiyama, T., However, the genetic regions for neuropeptide B (NPB) is cated in the genetic determina- Yamashita, J., Yokoyama, K., Kikuchi, Y., Nakajo, M., affected by hormones that expressed exclusively in some tion of sexual behavior. Miyazoe, D., Nishiike, Y., govern vertebrate sexual revers- nuclei in the female brain (see The way in which the Ishikawa, K., Hosono, K., ibility have remained elusive. top image). Importantly, the knockout affected sexual Kawabata-Sakata, Y. et al. Now, Towako Hiraki- brain region where Hiraki- behavior surprised the research- Neuropeptide B mediates female sexual receptivity Kajiyama at the RIKEN Center Kajiyama’s team discovered this ers. “Most females spawn within in medaka fish, acting for Brain Science and her female-specific NPB expres- a minute after viewing the in a female-specific but colleagues have examined the sion is the region most related courtship display of males, but reversible manner. eLife 8, brains of medaka (see bottom to sexual behavior. Together, many of the female knockout e39495 (2019). image)—a teleost fish—for gene these findings suggested that fish spawned without getting © 2019 RIKEN Center for Brain Science; plusphoto/a.collectionRF/Getty

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An artist’s impression of the distribution of dark matter in a region of space a few hundred megaparsecs across. Astrophysicists at RIKEN have set an upper limit for a potential interaction between dark matter and antimatter.

COSMOLOGY between dark matter and antimatter, and though we did not find a difference, we set a new Killing two cosmic mysteries upper limit for the potential interaction between dark matter with one hypothetical particle and antimatter,” says Christian Smorra, a member of the RIKEN Experimentalists test whether the problems of antimatter Ulmer Fundamental Symmetries and dark matter could be related Laboratory. The team intends to enhance the precision of their experiment. RIKEN-led team has matter content of the Universe than normal matter does. They “We plan to further improve the A completed the first lab are off by a factor of one billion, used a specially designed device accuracy of our measurements oratory experiments to probe and no one knows why the to magnetically trap a single of the antiproton’s spin preces- whether antimatter interacts asymmetry exists. antiproton, preventing it from sion frequency, allowing us to slightly differently with dark In the case of dark matter, contacting ordinary matter and set more and more stringent matter than normal matter astronomical observations being annihilated. constraints on the fundamental does1. If found, such an inter indicate that some unknown The team then measured a invariance of charge, parity, and action could be the key to solve mass is influencing the orbits of property of the antiproton called time, and to make the search for the mysteries of dark matter stars in galaxies, but the prop- its spin precession frequency. dark matter even more sensitive,” and antimatter—two of the erties of dark-matter particles Normally, this should be says Stefan Ulmer, who leads biggest unsolved mysteries of remain unknown. One theory is constant in a given magnetic the laboratory. modern physics. that they are a type of hypotheti- field, and a modulation of this The Big Bang should have cal particle known as an axion, frequency could be accounted created equal amounts of which plays an important role in for by an effect mediated by Reference matter and antimatter, but the explaining the lack of symmetry axion-like particles, which are 1. Smorra, C., Stadnik, Y. V., Blessing, P. E., Bohman, M., Universe we live in is made only violation in the strong interac- hypothetical candidates for Borchert, M. J., Devlin, J. of matter. Antimatter is created tion in the standard model of dark matter. A., Erlewein, S., Harrington, every day in experiments and particle physics. While the experiment did not J. A., Higuchi, T., Mooser, even by natural processes such The researchers designed an measure any variation in the spin A. et al. Direct limits on the as lightning, but it is quickly experiment to test whether the precession frequency, the results interaction of antiprotons with axion-like dark matter. annihilated when it collides with lack of antimatter might be are useful for theorists. “For Nature 575, 310–314 regular matter. Predictions based because antimatter interacts the first time, we have explic- (2019). on our understanding of the differently with dark matter itly searched for an interaction LIBRARY PHOTO GARLICK/SCIENCE MARK ©

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QUANTUM PHYSICS Kondo cloud spotted for the first time Predicted more than half a century ago, a quantum effect has now been directly observed

quantum object known as A the Kondo cloud has been directly observed by RIKEN experimentalists, ending a half-century quest1. This cloud is important for many physical systems including high-temperature superconductors and could provide physicists with new ways to manipulate such systems. Magnetism arises from a property of electrons known as spin, which is essentially the angular momentum of an electron. The spins of electrons that flow freely in a material, known as conduction electrons, become entangled with a localized magnetic impurity and effectively screen it. This is called the Kondo effect after the Japanese theoretical physicist Jun Kondo who first revealed the effect in the mid-1960s, and its strength is known as the Kondo temperature. The cloud size is another important parameter for materials that contain more than one magnetic impurity because Schematic depiction of the setup used to detect a Kondo cloud. (Image was created by Jeongmin Shim at KAIST based on his the spins in the cloud couple theoretical calculation of the Kondo cloud shape.) with one another and mediate the coupling between magnetic Now, Michihisa Yamamoto of the quantum dot and interfered containing multiple magnetic impurities when the clouds the RIKEN Center for Emergent with itself, similar to how a water impurities,” says Yamamoto. overlap. This happens in various Matter Science and his co- wave forms striped ripples on “This achievement was only materials including high-tem- workers have observed a Kondo being scattered by a barrier. The made possible by close collabora- perature superconductors. screening cloud formed by an researchers measured changes in tion with theorists. This opens Although the Kondo effect impurity consisting of a localized the Kondo temperature, allowing up a novel way to engineer spin for a single magnetic impurity electron spin in a quantum them to investigate the extent of screening and entanglement.” is covered in textbooks on dot—a type of artificial atom— the cloud at the location of the many-body physics, the Kondo coupled to conduction electrons perturbation. They found that cloud had not been directly that are nearly aligned along a the size and shape of the cloud Reference 1. Borzenets, I. V., Shim, J., detected until now despite straight line (see image). agreed well with theoretical Chen, J. C. H., Ludwig, A., many attempts over the past five The researchers slightly calculations. Wieck, A. D., Tarucha, S., decades. It was known to exist, perturbed conduction electrons “It is very satisfying to have Sim, H.-S. & Yamamoto, M. but its spatial extension had far from the quantum dot using been able to obtain a real-space Observation of the Kondo screening cloud. Nature never been observed, creating a an electrostatic gate. The wave of image of the Kondo cloud, as in press. DOI: 10.1038/ controversy over whether such conducting electrons scattered it is a real breakthrough for s41586-020-2058-6

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SPIDER SILK A new spin on spider webs Two kinds of ions are shown to have opposite effects on spider silk protein

rtificial spider silk is a step Acloser to become a reality after an all-RIKEN team has revealed the role ions play in the production of spider silk1. Spider silk is one of nature’s super materials, being light, flexible and biodegradable, while being stronger than steel on a weight-for-weight basis. But spiders cannot be cul- tivated like silkworms. “We can’t farm spiders because they kill each other,” explains Nur Alia Oktaviani of the RIKEN Center for Sustain- able Resource Science (CSRS). “In our lab, if we don’t keep them in separate boxes, they start fighting to the death within seconds.” As a result, there is a strong desire to produce artificial spider silk. However, while many venture companies are making artificial silk fibers, Silk being secreted from the abdomen of a Golden Silk spider (Nephila clavipes). Chemists at RIKEN have shown the role that the fibers lack the strength of ions play in the formation of spider silk. natural spider silk. “We’d like to produce tougher artificial fibers solidifies into a fiber on being contrast, ions of phosphate and to solidify on ejection from the that are more like natural spider ejected from the spider’s sulfate promote the formation spinning duct. silk,” says Keiji Numata, also spinning duct. of hydrogen bonds between This finding will help inform of CSRS. Now, Oktaviani and Numata, protein molecules and hence efforts to produce artificial spider with two co-workers, have used promote the solidification of silk. “In the future, researchers nuclear magnetic resonance spider silk. should consider ion gradients “We’d like to (NMR) to see how ions affect the The team was inspired to if they want to make artificial discover the shape and dynamics of a highly look at the effects of ions by spider silk,” Numata says. pure form of spider silk protein previous studies that had found secrets of natural produced by bacteria that had that an ion gradient exists spinning systems.” been genetically engineered to inside a spider’s abdomen: the Reference produce the protein. concentration of the bond- 1. Oktaviani, N. A., The researchers discovered inhibiting ions decreases Matsugami, A., Hayashi, F. & Numata, K. Ion effects There are still many things that two types of ions in a toward the end of the spinning on the conformation and scientists don’t understand spider’s abdomen have different duct, whereas that of the bond- dynamics of repetitive about how spiders produce silk. effects on spider silk protein. inducing ions increases. This domains of a spider silk “We’d like to discover the secrets Ions of sodium and chlorine gradient now makes perfect protein: implications for solubility and β-sheet of natural spinning systems,” inhibit the formation of bonds sense in light of the current formation. Chemical comments Oktaviani. In par- between the molecules of results: the spider silk protein Communications 55, ticular, it is not clear how the spider silk protein and thus needs to be liquid in the 9761–9764 (2019).

liquid in the spider’s abdomen keep it in the liquid state. In spider’s abdomen, but it needs Sciences Sustainable Resource for RIKEN Center 2019 ©

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A fluorescence micrograph of HeLa cells—cervical cancer cells belonging to the first human cell line. A technique developed by RIKEN researchers can sensitively detect cell metabolites. This will help scientists determine how cancer cells alter their immediate environment to ensure their survival.

METABOLOMICS Detecting the metabolites of a single cell An ultrasensitive analysis technique can detect the small molecules that a single cell makes

n analytical technique that single cell produces. Researchers spectrometry (CE-MS) by up The team is looking for ways to A is so sensitive it can identify would dearly love to be able to do to 800 times, allowing them to apply their technique to areas of the small molecules produced by this because it would provide a profile the metabolites that a clinical interest. “This technique a single cell has been made and valuable window into how single single cell produces. allows us to directly analyze demonstrated by an all-RIKEN cells react to their environment. The researchers improved metabolites from cellular micro- team1. This opens up the pos- One area where such a CE-MS, which is typically used environments in humans such sibility of analyzing the roles technique is badly needed is to analyze tens of thousands of as tumors,” says Kawai. “We’re individual cancer cells play in cancer biology. “Cancer stem cells, in two ways—they used now searching for good target tumor growth and survival. cells regulate their environment a specially designed system to molecules for clinical applica- Cells are tiny chemical so that it is acidic and has low concentrate the sample before tions, such as drug discovery and factories, constantly manufac- oxygen levels—this is a vital analysis and they used a thin- diagnosis.” turing the compounds they need survival strategy for cancer walled, tapered glass capillary to survive and thrive. Their DNA cells,” explains Takayuki Kawai tube to deliver the sample to the contains instructions for how to of the RIKEN Center for mass spectrometer. Reference make these compounds. Which Biosystems Dynamics Research. The team demonstrated the 1. Kawai, T., Ota, N., Okada, compounds they produce at any “But since this is a microscale sensitivity of their technique K., Imasato, A., Owa, Y., Morita, M., Tada, M. & particular time is determined in phenomenon involving 10 to 100 by using it to identify 40 Tanaka, Y. Ultrasensitive part by their environment. cells, it is important to analyze metabolites from a single human single cell metabolomics by Geneticists can currently microscale samples, even down cervical cancer cell. “This is the capillary electrophoresis− determine the genetic makeup of to a single-cell level.” first time this level of analysis mass spectrometry with a a single cell and the messenger Now, Kawai and his co-work- has been achieved,” notes Kawai. thin-walled tapered emitter and large-volume dual RNA that it produces. But ers have boosted the sensitivity “That’s because our system is sample preconcentration. there is no technique capable of a conventional metabolomic currently the most sensitive in Analytical Chemistry 91, of reliably profiling the small analytic technique known as the metabolomic analysis system 10564–10572 (2019).

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WEARABLE ELECTRONICS Wearing your heart monitor on your sleeve Strong bonds between metal nanowires and polymer nanofibers enable a composite film to realize good electrical conductivity and high stretchability

IKEN engineers have made other. “There’s very good R a breathable material that adhesion between the silver is both highly stretchable and nanowires and the polyurethane has good electrical conductivity, nanofibers,” notes Fukuda. making it promising for on-skin “This is why we simultaneously electronics for people and wiring achieved a very good stretchabil- for robots1. ity and conductivity.” The team To be suitable for use as suspects that hydrogen bonds— wearable electronics, a material the same bonds that hold pulp needs to be both stretchable fibers together in a sheet of and conductive. It should also paper—are responsible for this be breathable and durable. good adhesion. Finding a material that satisfies The film could find use as all four criteria is not easy. electrical wiring that can be One promising strategy is used on the skin. Its flexibil- to combine elastic polymer ity allows it to stretch when a nanofibers with a network of person bends their elbow or conductive metal nanowires, but knee, and it can be stretched to it is challenging to get the two three times its initial length. In components to bond tightly to the same way, it could also be each other. used for wiring on robots. Another potential use is as a sensor. Because its con- A photo of the film attached to a person’s finger. It can be used as a wearable The film could ductivity changes when it is sensor to monitor heart rate and other movement. stretched, it can be used to find use as detect movement. The team for the mass production of the of these breathable conductors electrical wiring demonstrated this by using industrial product.” in real-time health monitoring that can be used their film to monitor the angle Fukuda notes that his team systems and soft robotics. of a bent wrist and detect a resembles the material in that on the skin. person’s pulse. it combines researchers with The film has other advantages different fields of expertise. Reference besides good stretchability Jiang brought his knowledge 1. Jiang, Z., Nayeem, M. O. Now, Kenjiro Fukuda and and conductivity. When the of stretchable nanowires to G., Fukuda, K., Ding, S., Jin, Zhi Jiang of the RIKEN researchers tested their film by the project, while Fukuda and H., Yokota, T., Inoue, D., Hashizume, D. & Someya, Thin-Film Device Labora- stretching and releasing it 1,000 other team members supported T. Highly stretchable tory and their co-workers times, they observed that its the fabrication of the polymer metallic nanowire have succeeded in producing conductivity dropped off only nanomesh structures. networks reinforced by a stretchable and conductive moderately, indicating that it The team intends to improve the underlying randomly distributed elastic polymer material by combining poly has good durability. Further- the stretchability of the material nanofibers via interfacial urethane nanofibers with silver more, it is easy to fabricate. by using longer silver nanowires. adhesion improvement. nanowires. “This film can be obtained They also plan to experiment Advanced Materials 31, Importantly, the two com- by solution processes,” says with other combinations of 1903446 (2019). ponents bond strongly to each Fukuda. “That’s very important materials and pursue applications Reproduced, with permission, from Ref. 1 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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GENOME-WIDE ASSOCIATION STUDIES Coffee habit could be genetically brewed Certain genes make a person more predisposed to habitually consume a particular kind of food

eneticists at RIKEN have G found nine gene locations that are associated with the consumption of various foods and drinks such as meat, tofu, cheese, tea and coffee1. Among them, three were also related to having particular diseases such as cancer or diabetes. Scientists usually conduct genome-wide association studies to determine whether a disease is related to a specific genetic variation. To do this, they group hundreds of thousands of people depending on whether or not they have the disease, and compare the genomes across groups. They scan the whole genome looking at variations in DNA called single nucleotide polymorphisms (SNPs). If they find one that is consistently associated with the disease group, they can say that people with that genetic variation might be at risk of the disease. In the present study, rather Coffee drinking might be in your genes. RIKEN geneticists have found four genes that coffee drinkers often have. than looking first at diseases, the RIKEN team looked at dietary chromosomes—that were asso- all the dietary items that “By estimating individual dif- habits since they wanted to ciated with consuming coffee, were examined. ferences in dietary habits from determine whether any specific tea, alcohol, yogurt, cheese, “We found that this particular genetics, especially the ‘risk’ of genetic variations make people natto (fermented soy beans), variation in a single DNA nucleo- being an alcohol drinker, we can ‘at risk’ of habitually eating tofu, fish, vegetables or meat. tide at the ALDH2 gene was help create a healthier society,” certain foods. Initial diet-genome associations related to consuming less alcohol, Okada explains. “We know that what we eat showed that the ingredients natto, tofu and fish, and, at the defines what we are, but we mattered. For example, they same time, related to consuming found that what we are also found positive genetic correla- more coffee, green tea, milk and Reference defines what we eat,” says tions between eating cheese and yogurt,” says Okada. 1. Matoba, N., Akiyama, M., Yukinori Okada, a visiting eating yogurt. The researchers discovered Ishigaki, K., Kanai, M., Takahashi, A., Momozawa, scientist at the RIKEN Center for The team discovered ten diet– that six of the SNPs were related Y., Ikegawa, S., Ikeda, Integrative Medical Sciences. genome associations that have to at least one disease phenotype, M., Iwata, N., Hirata, M. Using genetic data from never been reported before. Four including several types of cancer et al. GWAS of 165,084 more than 160,000 Japanese of them were related to coffee as well as type 2 diabetes. Japanese individuals identified nine loci people who had filled out a and three to alcohol. One SNP As with genome-wide asso- associated with dietary food-frequency question- already known to be associated ciation studies for diseases, habits. Nature Human naire, the team found nine with coffee and alcohol was the current results can benefit Behaviour (2020).

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PLANT HORMONES Shining a new light on ethylene A specially designed biosensor can detect the distribution of an important hormone in plants

simple way to monitor and protects it. A the level of ethylene, an Tanaka and his team tested important hormone in plants, has their metalloenzyme on various been developed by chemists at fruits and vegetables and found RIKEN1. This development will that it could detect ethylene in help researchers probe in more fruits as they ripened. Unlike detail than ever before the roles previous ethylene biosensors, it this hormone plays in plants. could show the distribution of the Ethylene is involved in many ethylene over the fruit, providing processes in plants, including a detailed spatial and temporal the ripening of fruit and the map of how ethylene spreads. shedding of leaves in the fall. The researchers then used It is commonly used to induce the experimental plant model fruit to ripen. But ethylene is a Arabidopsis thaliana to examine tiny molecule (C2H4) that readily the release of ethylene in diffuses across membranes, response to stresses such as making it difficult to detect at pathogens. They found that the the point where it is produced in biosensor accurately detected the a plant. presence of ethylene. Metal catalysts encased in “Our work has two important proteins known as artificial implications,” says Tanaka. “One metalloenzymes are promising is in the field of artificial metal- as sensors because scientists can loenzymes, where we have been design them to detect molecules able to use a principle of nature of interest. to produce something that does Now, a team led by Katsunori not exist in nature. And secondly, Tanaka of the RIKEN Biofunc- our work will contribute to tional Synthetic Chemistry Labo- understanding how ethylene is ratory has developed a biosensor produced in plants, as we can based on an artificial metalloen- measure the concentration of zyme that can detect ethylene gas ethylene when it is still within in fruits and leaves. cells.” The team designed an artificial The team now intends to metalloenzyme, which consisted improve the biosensor by making of a ruthenium-containing its reactivity faster so that it complex encased in an albumin can measure ethylene before it scaffold, such that it fluoresces becomes gaseous. They also plan in the presence of ethylene. to enhance its ability to enter Specifically, the ruthenium cells rather than remaining in the complex has two components: extracellular environment. one that fluoresces and one that quenches the fluorescence. When ethylene reacts with the artificial metalloenzyme, the fluorescence- Reference quenching molecule is released 1. Vong, K., Eda, S., Kadota, Y., Nasibullin, I., Wakatake, T., Yokoshima, S., Shirasu, K. & Tanaka, K. An artificial and the complex starts to metalloenzyme biosensor can detect ethylene gas in fruits and fluoresce. The protein casing both Arabidopsis leaves. Nature Communications 10, 5746 (2019). makes the metal complex soluble

24 RIKEN RESEARCH RESEARCH HIGHLIGHTS

IMMUNOLOGY The killer cells for a ripe old age A certain kind of immune cell may hold the secret to a long life

eople over the age of 110 have P high levels of a certain type of immune cell, RIKEN researchers have discovered1. This finding could provide important clues about how to enhance the body’s immune system to fight diseases like cancer. Supercentenarians, or people over 110, are extremely rare. For example, in 2015, Japan had more than 61,000 centenarians, but just 146 supercentenarians. “We were especially interested in studying this group of people, because we consider them to be . a good model of healthy aging, et al and this is important in societies like Japan where aging is pro- ceeding rapidly,” comments Kosuke Hashimoto of the RIKEN Center for Integrative Medical Science (IMS). Supercentenarians are relatively immune to illnesses such as infections and cancer during their lifetimes, suggesting that their immune systems may be RIKEN researchers found that supercentenarians had higher levels of cytotoxic CD4-positive cells—a kind of immune cell— particularly strong. To explore than a younger control group. this idea, the researchers looked at circulating immune cells from while those with the CD4 marker “This research shows how sin- it has given us new insights into two groups: supercentenarians are not. But the CD4-positive gle-cell transcription analysis can how people who live very long and younger controls. They found cells of the supercentenarians had help us to understand how indi- lives are able to protect them- that the supercentenarians had become cytotoxic. Intriguingly, viduals are more or less suscepti- selves from conditions such as fewer B-cells than the younger young donors had relatively few ble to diseases. CD4-positive cells infections and cancer.” controls, but the two groups had CD4-positive cytotoxic cells in generally work by generating about the same number of T-cells. their blood, indicating that this cytokines, while CD8-positive However, the supercentenar- was not a marker of youth but a cells are cytotoxic, and it may be Reference ians had more of one subset of characteristic of the supercente- that the combination of these two 1. Hashimoto, K., Kouno, T-cells. Analysis of these cells narians. The team speculates that features allows these individu- T., Ikawa, T., Hayatsu, N., Miyajima, Y., Yabukami, revealed that the supercentenar- the cells might be an adaptation als to be especially healthy,” says H., Terooatea, T., Sasaki, ians had very high levels of cells to the late stage of aging. Piero Carninci, also of IMS. “We T., Suzuki, T., Valentine, that are cytotoxic, meaning To look at how these special believe that these types of cells, M. et al. Single-cell that they can kill other cells, cells were produced, the team which are relatively uncommon transcriptomics reveals sometimes amounting to 80% of examined the blood cells of two in most individuals, even young expansion of cytotoxic CD4 T cells in supercentenarians. all T-cells (compared to just 10% supercentenarians in detail and people, are useful for fighting Proceedings of the National or 20% in the controls). found that many of the cells against established tumors, and Academy of Sciences USA Normally, T-cells with markers were the progeny of a single could be important for immuno- 116, 24242−24251 (2019).

© Reproduced from Ref. 1 and licensed under CC BY 4.0 [https://creativecommons.org/licenses/by/4.0/legalcode ] © 2019 K. Vong known as CD8 are cytotoxic, ancestor cell. surveillance. This is exciting as

SPRING 2020 25 PERSPECTIVES

Building a roadmap to real world outcomes With the launch of a new company, the deepening integration of industry and RIKEN researchers is poised to create a suite of new patent-winning products, says Hidetoshi Kotera.

26 RIKEN RESEARCH PERSPECTIVES

s scientists, there is nothing more RIKEN continues to partially fund the program rewarding than seeing years’ worth of thereafter, as we see value in the seeds of ideas born relentless research effort make an impact from collaborations. in the real world. If inventing products While the Baton Zone is designed for projects Afrom academic labs were simple, industry collab- close to the commercialization stage, the Industrial orations would be a clear win-win for everyone. Co-creation Program (ICoP) facilitates open inno- The reality, however, is that the path is fraught with vation for research concepts in an earlier stage of obstacles—and more often than not it’s human development. The objective is for upper-level manage- factors, such as emotions and motivations, that ment and researchers from industry to join RIKEN in impede progress. RIKEN is now working on ways to brainstorming ideas for projects that tackle societal support researchers in their efforts to develop inno- issues. The ideas emerging from ICoP tend to be for vative products. A new RIKEN-funded corporation basic research, and these eventually mature into col- is yet another leap forward in making industry– laborative research projects like the ones undertaken HIDETOSHI KOTERA academia partnerships fruitful. in the Baton Zone program. As of spring 2019, we have Executive Director Businesses, I should add, are also keen on having 11 business partners working with RIKEN research academics on board. Until a product is ready for the centers—Toyota, Olympus, and Kao, to name a few. Hidetoshi Kotera was market, there are almost always small modifica- Interest in collaborations for artificial intelligence appointed an executive director at RIKEN in April tions—adjustments to engineering specs or tweaks to (AI) has also soared over the past few years, with four 2018. He is also program computational formulas—best done by the innovators partners joining forces with the RIKEN Center for director of the RIKEN already deeply involved in its development. However, Advanced Intelligence Project (AIP). One of these Industrial Co-creation Japanese academics consider the time it takes to do is a partnership with Toshiba that seeks to develop Program (ICoP), this detailed work as drawing them away the next big self-learning AI software to facilitate next-generation which supports joint discovery. In the past, the researchers who collabo- manufacturing and social infrastructure projects. research with industry, rated to do this have been the outliers. One potential application, for example, is to control and the RIKEN Baton Zone Program, which robots involved in routine infrastructure inspec- helps transfer RIKEN’s BATON ZONE tions—at present, these robots don’t function well in scientific achievements Baton Zone is RIKEN’s flagship program bridging changing environmental conditions, including rain so that they can be used research and business. Within this program, we and wind. in commercial products designate project leaders from industry and sub-leaders through partnerships from RIKEN to form a joint team on one of RIKEN’s with private companies. Additionally he serves campuses. The attraction for RIKEN researchers here is As of spring 2019, as the director of the the potential to discover new ideas for research through RIKEN Cluster for the repeated trial and error of developing a product. we have 11 business Science, Technology During this time, researchers may begin to see their and Innovation Hub, work in a different light—I’m told it gives them inspira- partners working which aims to create and tion for new studies, which could evolve into yet more strengthen networks for research and products worth developing. withRIKEN research development. Since its launch 16 years ago, the program has brought together businesses and RIKEN research centers—Toyota, labs in 36 mid- to long-term projects. We’ve seen incredible cases of success; an example from the field Olympus, and Kao, of medicine is DuraBeam, an artificial dura mater (a to name a few. membrane that surrounds the brain and spinal cord) that is pasted onto a patient’s skull during surgery. Using a RIKEN-developed polymer resin processing NEWCOMER TO COMMERCIALIZATION technology, DuraBeam overcomes the difficulties that A newcomer to RIKEN’s industry collaboration other products have had with adhesion, minimizing ecosystem is RIKEN Innovation Co., Ltd., an external the time it takes for surgery and thus reducing the risk corporation established in September 2019 to bolster of infections. With its high biocompatibility, it also support for collaborations with industry. Concern- overcomes the risk of adhesion to other organs, which ingly, the conversation about industry–academia becomes an issue in the long term. collaboration in Japan is heavily skewed towards ini- In spring 2019, we moved from a funding system tiating a partnership and tends to overlook providing in which costs are shared equally by RIKEN and a support throughout the lifetime of a project. At the partner company, to a new structure in which moment, collaborative teams are generally left to their RIKEN funds a quarter of total research costs. This, own devices after partnerships kick off; given the I believe, is a healthier funding balance, as profits aforementioned cultural disparities in academia and from commercialized products go to the business. industry, it’s an invitation for failure. One of the main

SPRING 2020 27 PERSPECTIVES

to strengthen patents, and ultimately help to organize appropriate and nuanced contracts, for instance, flexible types of contracts for emerging areas such as A FEW OF RIKEN’S TANGIBLE CONTRIBUTIONS artificial intelligence. RIKEN partners have commercialized many of its findings and RIKEN will soon have a greater hand in this process. The company will also assist in developing ideas for startups derived from RIKEN research. This new capacity will especially be useful to the large number of projects where the market size for a promising 1925 1987 2015 RIKEN scientists Kao Corporation launches The PASESA Blood Pressure product is viable, but relatively small, as projects like invent almite, Attack, a laundry detergent Monitor is released. The these tend to fly under the radar at large corporations. which is used to produced using alkaliphilic monitor includes the AVI The new company will also help advise RIKEN on coat aluminum bacteria discovered by Index, co-developed for strong RIKEN’s Koki Horikoshi. by RIKEN to analyze the its funding distribution strategy among its existing kitchenware. condition of the central startups and provide business management support. arteries near the heart. RIKEN’S BIG INVESTMENT 1936 1990 2017 The predecessor Hitoshi Ohmori and DuraBeam, an With the RIKEN Innovation Company, we’re of today’s Ricoh Takeo Nakagawa develop artificial dura piloting—for the first time in Japan—a scheme that (known now for a highly efficient process mater developed brings together, in an external entity, support for tech- photocopiers) for grinding ceramics at RIKEN, is is formed to (ELID technique). approved for nology licensing and for startups. We absolutely need sell positive This technology is now production and the company to grow, since we expect it to channel sensitized paper. in use in processing distribution. automobile components. significant output from RIKEN’s basic research into society. A handful of unforeseen challenges will come our way, and that’s okay; it’s part of our intention to adapt the scheme as we go along. One criticism I anticipate is this: Why establish an external corporation when the same tasks can be undertaken internally? My answer is that it is for the sake of customer satisfaction. If the organization were part of RIKEN, the services it provides would be RIKEN-centric, following rigid institutional rules for 2004 2019 budgeting and staffing. On the other hand, with an Launch of the Baton Zone program Establishment of RIKEN to support the transformation of Innovation Co., Ltd., an external organization, RIKEN and industry partners RIKEN’s scientific achievements external corporation to both become clients. The organization’s priority is to into commercial products through support collaborations offer a solution that maximizes the benefits for both partnerships with private companies. with industry. parties. That makes it much easier to identify priori- ties on actionable items. At the end of the day, it’s the soft skills like a service-oriented business mindset and a fast-paced company culture that make or break a project. The bureaucratic, first-in first-out work functions of the new company is to provide ongoing style of traditional academic institutions simply will project management, based on the personalities and not work for securing patents in a fast-paced environ- work styles of the teams. ment. An additional plus is that being a corporation Thanks to a revision in the law in 2019, RIKEN lowers the barriers for other businesses reaching out is now able to invest in businesses that profit from for collaboration opportunities. RIKEN’s research output. As a result, the RIKEN We’ve analyzed a wealth of data and are confident Innovation Company is, and will be, wholly funded that RIKEN Innovation will be able to carry industry– by RIKEN. In addition to research coordination, the academia collaborations forward. Now, it’s a matter company provides multifaceted support, notably, in of making a success of the new strategy. The staff at applying for technology licensing and venture capital. the new company come from various backgrounds Patents are key to launching start-ups and protecting in academia and business; I anticipate three years for high-profile projects; there is now a stronger need the company’s culture to meld with RIKEN’s, and five than ever before to strategically foster patent-win- years until it is fully operating. At this point, micro- ning work years in advance of commercialization. To management and nit-picking will kill the program. make sure this happens, RIKEN’s new company will For the five years it takes until this new arm is at work in tandem with research teams. Its employees full throttle, I’d like to ask you all to provide only will start with market research on intellectual constructive feedback that will help the project property strategies, help collecting supporting data to improve.

28 RIKEN RESEARCH FEATURES

NEW CLUES IN AI CANCER PROGNOSES

Understanding artificial intelligence’s reasoning has taken it from cancer prognosis tool to a means to understand why cancers reoccur © 2020ANNE RIKEN WESTON, FRANCIS CRICK INSTITUTE / SCIENCE PHOTO LIBRARY

SPRING 2020 29 FEATURES

DIGGING INTO DEEP LEARNING A deep-learning algorithm developed by By selecting a column RIKEN researchers discovers features in pathology (one shown in yellow), images that suggest a cancer might reoccur and doctors can bring up the presents this in a way that doctors can understand. images associated with it.

[87] [0.690] [0.511]

The red on the pathology image show areas that indicate that there is a high probability of cancer recurrence (the heights of the red columns correspond to the probability of cancer reoccurring).

rtificial intelligence (AI) is quickly accountable manner with transparent decision-mak- changing the way medical diagnoses ing processes and appropriate safeguards. and prognoses are made. For example, machine learning systems can already OPENING THE BLACK BOX Adiagnose Alzheimer’s disease from pathology images Now, Yoichiro Yamamoto of the RIKEN Center for with greater accuracy than human experts. Advanced Intelligence Project and his co-workers in But AI suffers from a major limitation: the reasons Japan are lifting the lid on this black box. it makes a prediction are so complicated that it is Yamamoto’s team has developed a deep-learning effectively a black box to human experts. The AI deep system that can surpass human pathology experts learning systems used in medical research often rely in accurately predicting the probability that prostate on algorithms in which correlations are reinforced cancer will reoccur within one year1. (backpropagation), forming complex networks to They trained their system by using a portion provide suggested prognoses or diagnoses. But it can of more than 13,000 pathological images of whole be a bit like looking up the answer to a math problem prostates acquired from a hospital in Tokyo. The at the back of a text book—it might give you the right researchers then evaluated its performance by letting answer, but if you don’t delve into the process of how it loose on the remaining images and seeing how well it was derived, you’re none the wiser when confronted its predictions matched actual outcomes. with a different problem. In the study, human pathologists scored an This issue was acknowledged by the guidelines accuracy, as AUC (area under the curve), of 0.744 on drawn up by the G20 summit held in Osaka in June a scale between 0 and 1 (where a score of 1 indicates 2019, which call for AI to be developed in a fair and perfect accuracy), while the machine achieved an

30 RIKEN RESEARCH FEATURES

of their prognoses; it is also a powerful research assistant that can uncover new areas for human researchers to explore. “This is breaking new ground for AI,” notes Yamamoto.

BETTER WORKING AND LEARNING TOGETHER While the deep-learning system was more accurate than human pathologists, the highest accuracy was achieved when both AI and humans cooperated in making prognoses (a score of 0.842). Yamamoto thinks this is because humans and machines complement each other. “Humans and AI have different strengths when evaluating pathology images: humans tend to be better This feature looks at focusing on the small areas that contain cancer cells, at the work of whereas AI is better at getting an overall view based YOICHIRO YAMAMOTO on the entire image.” So Yamamoto doesn’t anticipate that AI will replace human pathologists any time soon. Yoichiro Yamamoto received his Doctor Indeed, he sees a two-way interaction in which humans of Medicine and PhD 1447 1447 1447 1447 503 503 will learn from machines and machines from humans. degrees from Tohoku University. His PhD ROBUST ACROSS HOSPITALS thesis focused on 503 503 503 503 503 503 Another critical point is that the deep-learning system the cell dynamics had similar accuracies when it was used in two other in the carcinogenesis hospitals in different prefectures in Japan. “This is process. From 2012 onwards, he focused on a very significant result,” says Yamamoto. He says it 503 503 503 1426 1426 1426 mathematical modeling reveals the potential for very broad use of their system. of cancer cell dynamics This robustness in different settings is the result of at the Mayo Clinic and the use of our unsupervised learning-based algorithm, Harvard University. 1426 1518 614 665 1331 1331 says Yamamoto. In this type of learning, a computer This led to his current is fed unlabeled images and the outcome and has to interest in artificial intelligence (AI). In figure out the relationship between the two on its 2014–2015, his research own. In contrast, supervised deep learning involves at Heidelberg University spoon-feeding the machine with data that has been in Germany focused labeled with various output parameters. This makes on computer science, it easier to implement, but its accuracy sometimes and he succeeded in reduces markedly when it is used in environments developing a new way to combine pathology impressive 0.820. In the clinic, this could help doctors different from the one in which it was trained, in and machine learning. decide whether a patient needs additional treatments which labeling or imaging might be slightly different. In 2017, he moved to or merely to be monitored. In contrast, unsupervised learning was much more the RIKEN Center for But Yamamoto’s system goes further and shows stable in their dataset. Advanced Intelligence what image features the AI has correlated positively Yamamoto thinks that unsupervised learning Project (AIP) to start or negatively with recurrence, so that pathologists can should be highlighted in medicine more often and he his own lab. His lab’s try to better understand why. says th e technique is not restricted to prostate cancer. mission is to discover disease mechanisms One example of a novel insight that the team’s Yamamoto and his team are now applying it to breast and new therapies deep-learning technology has uncovered is that it cancer and other rare cancers. They may also extend through state-of-the-art sometimes highlights images that don’t include any it to other, non-medical fields that involve large AI technologies and cancer cells. “AI says these images are very important amounts of images. medical big data. for predicting cancer recurrence, but you won’t find them in pathology books produced by humans,” says REFERENCE Yamamoto. “This is new knowledge.” More research is 1. Yamamoto, Y., Tsuzuki, T., Akatsuka, J., Ueki, required to find out what is important in these images. M., Morikawa, H., Numata, Y., Takahara, T., “Most AI techniques have only been used for classifi- Tsuyuki, T., Tsutsumi, K., Nakazawa, R., Shimizu, cation, so they essentially mimic human pathologists,” A., Maeda, I., Tsuchiya, S, Kanno, H., Kondo, Y., explains Yamamoto. “But our deep-learning technol- Fukumoto, M., Tamiya, G., Ueda, N. & Kimura, G. ogy goes beyond that—it can glean new insights.” Automated acquisition of explainable knowledge The technology is therefore more than just a tool from unannotated histopathology images. Nature

SPRING 2020 31 INFOGRAPHIC

CREAM OF THE CROP The RIKEN Center for Sustainable Resource Science (CSRS) is led by a number of researchers listed among 2019’s top 1% in plant and animal science by citations. Two are at the center of an influential group of long-term collaborators that currently lead the world’s top 15 plant science researchers by citations (below). Their findings are improving crops and cultivation knowlege around the globe.

TOP 15 RESEARCHERS BY CITATIONS IN PLANT SCIENCE GLOBALLY (1980–2019) 2 12 Primary RIKEN affilation Unaffiliated with RIKEN

Kazuo Shinozaki Motoaki Seki Director, RIKEN Center Team Leader, Plant borativ (colla e cita for Sustainable Resource Genomic Network 825 tion 19, s) Science (CSRS) Research Team, CSRS 1,072 51,982 plant science citations 21,572 plant science citations 401 (74,276 total citations) (26,551 total citations)

1,072 401 PAPER HIGHLIGHT: PAPER HIGHLIGHT: A 1998 Plant Cell paper on A 2002 paper on the the importance of DREBs transcriptome analysis of transcription factors in Arabidopsis genes under 33,766 11,746 drought and cold stress drought, cold and high- responsive gene expression. salinity stresses. • 1,788 citations • 1,330 citations • 55 patent citations • 27 patent citations One involved improving One on a method to the drought resistance of increase stress tolerance rice by overexpressing an in plants. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Arabidopsis gene.

ALSO IN THE TOP 1% OF RESEARCHERS IN PLANT AND ANIMAL SCIENCE GLOBALLY

Kazuki Saito Ken Shirasu Lam-Son P. Tran Hitoshi Yuji Kamiya Group Director, Group Director, Unit Leader, Sakakibara Research consultant Metabolomics Plant Immunity Stress Adaptation Senior Visiting Scientist, 19,802 total citations Research Group, CSRS Research Group, CSRS Research Unit, CSRS Mass Spectrometry and 24,142 total citations 12,295 total citations 12,025 total citations Microscopy Unit PAPER HIGHLIGHT: 15,308 total citations A 2011 PNAS paper PAPER HIGHLIGHT: PAPER HIGHLIGHT: PAPER HIGHLIGHT: on a key auxin (plant A 2010 paper on a A 2008 Nature paper A 2004 Plant Cell PAPER HIGHLIGHT: hormone) biosynthesis repository of mass on the inhibition of paper that also A 2007 Nature paper pathway indispensable spectra of small shoot branching involved Kazuo on a pathway critical to to growth and natural compounds for by new terpenoid Shinozaki on how rice size and branching. development. metabolomics study. plant hormones. It’s NAC transcription • 449 citations • 391 citations • 820 citations among the top 5% of factors regulate • 4 patent citations all research outputs drought tolerance. One to produce scored by Altmetric. • 751 citations plant compounds • 992 citations • 6 patent citations to defend against • 6 patent citations One on a method pathogenic microbes One on a method to increase grain and herbivores. for controlling root protein content and parasitic plants. delay deterioration. Source: InCites; *All papers can be found online at www.riken.jp/en at online found be can papers *All InCites; Source:

32 RIKEN RESEARCH RIKEN’S CENTERS AND FACILITIES across Japan and around the world

LEGEND WAKO ●● (RIKEN’s Headquarters) Strategic Research Center ■■ Research Infrastructure Center ●● Interdisciplinary Theoretical and ◆◆ Large Research Infrastructure Mathematical Sciences Program (iTHEMS) ▲▲ Research Cluster ●● Center for Brain Science (CBS) ▼▼ Other ●● Center for Sustainable Resource Science (CSRS) ●● Center for Emergent Matter Science (CEMS) ●● Center for Advanced Photonics (RAP) ●● Nishina Center for Accelerator-Based Science (RNC) ▲▲ Cluster for Science, Technology, and Innovation Hub (CSTIH) ▲▲ Cluster for Pioneering Research (CPR) ◆◆ Radio Isotope Beam Factory (RIBF) ▼▼ Head Office for Information Systems and Cybersecurity SENDAI ●● Center for Advanced Photonics (RAP)

YOKOHAMA ●● Center for Integrative Medical Sciences (IMS) ●● Center for Biosystems Dynamics Research (BDR) TSUKUBA ●● Center for Sustainable Resource Science (CSRS) ■■ BioResource Research ■■ SPring-8 Center (RSC) Center (BRC) ▲▲ Cluster for Science, Technology, and Innovation Hub (CSTIH) ◆◆ BioResource ◆◆ Genome Sequencing ◆◆ Nuclear Magnetic Resonance (NMR) TOKYO ●● Center for Advanced Intelligence Project (AIP) HARIMA ▼▼ Innovation Design Office ■■ SPring-8 Center (RSC) ◆◆ SPring-8 ◆◆ SACLA NAGOYA

KEIHANNA ●● Center for Advanced Intellegence Project (AIP) ■■ BioResource Research Center (BRC) KOBE ●● Center for Biosystems Dynamics Research (BDR) ■■ Center for Computational Science (R-CCS) ▲▲ Cluster for Science, Technology, and Innovation OSAKA ● Hub (CSTIH) ● Center for Biosystems

◆◆ Molecular Imaging Dynamics Research (BDR)

Since relocating its original campus from central Tokyo Singapore and other countries. To expand our network, to Wako on the city’s outskirts in 1967, RIKEN has rapidly RIKEN works closely with researchers who have returned to expanded its domestic and international network. their home countries or moved to another institute, with help RIKEN now supports five main research campuses in Japan from RIKEN’s liaison offices in Singapore, Beijing and Brussels. and has set up a number of research facilities overseas. In addition to its facilities in the United States and the United For more information, please visit: Kingdom, RIKEN has joint research centers or laboratories www.riken.jp/en/research/labs/ in Germany, Russia, China, South Korea, India, Malaysia, www.riken.jp/en/collab/research/ www.riken.jp/en

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RIKEN 2020-016