RIKEN Research Is Published ISSN 1883-3519 • Makoto Taketani (RCH) • Yasunori Yamazaki (CPR) Institute in 2015

WINTER 2019

SHOWCASING THE BEST OF JAPAN’S PREMIER RESEARCH ORGANIZATION • www.riken.jp/en/ LEAVING NO CELL UNTURNED Mapping the human body in its entirety

WORM POWER GENEROUS THINKING IMAGING A COSMIC WEB Device powered by The neural origins of Gas filaments that birthed muscles from earthworms generosity uncovered galaxies spotted e ▲ UNDERSTANDING ACTIVATED CANCER CELLS A human lung fibroblast cancer cell (orange) among healthy fibroblasts (purple). Lung cancer, also called lung carcinoma, is a malignant lung tumor. It is characterized by uncontrolled cell growth in the tissues of the lung, especially lung epithelial cells. One of the aims of the Human Cell Atlas (see page 29) is to understand the different states of cells, such as how healthy fibroblasts become ‘activated’ and cancerous.

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) © DENNIS KUNKEL MICROSCOPY / SCIENCE PHOTO LIBRARY TABLE OF CONTENTS

Editorial Research 3 New subsidiary to bring 10 highlights findings to fruition COVER STORY 10 Massive filaments fuel People the growth of galaxies 11 New magic number 4 How mitochondria confirmed influence our mood 12 Tuning neurotransmission Emilie Kristine Bagge p.12 Research Scientist COVER STORY The dynamics 13 Harnessing the muscle of single cells power of worms

Hirofumi Shintaku 14 Light puts electrons RIKEN Hakubi Research in a spin Team Leader 15 RIKEN click reaction weaponizes antibodies

16 Revisiting catalyst calculations after a century

17 Blasts from the past p.17

Briefs 6 Center for Brain Science Summer Program

A new ultraviolet eye on our planet

RIKEN opens joint lab in Luxembourg

Eighth Global Summit of Research Institute Leaders

RIKEN–Max Planck joint symposium

Tsinghua University–RIKEN IMS joint summer program

Nishina School

WINTER 2019 1 TABLE OF CONTENTS

Research COVER STORY 18 highlights Feature 26 Deepening our understanding of selfish behavior RIKEN researchers have identified distinct neural processes 18 Analyzing genome structure at ultrahigh that occur when we make decisions for the benefit of others. resolution

19 Structural study reveals secret of stressed cells

20 Turning stem cells into blastocyst-like structures

21 Enhancing enhancers

22 Brain tissue kept alive for weeks

23 Catching chromosomes changing their shape

24 Searching for the Majorana quasiparticle

25 A polarizing influence in cells

Perspectives COVER STORY 29 Why map every cell in the human body? RIKEN is spearheading Asia’s efforts for the Human Cell Atlas, a push to understand the regulatory networks that make human cells unique.

p.21

p.25

2 RIKEN RESEARCH EDITORIAL

New subsidiary to bring findings to fruition

Hiroshi Matsumoto President, RIKEN

have some exciting news to report. of Japanese industry. And in the 1920s and On September 5, RIKEN established a fully 1930s, several companies—many still active WINTER 2019 owned subsidiary called RIKEN Innovation, today—were established under RIKEN’s umbrella. SHOWCASING THE BEST OF JAPAN’S PREMIER RESEARCH ORGANIZATION • www.riken.jp/en/ I LEAVING which will work closely with our laboratories RIKEN is one of Japan’s leading innovators, as NO CELL UNTURNED and industry partners to ensure that the fruits our research papers are frequently cited in patent Mapping the human body of our research are used to benefit society. The applications filed by private companies. in its entirety company will be staffed by professionals skilled Like past issues, this issue of RIKEN Research at identifying potentially useful discoveries and contains several examples of research that could finding suitable partners, both in Japan and lead to commercial applications. For example, overseas. RIKEN researchers have developed an earthworm WORM POWER GENEROUS THINKING IMAGING A COSMIC WEB Device powered by The neural origins of Gas filaments that birthed The Japanese name of the subsidiary is muscle-derived valve that can operate without muscles from earthworms generosity uncovered galaxies spotted RIKEN Teigyo, which includes the Japanese electricity (page 13) and a simple chemical COVER STORY: character (鼎) for a bronze vessel with reaction that could make radioactive particles RIKEN is leading the three legs. In the case of RIKEN Teigyo, more efficient at destroying cancer cells (page 15). Human Cell Atlas’ the three legs signify the pillars of the new I hope you will find this issue enlightening, efforts in Asia to create company: management, technology and and I look forward to working ever more closely a baseline reference social responsibility. with our partners around the world to solve the dataset of human cells. Page 29 RIKEN has a reputation for focusing on major challenges confronting humanity. fundamental research, but in reality many of our © ALFRED PASIEKA / research advances have been used by industry. In SCIENCE PHOTO fact, when RIKEN was established in 1917, its main LIBRARY mission was to contribute to the development

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WINTER 2019 3 PEOPLE

“My research is important for society because….” How mitochondria Many think of neuropsychiatric disorders as ‘mental disorders’, separate from the physical body. I hope that discover- influence our mood ing and describing the molecular mechanisms in patients can help Emilie Kristine Bagge alleviate the taboo often associated Research Scientist, Laboratory for Molecular Dynamics with these disorders. of Mental Disorders, RIKEN Center for Brain Science What made you decide to become a scientist? I am not sure I ever decided to become a scientist—I often think it kind of just Please describe your current Disorders we are trying to elucidate the happened! My plan was to study English research at RIKEN molecular mechanisms of such mitochon- at university, but then I discovered I’m a research scientist at the RIKEN drial dysfunction on whole cell function. molecular biology during my first year of Center for Brain Science, where I study high school and was hooked. the influence of mitochondria on Describe your role at RIKEN neuropsychiatric disorders, especially I am employed as a research scientist mood disorders (bipolar and depres- at the RIKEN Center for Brain Science. sion). While we know very little about the That means I’m responsible for my own molecular pathology of research projects, from coming up with We are often these disorders— research ideas and performing experi- looking to find a risk one theory is that ments to data analysis in close collabo- gene, but in our search to mitochondria ration with other lab members and the and their loss of lab’s team leader, Tadafumi Kato. understand disease we functionality may sometimes overlook be involved. How did you become interested in At the RIKEN your current field of research? genomic structure Laboratory I have always been very interested in for Molecular how cells integrate all the signals they Dynamics are constantly exposed to, as there How and when did you join of Mental is a constant need to respond and RIKEN? adjust to different cues to ensure I joined RIKEN in September 2017, a the stability of not just the cell, but few months after finishing my PhD. I the entire organism. This is espe- was hoping to find a position in Wako cially true in the brain. Add to that a or Tokyo, and when I was preparing disease state, and signal integration my application for this position I becomes extremely complex—and was surprised how much my skills in extremely exciting! molecular biology and genomics could actually contribute to neurobiology. What excites you the most I had no prior experience in the area, about your current research? so I was extremely appreciative Probably that the area is still of RIKEN’s open-minded approach so poorly understood—we to hiring new staff. I think this is recognize and treat mood one of RIKEN’s real strengths—an disorders, but can’t really explain interdisciplinary mindset. how they manifest. There are so many questions waiting to be How has being at RIKEN helped answered. We’re often looking to your research? find a risk gene, but sometimes RIKEN is inhabited by excellent research- overlook genomic structure ers—there’s always an expert around! I’m in our search to understand also constantly impressed by the willing- disease; I think we need to have ness of others to help you and contribute a keen focus on that when we to your ideas and projects I think this is

study mood disorders. very much in the spirit of RIKEN. ■ RIKEN 2019 ©

4 RIKEN RESEARCH PEOPLE

How has being at RIKEN helped your research? The dynamics RIKEN is a research institute that embraces scientists from many fields. The Cluster for Pioneering Research, of single cells which I belong to, is a real melting pot of all kinds of scientists. I’ve Hirofumi Shintaku noticed a wider variety of people RIKEN Hakubi Research Team Leader, Microfluidics RIKEN Hakubi expressing interest in my work since I Research Team, Cluster for Pioneering Research moved to RIKEN. What is the best thing about working at RIKEN? Great staff. They think of researchers Please describe your role at RIKEN During the last decade, the field of first—which allows us to focus on the I joined RIKEN in April 2018 to lead the microfluidics has offered number of science. My team started from scratch, Microfluidics RIKEN Hakubi research disruptive technologies that allowed and so we renovated our research team, which consists of engineers and researchers to characterize single cells space. Although I knew zero about the scientists with backgrounds in mechani- at unprecedented resolution basics like air conditioning, lighting, cal engineering, biophysics and and throughput. water supply, etc., we accomplished biology. We develop new microfluidic the renovations thanks to the support technologies to uncover the hierarchi- How did you become interested in of RIKEN staff. ■ cal systems underlying the apparently your current field of research? stochastic behavior of single cells. I started my research career as a Careers at RIKEN mechanical engineer with an For further information, Please briefly describe your emphasis on microelectromechani- visit our Careers page: current research? Website: www.riken.jp/en/ cal systems and fluid dynamics. careers In 2014, I found that an electric field I have always been passionate E-mail: [email protected] can selectively break down the about applying new technolo- plasma membrane of eukaryotic gies to solve biological questions. cells while retaining the integrity of Ultimately, I would like to describe nuclei membrane. This discovery led single cells with a physical model, me to develop a new approach to and develop a mathematical descrip- separating cytoplasmic contents from tion that predicts the future fate of nuclear components in single cells. My single cells. team exploits this approach to study localization and regulation of tran- What excites you the script abundance across the nuclear most about your current membrane in single cells. We are now research? working to extend the approach to We are now putting our do sequencing-free characterization efforts into develop- of single cells. I believe this series of ing a sequencing-free studies will contribute to understanding approach to understand the most basic elements of life. new molecular mechanisms within single What has been the most cells. This approach interesting discovery in your field will complement state- in the last few years? of-the-art sequenc- Single cells are known to be unique, ing technology to even if they are from a same popula- reveal dynamics and tion. This diversity is important to real instantaneous complex biological functions and snapshots of single hierarchical structures. However, until cells—I’m really recently we had no means to explore excited about this these differences in more depth, project, both as an because of limitations in throughput engineer and as

WINTER 2019 5 BRIEFS

Center for Brain Science Summer Program participant, Maria Scala, discusses sex-specific brain activation networks in zebrafish during a poster session. Center for Brain Science Summer Program

From early June to early August 2019, the Center for Brain Science (CBS) hosted roughly 40 young neuroscientists and emerging researchers. The selection for the CBS Summer Program is highly competitive, with only about one in six applicants being selected. The main theme of the lecture course changes every year. The topic of the 2019 lecture course was “Neurotechnology—Understanding the brain in health and disease". Keynote speaker Susumu Tonegawa, Nobel laureate and RIKEN fellow, spoke on the mechanisms underlying the encoding, consolidation and retrieval of memories. Since the program began in 1999, nearly 300 prominent researchers and more than 800 students have participated. The Summer Program consists of two Panels discussed a wide range of topics including what to think about when looking for a postdoc lab. courses: a two-month internship course or a week-long lecture course. The lecture course laboratories and program participants. an optional Tokyo Bay cruise and a discussion features presentations from prominent The program provided lots of opportunities session with CBS postdoctoral fellows. scientists and poster sessions from CBS for extracurricular interaction, also, including https://cbs.riken.jp/en/summer RIKEN 2019 ©

6 RIKEN RESEARCH BRIEFS

Mini-EUSO (below) was made at RIKEN and has been delivered to the A new ultraviolet International Space Station by a Russian Soyuz rocket to carry out the first ever eye on our planet night observations of the Earth’s atmosphere from On 22 August 2019, a Russian Soyuz rocket help the search for dark matter by putting space in the near- ultraviolet band. took off from the Baikonur launch site on upper limits on the mass of such objects. an experimental mission to the Interna- Another goal is to look at ultrahigh-energy tional Space Station (ISS). Hitching a ride cosmic rays, with energies above 1021 electron on the flight was a revolutionary telescope volts. There are no certain observations of developed by an international team led by events at this energy, with the highest energy Japan’s RIKEN national laboratory. The recorded on the ground being 3 × 1020 electron experiment, dubbed Mini-EUSO, will look volts, so the observations may find that they down at the Earth’s night atmosphere from do not exist. the ISS, essentially using the atmosphere Other goals are to look at biolumines- as an enormous observatory for exploring cence from plankton in the oceans, helping poorly understood phenomena, carrying out to understand sea life and pollution, and to the first night observations of the Earth’s observe high-altitude atmospheric lighting atmosphere from space in the near-ultra- and meteoroids entering the atmosphere. violet band. It has been installed in front Those these phenomena have been examined of the ultraviolet-transparent window in in other light bands; seeing them from above the Russian Zvezda module on the ISS, in ultraviolet could reveal new findings looking at Earth in a nadir position. regarding their mechanisms. Mini-EUSO will have a long list of Mini-EUSO was developed by the JEM– scientific missions. First, it will observe EUSO collaboration, which brings together the near-ultraviolet background level in 306 researchers from 84 institutes in 16 preparation for ultrahigh-energy cosmic- countries. The entire detector was realized ray space observatory missions. Second, it in-house, with the large Fresnel lenses will look for strange quark matter, a type manufactured at RIKEN and the detectors of hypothesized super-dense matter that and electronics integrated and tested at the has never been observed but might create various institutes, leading to a significant cost traces by burning up in the atmosphere. reduction compared to other detectors. Small pieces of this type of matter, www.riken.jp/ called strangelets, are one candidate en/news_pubs/ for dark matter, which is currently the news/2019/20190820_1 subject of a massive scientific search. A failure to see such traces could © 2019 RIKEN 2019 ©

WINTER 2019 7 BRIEFS

MEETINGS AND EVENTS RIKEN opens joint lab in Luxembourg On 9 July, a ceremony was held in Luxembourg to commemorate a memorandum of understanding between RIKEN and the University of Luxembourg’s Luxembourg Center for System Biomedicine (LCSB) and the Luxembourg Institute of Health. Based on this agreement, a joint laboratory will be established. RIKEN’s ties with Luxembourg began with an agreement between RIKEN and LCSB in 2014, and a joint annual symposium has been held since then. In 2015, RIKEN and the Luxembourg National Research Fund signed another agreement. The joint laboratory will work on several areas, including immunology, microbiome and inflammation research. Luxembourg is a world leader in the collection and management of data related to clinical specimens, and the joint research will take advantage of this strength. The plan is to develop a comprehensive medical data system that records patient-derived data in disease models and to research neuroinflammation using human-derived induced pluripotent stem cells. www.riken.jp/en/news_pubs/ news/2019/20190806_1/index.html

ESCH-SUR- ALZETTE, Eighth Global LUXEMBOURG University of Summit of Research Luxembourg Institute Leaders

For the eighth consecutive year, prominent GERMANY academics from 21 institutes and 12 different countries came to Kyoto to attend the Eighth Global Summit of Research Institute Leaders, which was held in conjunction with the 16th Annual Meeting of the Science and Technology LUXEMBOURG in Society (STS) forum. The Japan Science and Technology Agency (JST) and the US Department of Energy provided guest speakers SOUTH OF and mechanisms to support multilateral MUNICH, collaboration were discussed. The meeting was GERMANY Ringberg Castle co-hosted by RIKEN and the Japan Advanced Institute for Science and Technology (AIST) and co-chaired by Matsumoto Hiroshi, president of RIKEN, and Matthias Kleiner, president of the Leibniz Association. www.riken.jp/en/news_pubs/ news/2019/20191021_3/index.html

8 RIKEN RESEARCH BRIEFS

RIKEN–Max Planck joint symposium Researchers from RIKEN and the Max Planck Society in Germany gathered at Ringberg Castle in the Bavarian Alps to discuss systems chemical biology. The meeting, held in September 2019, was the seventh in a series of joint symposiums between the two organi- zations. A jointly managed center is led by Herbert Waldmann, director of the Max Planck Institute of Molecular Physiology, Peter Seeberger, director of the Max Planck Institute of Colloids and Interfaces, Hiroyuki Osada, BEIJING, director of the RIKEN Center for Sustain- CHINA Tsinghua able Resource Science’s RIKEN–Max Planck University Joint Research Division for Systems Chemical Biology, and Chief Scientist Katsunori Tanaka. UNITED STATES www.riken.jp/en/news_pubs/ news/2019/20191025_1/index.html

SOUTH Tsinghua University– KOREA RIKEN IMS joint CHINA WAKO, JAPAN summer program Nishina Center for Accelerator- Based Science In June 2019, the RIKEN Center for Integra- tive Medical Sciences (IMS) co-organized an international summer school in Beijing with Tsinghua University Institute of Immunology. HONG KONG Seminars by leading international researchers discussed immunology, genomics and medical KYOTO, JAPAN science. About 50 young researchers partici- Eighth Global Summit of Research pated. The summer school will be held again Institute Leaders in 2020 at the IMS in Yokohama, Japan. www.ims.riken.jp/english/jobs/summer_ program.php

Nishina School

In July and August 2019, 22 students were shown nuclear physics experiments at the RI Beam Factory located on RIKEN’s Wako campus as part of the 13th Nishina School. Participants arrived from: Peking University, China; Rikkyo University, Japan; Seoul National University, Korea; Tohoku University, Japan; Hong Kong University, China; and, as guests, Phillips Exeter Academy, United States. This year, the school focused on reactions involved in the process of stellar nucleosynthesis. https://indico2.riken.jp/event/3068

WINTER 2019 9 RESEARCH HIGHLIGHTS

Astronomers at RIKEN have mapped in detail the filaments in a massive protocluster of galaxies that lie about 12 billion light years away.

they identified is home to super- The radiation was found to be INTERGALACTIC MEDIUM massive black holes, which act as intense—too high to originate active galactic nuclei, and ‘star- from the ultraviolet background bursting’ galaxies that have very radiation of the Universe. Their Massive filaments fuel active star formation. calculations indicated that “This suggests very strongly the high radiation was likely the growth of galaxies that gas falling along the triggered by star-forming galaxies Gas filaments that spanned millions of light years filaments under the force of and forming black holes. gravity triggers the formation of “It’s very exciting to clearly and spawned galaxies have been spotted for the starbursting galaxies and super- see for the first time multiple first time massive black holes, giving the and extended filaments in the Universe the structure that we early Universe,” says co-author see today,” comments Umehata. Michele Fumagalli from Durham as filaments that connected model is well supported by simula- “Previous observations had University in the UK. “We finally G galaxies in a large pro- tions, it has been difficult to dem- shown that there were emissions have a way to map these struc- tocluster in the early Universe onstrate through observations. from blobs of gas extending tures directly, and to understand were extensive, extending over Now, an international team beyond the galaxies, but now we in detail their role in regulating more than 3 million light years, that included Hideki Umehata have been able to clearly show the formation of supermassive RIKEN astronomers have found¹. of the RIKEN Star and Planet that these filaments are extremely black holes and galaxies.” This finding provides important Formation Laboratory has found long, going even beyond the insights into how galaxies formed observational confirmation of edge of the field that we viewed. in the early Universe. this model of galaxy formation. This adds credence to the idea Reference 1. Umehata, H., Fumagalli, Most of the gas in the Universe They created a very detailed map that these filaments are actually M., Smail, I., Matsuda, Y., lies in intergalactic space, where of the filaments in a massive powering the intense activity that Swinbank, A. M., Cantalupo, it forms filaments that make up a protocluster of galaxies located we see within the galaxies inside S., Sykes, C., Ivison, R. J., cosmic web. Cosmologists con- about 12 billion light years away— the filaments.” Steidel, C. C., Shapley, A. jecture that, in the early Universe, making it a structure that existed Their observations are based E. et al. Gas filaments of the cosmic web located galaxies and supermassive black when the Universe was only on the detection of ultraviolet around active galaxies in a holes formed at the intersection about 1.8 billion years old. The light that is produced when protocluster. Science 366, of these filaments, where matter team found that the intersection neutral hydrogen gas is ionized 97–100 (2019). was concentrated. Although this between the enormous filaments and returns to its ground state. Illustris 2019 (https://www.illustris-project.org)©

10 RIKEN RESEARCH RESEARCH HIGHLIGHTS

NUCLEAR PHYSICS New magic number confirmed Measurements on calcium nuclei show that 34 should join the ranks of magic numbers, which confer greater stability to nuclei

uclear physicists at RIKEN N have shown that 34 is a ‘magic number’ for neutrons, meaning that atomic nuclei with 34 neutrons are more stable than would normally be expected¹. This confirms the suggestions of earlier experiments and provides physicists with greater insight into the structure of the nucleus. Protons and neutrons are organized in shells within a nucleus. A nucleus that has a full shell—in other words, one that has a magic number of protons or neutrons—is particularly stable. This high stability is reflected in nuclear properties, which can be probed in experiments using nuclear- beam facilities such as RIKEN’s Radioactive Isotope Beam Factory (RIBF). Recent studies on neutron- rich nuclei have hinted that new numbers should be added to the known magic numbers of 2, 8, By performing experiments on calcium-54, nuclear physicists at RIKEN have shown that 34 is a magic number for neutrons. 20, 28, 50, 82 and 126. Initial tests at the RIBF in 2013 on calcium- about 60% of the speed of light. exotic systems are currently 54, an unstable nucleus with 20 “This finding They used a specially designed beyond the reach of the RIBF for protons and 34 neutrons, had isotope separator to select and detailed studies, but we believe suggested that 34 was one such demonstrates identify calcium-54 nuclei and that thanks to its increasing missing magic number. that 34 is a part then collided this beam into a capabilities, they will become Now, by painstakingly target of thick liquid hydrogen, accessible in the foreseeable knocking out neutrons one at of the set of or protons, cooled to 20 kelvin. future.” a time, a team led by Sidong magic numbers” The researchers could infer the Chen of the University of Hong detailed shell structure of the Kong has directly measured isotope from the cross-sections Reference how many neutrons occupy were able to demonstrate of the neutrons knocked out as 1. Chen, S., Lee, J., Doornenbal, P., Obertelli, each shell of calcium-54. They quantitatively that all the they collided with the protons, A., Barbieri, C., Chazono, found that calcium-54 exhibits neutron shells are completely allowing them to associate them Y., Navrátil, P., Ogata, K., strong shell closure. This finding filled in calcium-54, and that 34 with different shells. Otsuka, T., Raimondi, F. et al. Quasifree neutron demonstrates that 34 is a part neutrons is indeed a good magic “Major efforts in the future 54 of the set of magic numbers, number,” says Pieter Doornenbal will focus on delineating this knockout from Ca corroborates arising N = though its appearance is of the RIKEN Nishina Center for region,” says Chen. “Moreover, 34 neutron magic number. restricted to a very limited region Accelerator-Based Science. for more neutron-rich systems, Physical Review Letters of the nuclear chart. The team accelerated a beam like calcium-60, further magic 123, 142501 (2019).

© CAROL & MIKE WERNER/VISUALS UNLIMITED, INC./SCIENCE PHOTO LIBRARY PHOTO INC./SCIENCE UNLIMITED, WERNER/VISUALS MIKE & CAROL © “For the first time, we containing calcium-54 to numbers are predicted. These

WINTER 2019 11 RESEARCH HIGHLIGHTS

NEUROSCIENCE Tuning neurotransmission The different regulation of signal strength in neurons across the two sides of a synapse contributes to information processing in the brain

ynaptic strength is Goda at the RIKEN Center S regulated differently in for Brain Science, Japan, response to activity across the and Mathieu Letellier at the two sides of a synapse in mice, University of Bordeaux, France, RIKEN neuroscientists have have assessed the strengths found¹. The finding provides of individual synapses and evidence for a neural mechanism explored how they are modified that compensates for the plastic by neural activity in relation to changes within a single synapse. neighboring synapses. Neurons receive, integrate They found that the efficacy and transmit information as of neurotransmitter release electrical or chemical signals. from presynaptic sites, which Importantly, neurons can alter correlates with presynaptic the strength of their connections, strength, depends on both or synapses, in response to the identity of the presynaptic the inputs they receive. This cell and the location of the synaptic plasticity controls presynaptic site along the how effectively two neurons dendrite. A branch of the communicate with each other tree-like extension in the and is crucial for memory postsynaptic cell, the dendrite Dendrites of hippocampal neurons receive and process information from other formation, consolidation and receives the input from other neurons in the brain. retrieval. However, little is cells (see image). By contrast, known about how changes in the postsynaptic strengths of postsynaptic neuron to produce the specificity of incoming infor- individual synaptic strength are individual synapses, determined an output signal. mation,” Goda explains. regulated within neurons and from dendritic spine size, The researchers also showed The team is now seeking to across networks. depended less on the identity of that presynaptic cell stimulation, determine how activity-depend- the presynaptic cell and mainly which led to a normalization of ent synaptic strength regulation on local synaptic contacts along presynaptic strengths, whereby produces effective signal integra- This mismatch the dendritic branch of the synapses with a low initial neu- tion and processing. “We aim postsynaptic cell. rotransmitter release probability to understand the relevance of between the These findings highlight showed a large increase in this synaptic strength tuning to hip- regulation of a role for local interactions parameter and vice versa, was pocampal memory circuits and between postsynaptic accompanied by a decrease in make this knowledge available synaptic strength compartments along the postsynaptic strengths. for the design of efficient artifi- at pre- and post- dendritic branch that could This mismatch between the cial networks,” she adds. lead to the sharing of plasticity- regulation of synaptic strength synaptic sites was related molecules and spine at pre- and postsynaptic sites clustering or, alternatively, to was unexpected. “Our findings Reference unexpected. 1. Letellier, M., Levet, F., competition for such molecules indicate that the directions Thoumine, O. & Goda, Y. and an overall reduction in of synaptic strength changes Differential role of pre- and Now, by combining postsynaptic strengths. The between the pre- and postsyn- postsynaptic neurons in the electrophysiological recordings resulting synaptic strength aptic sites are not necessarily activity-dependent control with live-cell imaging of distribution in the dendrite parallel and may represent a of synaptic strengths across dendrites. PLoS Biology 17, pyramidal neurons from the will ultimately determine how means to preserve network e2006223 (2019). hippocampus of mice, Yukiko each input is integrated in the stability without compromising © 2019 RIKEN Center for Brain Science

12 RIKEN RESEARCH RESEARCH HIGHLIGHTS

BIOMEMS Harnessing the muscle power of worms By using the muscles of earthworms as a power source, researchers have created a valve that can operate without electricity or fluid pressure

microchip valve powered acetylcholine was applied, the A by earthworm muscle— muscle contracted. The resulting the first valve to be powered by force was transduced to a bar living cells—has been developed that was pushed down to close by RIKEN scientists¹. It doesn’t the valve, stopping the flow of need an external power source, liquid. When the acetylcholine making it promising for use in was washed away, the muscle biomedical applications. relaxed and the valve reopened, An actuator is a mechanical allowing the fluid to flow component that converts energy again. into motion in response to a “Not only can our signal. A common example is a bioMEMS work without valve, which can open and close. an external power source, Actuators are typically powered but unlike other chemi- by electricity or fluid pressure. cally driven valves But using muscles as actuators that are controlled by in a biomedical microelectro- acids, our muscle- mechanical system (bioMEMS) driven valve runs on would have the advantage that molecules that are they can be powered chemi- naturally abundant in cally—the same way as muscles living organisms,” says are powered in living bodies. For Tanaka. “This makes it muscles, the signal for contrac- biofriendly and espe- tion is the molecule acetyl- cially suited for medical choline, which is delivered by applications in which the neurons, while the energy source use of electricity is difficult is adenosine triphosphate (ATP), or not advised.” which is stored in muscle cells. “Now that we have shown Now, Yo Tanaka from the that on-chip muscle-driven RIKEN Center for Biosystems valves are possible, we can work Dynamics Research and his on improvements that will make co-workers have produced it practical,” explains Tanaka. a bioMEMS valve that uses “One option is to use cultured earthworm muscle tissue to muscle cells. This might enable generate a high contractile mass production, better control, force that can be sustained for and flexibility in terms of shape. RIKEN scientists minutes. The team built a micro- However, we will have to account have developed fluidic channel and valve on a for the reduction in the amount a microchip valve that is powered microchip that could be con- of force that can be produced by attaching trolled by the contraction and this way compared with real an earthworm relaxation of earthworm muscle muscle sheets.” muscle to it. stimulated by a very small amount of acetylcholine. The researchers then used a Reference 1. Tanaka, Y., Funano, S., Noguchi, Y., Yalikun, Y. & microscope to monitor fluores- Kamamichi, N. A valve powered by earthworm cently labeled microparticles in muscle with both electrical and 100% chemical liquid as they flowed through control. Scientific Reports 9, 8042 (2019).

WINTER 2019 RESEARCH HIGHLIGHTS

Electron spin created by circularly polarized light (purple arrows, with pink arrows indicating direction of polarization) is converted to an electric current at the interface between copper (Cu) and bismuth oxide (Bi2O3).

SPINTRONICS asymmetric arrangement of atoms. So instead, Puebla’s team showed that a very large Rashba Light puts electrons in a spin effect can be produced at the interface between copper and The interface between a metal and an oxide creates the right bismuth oxide. conditions for optically controlling electrons To experimentally demonstrate this idea, the team shone a spiraling beam of laser light on combination of two polarized light, because it non-magnetic material in which the interface. They were able to A materials that can also rotates about its axis of they could optically induce a spin measure a large light-induced detect rotating light has been propagation (see image), can current and then convert it to a voltage across the materials. “We demonstrated by physicists at create spin-polarized electrons measurable electrical current. demonstrated the absorption of RIKEN¹. This approach could when it is absorbed by an They took advantage of a light with spin information,” says help develop information appropriate material. But this list phenomenon called the Rashba Puebla. processing devices that have of materials is small and limited effect. This effect couples the This effect cannot be seen ultralow power consumption. to those that are intrinsically spin of the electrons to their in either of the two materials In addition to their mass and magnetic. spatial motion, which can separately. “Our work motivates electrical charge, electrons have convert spin current to electrical us to explore whether other a property called spin. Spin can charge current. interfaces have properties that be thought of as the electron’s “We demonstrated “The effect of this ‘Rashba differ drastically from those of rotation on its own axis, and it the absorption field’ is that up and down the materials that make up the takes one of two values: clockwise spin-polarized electrons interface,” says Puebla. or counter clockwise, which are of light with spin move in opposite directions often more simply referred to information” perpendicular to the direction as just ‘up’ and ‘down’. And just that the electrons are flowing,” Reference 1. Puebla, J., Auvray, F., like a flow of electrons generates explains Puebla. “In this way, Yamaguchi, N., Xu, M., Bisri, an electrical current, a flow Now, Jorge Puebla and Florent an electrical current can be S. Z., Iwasa, Y., Ishii, F. & of electrons of the same spin Auvray from the Quantum converted into a spin current and Otani, Y. Photoinduced creates a spin current, which has Nano-scale Magnetism Research vice versa.” Rashba spin-to-charge been heralded as the future of Team (led by Yoshichika Again, the family of materials conversion via an interfacial unoccupied low-power electronic devices. Otani) at the RIKEN Center for that intrinsically exhibit the state. Physical Review One way to create a spin Emergent Matter Science and Rashba effect is small because Letters 122, 256401 (2019). current is to use light. Circularly their co-workers have created a it requires a very specific Matter Science Emergent for RIKEN Center 2019 ©

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RADIOTHERAPY RIKEN click reaction weaponizes antibodies A simple reaction can arm an antibody with a radioactive element that enables it to destroy cancer cells

IKEN chemists have come R up with a potent weapon against tumors in mice by adding a radioactive element to an antibody¹. Tumor-targeting therapy is sometimes referred to as ‘missile therapy’ by researchers in Japan, says Katsunori Tanaka, who heads the RIKEN Biofunctional Synthetic Chemistry Labora- tory (BSCL). That is because two components are needed: a guided missile and a warhead. In the case of radiotherapy, the warhead is a radioactive isotope that kills tumors by subjecting them to high doses of radioactivity. Most isotopes used in radiotherapy are beta-particle emitters— that is, they give off electrons when they decay. But alpha-particle emitters, which release helium nuclei consisting of two protons and two neutrons, are much Chemists at RIKEN have used the RIKEN click reaction to attach the alpha-emitter astatine-211 to antibodies (depicted) preferred since alpha particles to target skin cancer cells. are more than 7,000 times more massive than electrons. As a They then used a reaction The RIKEN click reaction other vehicles for conveying result, they travel far shorter they had previously developed, was crucial for combining astatine-211 to tumors such as distances before stopping, thereby the RIKEN click reaction, to astatine-211 to antibodies, glycoclusters. They are also minimizing collateral damage to attach astatine-211 to antibodies Tanaka notes. “The RIKEN keen to partner with medical healthy cells near a tumor. to target skin cancer cells. The click reagents just go to the researchers to bring the therapy But Tanaka notes there are reaction is very attractive, having surface locations of the to patients. two problems to using alpha- many advantages over conven- antibodies—they don’t react particle emitters in radiotherapy: tional reactions. “Since it is a indiscriminately with all sites producing alpha-particle ‘one-pot’ reaction you don’t have on the antibody,” he says. Reference emitters and then chemically to make each reaction, sequence “This ensures that the antibody 1. Fujiki, K., Kanayama, attaching them to antibodies. of the reactions, and isolate each retains its activity.” Y., Yano, S., Sato, N., Yokokita, T., Ahmadi, P., Now, he and his colleagues have compound and then go to the With help from colleagues at Watanabe, Y., Haba, H. & overcome both problems. next step,” says Tanaka. “We just the RIKEN Center for Biosys- Tanaka, K. 211At-labeled To make an alpha emitter, take the components we need tems Dynamics Research, the immunoconjugate Tanaka and Katsumasa Fujiki, and mix them together.” researchers demonstrated the via a one-pot three- also at BSCL, teamed up with Furthermore, the RIKEN effectiveness of their compound component double click strategy: practical physicists at the RIKEN Nishina click reaction can be performed by using it to target skin cancer access to α-emission Center for Accelerator-Based under mild conditions, which is tumors in mice. They showed cancer radiotherapeutics. Science to use its world-class important since the harsh condi- that it accumulated at tumors Chemical Science 10, cyclotron facility to produce tions of conventional reactions and suppressed their growth. 1936–1944 (2019).

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CATALYSIS Revisiting catalyst calculations after a century Improving on a hundred-year-old approach for analyzing heterogeneous chemical reactions could lead to cheaper, more ecofriendly catalysts

n a discovery that could I lead to novel catalysts that do not contain expensive rare metals, two RIKEN chemists have shown that traditional Hydrogen (H₂) Proton (H+) catalyst-design strategies based on equilibrium thermodynamics may be inapplicable at high reaction rates and have created a framework for performing more- Adsorbed hydrogen accurate calculations1. This means that the design of catalysts will need to be reconsidered to − achieve the highest activities. Electron (e ) Determining the optimal binding energies for heterogeneous chemical reactions—where usually the reactant is in the gas or liquid phase and the catalyst is a solid— is critical for many aspects of modern society, as we rely on such reactions for processes as diverse Two RIKEN chemists have improved chemical century-old calculations for catalysts and demonstrated it using the hydrogen as the production of fertilizers oxidation reaction in which a hydrogen molecule (two red spheres on the left) is converted into two protons (blue spheres) and plastics. The binding energy and two electrons (gold spheres) on a catalyst surface. between the reactants and the catalyst needs to be optimized to thermodynamically favorable. thermodynamically efficient. But have been obtained using the ensure the process is as efficient as Within this framework, the role in the real world, it is often more traditional, thermodynamic possible: if the binding energy is of the catalyst is to improve the practical to have a higher rate of approach,” says Ooka. too positive, the reactants will not thermodynamics of the most catalysis, even if a larger driving “We plan to look for new react with the catalyst, whereas if unfavorable step. force is needed. catalysts, using elements such as it is too negative they will remain Now, Hideshi Ooka and copper or nickel, that can push bound to the catalyst. Ryuhei Nakamura of the RIKEN heterogeneous catalytic reactions In 1911, French chemist “We were happy Center for Sustainable Resource forward. They would be less Paul Sabatier proposed the to see that Science have performed a new set costly and more environmentally existence of an optimum of calculations based on reaction friendly than the current ones, binding energy that maximizes our calculations kinetic modeling that accounts which often require precious the catalytic activity. Recent predict new for this discrepancy. metals such as platinum and advances in computational Their calculations of the palladium,” adds Nakamura. chemistry have provided a strategies of hydrogen oxidation reaction framework that is commonly catalyst design” using heterogeneous catalysis used today to calculate this show how the optimal binding Reference optimal binding energy. These energy can deviate from the 1. Ooka, H. & Nakamura, calculations are based on The catch with this approach traditional understanding at R. Shift of the optimum binding energy at higher equilibrium thermodynamics is that ‘optimum’ is usually taken high reaction rates. “We were rates of catalysis. Journal of and assume that a process to mean that the driving force happy to see that our calculations Physical Chemistry Letters will proceed smoothly if all required to initiate the reaction predict new strategies of 10, 6706–6713 (2019). of the steps in the process are is minimized, so that it is catalyst design which could not © 2019 RIKEN CENTER FOR SUSTAINABLE RESOURCE SCIENCE

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Combined x-ray and infrared image (released by NASA in 2009) of the Tycho supernova remnant. The blast’s outer shockwave is seen here in blue.

“We didn’t know how long we would see an imprint of the explosion,” says Ferrand, “but now I think some of Tycho’s fluffy, irregular appearance was there from the very beginning.”

“We want to see if we can use visible remnants as a probe for the explosions themselves.”

The team has created 3D models for many different types of supernova that a dying white dwarf star can produce. SUPERNOVAE “We now have a way of testing the clumpy, irregular structure whether we can tell them apart,” of Tycho’s remnant. says Ferrand. “This will enable Blasts from the past Now, Gilles Ferrand at the astronomers to assess the RIKEN Astrophysical Big Bang different ways white dwarfs can The evolution of an exploding star begins Laboratory and his international meet their end.” more haphazardly than previously thought team have used recent three- Many supernova mysteries still dimensional (3D) simulations remain to be solved, such as the of a Tycho-like supernova as the appearance of heavy elements. “A IKEN astrophysicists have radiation for thousands of years. starting point for a more realistic clump at the edge of Tycho’s shell R bridged the gap between X-ray telescopes have picked remnant simulation. is rich in iron, which is surpris- studies of supernova and those up several of these supernova “We’re bridging the gap ing as iron usually forms at the of their remnants by using the remnants, which is allowing between the separate groups center,” says Ferrand. “We want output of a supernova model astronomers to glean insights modeling supernovae and to compute the x-ray emissions as the input for a model of into their evolution. those studying the remnants,” from the different elements, so a supernova remnant¹. This In 1572, a supernova was says Ferrand. “We want to see that we can model their distribu- approach offers a way to assess spotted—one of a handful ever if we can use visible remnants tion within the remnant.” the validity of supernova models. seen with the naked eye—and as a probe for the explosions Supernovae are the dazzling named Tycho, after the astrono- themselves.” displays of dying stars and mer Tycho Brahe. Almost 450 Ferrand’s team modeled the Reference 1. Ferrand, G., Warren, D. the birthplace of many heavy years later, x-ray emissions from dynamics of the gas as it evolved C., Ono, M., Nagataki, S., elements, yet how these explo- Tycho’s remnant are providing over the 450 years since the Röpke, F. K. & Seitenzahl, sions originate and evolve astrophysicists a portal to its supernova occurred. Because I. R. From supernova is not fully understood. The past (see image). their realistic 3D model of the to supernova remnant: initial burst of light fades after Previous supernova remnant explosion captured the instabil- The three-dimensional imprint of a thermonuclear a few weeks, but an invisible simulations assumed they ity within the original blast, the explosion. The shockwave continues to spread explode in a sphere, but these team was able to closely recreate Astrophysical Journal 877, out, driving an ever-expanding simplified, often one-dimen- the random, clumpy structure of 136 (2019).

X-ray data: NASA/CXC/SAO; Infrared data: NASA/JPL-Caltech; Optical data: MPIA, Calar Alto, O. Krause et al. shell of gas and dust that emits sional models fail to reproduce Tycho seen today.

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RIKEN researchers developed a technique that can reveal the positions and orientations of nucleosomes (spherical structures in the image) in the yeast genome at high resolution.

in the genome “The crucial advance in that cause gene regulation and our method over previous other genome functions. Hi-C methods is that it can An analytic technique known measure interactions not just as high-throughput chromosome between whole nucleosomes, conformation capture (Hi-C) but also between the DNA entry can reveal information about and exit points of the nucleo- large-scale chromatin structure, some,” explains Priest. “Since but it cannot show structure on the DNA enters and exits on the sub-nucleosome level. approximately opposite sides “The three-dimensional nucle- of the nucleosome, this sub- osome folding structure across nucleosome interaction data the genome was still unknown,” will allow us to map nucleosome CHROMATIN STRUCTURE comments Yuichi Taniguchi of orientations.” the RIKEN Center for Biosys- Using their technique, the tems Dynamics Research (BDR). researchers discovered that the Analyzing genome “If we can achieve a nucleosome- nucleosomes in yeast exhibit level resolution, I anticipate we two folding motifs: four adjacent structure at ultrahigh will see a very strong connection nucleosomes can form a between genome structure and pyramid-like structure or a flat function. I think it’s the next rhombus. This finding could resolution frontier in genetics.” explain two competing models The ability to explore the genome on a sub- The low resolution of Hi-C of chromatin structure proposed nucleosome level promises to lead to new means it cannot reveal the in earlier studies. orientations of nucleosomes—an The team intends to apply discoveries about how chromatin structure is important aspect of chromatin the technique to more complex linked to epigenetics structure. “Just like you can’t situations. “Our next challenge play dominoes without speci- is to apply the technique to the fying the orientation of each human genome and expand our powerful method that can 60 years, more recent research domino tile, you can’t know findings to more general cases,” A pinpoint the positions and has shown how DNA is packaged chromatin structure without says Masae Ohno, the first orientations of individual nucle- into cell nuclei as thread-like knowing the nucleosome orien- author of the study. osomes—one of the building chromatin interspersed with tations,” says David Priest, who blocks of chromatin, which nucleosome ‘beads’. But despite was a postdoctoral researcher at contains the genetic material of a recent advances, there is still a BDR at the time of the study. Reference cell—has been demonstrated on blind spot in our understanding Now, by combining Hi-C with 1. Ohno, M., Ando, T., Priest, yeast by a RIKEN team1. It will of genome structure, namely molecular dynamics simulations, D. G., Kumar, V., Yoshida, Y. & Taniguchi, Y. Sub- help researchers to explore the the details of how nucleosomes Taniguchi and colleagues have nucleosomal genome relationship between chromatin are folded. Such knowledge is been able to reveal the positions structure reveals distinct structure and function. important because nucleosome and orientations of nucleosomes nucleosome folding motifs. While the molecular structure positioning and orientation can in the yeast genome at high Cell 176, 520–534 (2019). of DNA has been known for over couple with molecular reactions resolution (see image). Biosystems Dynamics Research for RIKEN Center 2019 ©

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STRUCTURAL BIOLOGY Structural study reveals secret of stressed cells A study of molecular structure reveals how a small chemical change can make a big difference to function in a cell’s response to stress

tructural biologists at adding such a small group could S RIKEN have discovered have such a big effect on eIF2’s how a small modification to a function. key molecule can shut down Now, Takuhiro Ito and eIF2eIF2 a cell’s protein-producing Kazuhiro Kashiwagi of the machinery when the cell is RIKEN Center for Biosystems eIF2 stressed¹. This finding could Dynamics Research and their help to find new treatments for co-workers have used x-ray neurodegenerative diseases and diffraction and cryo-electron traumatic brain injury. microscopy to determine the Before a stressful event such molecular structure of eIF2 as giving an important speech, when it is bound to eIF2B, which many people experience loss of activates eIF2. They found appetite as the body redirects that eIF2 binds to eIF2B in a resources from digestion to completely different way when eIF2B ‘fight or flight’ responses. A it is phosphorylated compared eIF2B similar thing happens on a to its unphosphorylated form cellular level—cells will stop (see image). eIF2B producing proteins when “This difference in binding subject to a wide range of was really surprising for me,” stresses, including starvation recalls Ito. “When Kashiwagi or viral infection. showed me the density maps for the first time, I was totally shocked by the difference. I “I was totally couldn’t believe it.” shocked by the This finding was the culmination of about 15 years difference. I of work for Ito as he started couldn’t believe it.” investigating the structure of eIF2 when he was a postdoc in 2004. “It’s an interesting and The key event in this stress nice result at the end of a long response is the addition of a investigation,” he comments. phosphate group (PO43−) to It was also a race against time a protein called eukaryotic as other groups were studying Phosphorylated eIF2 translation initiation factor 2 the same system. Another study Phosphyorylated eIF2 (eIF2). As its name suggests, covering a different aspect of Phosphorylated eIF2 this protein plays a key role the eIF2−eIF2B system was in initiating the translation of published in the same issue of Unphosphorylated (top) and phosphorylated (bottom) forms of eIF2 (pink and messenger RNA into proteins in Science as Ito’s paper. purple complex) bind in completely different ways to eIF2B, explaining why eIF2 is the cells of eukaryotes. However, The team intends to determine inactivated by phosphorylation in a cell’s response to stress. the addition of a phosphate the structure of another group stops it from performing initiation factor associated this role, putting the brakes on with the system. They are also Reference 1. Kashiwagi, K., Yokoyama, T., Nishimoto, M., Takahashi, M., protein production so that the interested in finding out more Sakamoto, A., Yonemochi, M., Shirouzu, M. & Ito, T. Structural cell can concentrate its resources about the mechanism of eIF2 basis for eIF2B inhibition in integrated stress response. Science on processes more necessary for and eIF2B in the stress response 364, 495–499 (2019).

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PLURIPOTENT STEM CELLS Turning stem cells into blastocyst-like structures Mice stem cells have been used to produce structures closely resembling blastocysts

n an achievement that holds pluripotent cells—cells that can Now, the team has refined their those naturally found in I promise for fertility and become any type of cell in the reprogramming technique to early developing embryos. regenerative medicine research, body, but not the placenta—and produce embryo-like structures The embryos were eventually structures like the first stage of cells that form the placenta. that are closer to real embryos. resorbed, and the surrounding an embryo have been generated Previously, a team that “Perhaps our most important tissue showed signs similar to from mice stem cells by RIKEN included Cody Kime of the finding was that natural cases of natural resorption. researchers1. RIKEN Center for Biosystems molecules found in the early After fertilization, an egg Dynamics Research noticed mouse embryo can reprogram divides into two cells that can structures resembling cultured cells to become “Natural molecules become any cell type. After blastocysts when they converted surprisingly similar in function found in the early many more cell divisions, pluripotent mouse cells from to early embryos,” says Kime. the embryo becomes a ball of an implanted-like state to a The researchers examined mouse embryo can cells called a blastocyst and pre-implanted state. “Our small clusters of cells a few reprogram cultured implants in the womb, where it reprogramming experiments days before they matured into differentiates and grows into a suggested we had found a the blastocyst-like structures cells to become fetus. A blastocyst consists of way to increase cell potency and found that the cells surprisingly similar beyond pluripotency, which was contained gene expression for unlikely and had not been seen totipotency, which is found in in function to early before,” Kime explains. two-cell embryos. Comparing embryos” “We decided to the blastocyst-like structures find out if it with their precursors, they was real.” discovered that cells in the “Totipotency is the highest matured structures were bound order of cell potency: one close together—a hallmark totipotent cell can form of blastocyst formation and the placenta and the body,” polarization that is the result of a says Kime. “If our system process called compaction. Cells can be improved to fully in the precursors resembled reach that state, we will be embryos at a stage before able to improve basic research compaction, which was in the fields of embryogenesis good evidence that the and fertility, as well as precursor clusters might basic and clinical research include totipotent cells. in regenerative When transplanted medicine.” to the womb of a pseudo-pregnant mouse, the blastocyst- Reference like structures 1. Kime, C., Kiyonari, H., Ohtsuka, S., Kohbayashi, frequently induced E., Asahi, M., Yamanaka, S., changes to the uterus Takahashi, M. & Tomoda, K. needed for blastocyst Induced 2C expression and implantation. The implantation-competent implanted structures blastocyst-like cysts from primed pluripotent stem often grew and cells. Stem Cell Reports 13, produced many types 485–498 (2019). of cells that resembled

Computer artwork of a 100-cell blastocyst embryo. RIKEN researchers have

succeeded in converting mice stem cells into blastocyst-like structures. LIBRARY PHOTO SCIEPRO/SCIENCE ©

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Some portions of DNA (depicted) do not code for proteins. RIKEN scientists have developed an analytical technique for determining the structure of a type of non-coding portion of the genome called enhancers, which activate specific genes.

GENETIC TECHNIQUES

Enhancing enhancers examine five commonly used within cluster regions known as cancer cell lines and were happy super enhancers. By improving a technique for analyzing non-coding to find that the method can be “Using this technology, we are regions of the genome, researchers shed new light used on cryopreserved cells. making a comprehensive map on them “Our new method can be used of enhancer activation in the to study many aspects of biology,” human body,” says Murakawa. says Murakawa. “In the long term, “By integrating the knowledge new technique for elucidat- on. Promoters are located next to it can be implemented in next- with data on mutations associ- A ing the structure of a type the genes they activate, whereas generation genomic medicine.” ated with disease and cancer of non-coding portion of the enhancers are far away, but still The researchers used genomics data, we hope to genome called enhancers, which manage to act on the genes. NET-CAGE to make a series of increase our understanding of activate specific genes, has been Although various techniques interesting discoveries about the mechanisms of diseases.” developed by RIKEN scientists1. have been developed to map enhancers. They identified as The group is currently collabo- The technique will be useful for enhancers, they all have limita- many as 20,000 new enhancers rating with a genomics technol- shedding light on a previously tions. For example, some lack in humans. The team found that ogy company to commercialize a overlooked part of the genome. identification sensitivity, others while promoters are activated in NET-CAGE kit. Non-coding parts of the cannot pinpoint the location of a variety of cell types, enhancers genome used to be dubbed junk the regions, while still others are tend to function in just one cell DNA because they were not ill-suited for use on frozen cells. type, thus showing an important Reference considered to play any useful role. To overcome these limita- difference between the two types 1. Hirabayashi, S., Bhagat, S., Matsuki, Y., Takegami, But they are now known to be tions, a team led by Yasuhiro of region. Y., Uehata, T., Kanemaru, associated with various diseases, Murakawa and Hideya Kawaji of The team also uncovered A., Itoh, M., Shirakawa, and understanding their function the RIKEN Center for Integrative an intriguing link between K., Takaori-Kondo, has become an important goal in Medical Sciences has developed promoters and enhancers, A., Takeuchi, O. et al. genomic research. a method called NET-CAGE, finding that they are linked top- NET-CAGE characterizes the dynamics and topology Two types of genomic regions, which is an extension of the ologically according to their cell of human transcribed known as promoters and CAGE technology developed at type specificities. In addition, cis-regulatory elements. enhancers, coordinate the acti- RIKEN to identify non-coding they pinpointed the exact Nature Genetics 51, vation of protein-coding genes, regions of the genome with location of active enhancers 1369–1379 (2019).

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TISSUE CULTURE Brain tissue kept alive for weeks Tissue taken from animals can be kept alive longer in the lab thanks to a new microfluidic device

technique developed polydimethylsiloxane (PDMS), A by an all-RIKEN team that a material often used as a keeps brain tissue alive in the defoamer in over-the-counter laboratory for about 50 times drugs. The device had a longer than the conventional semi-permeable channel method and will facilitate surrounded by an artificial longer-term studies1. membrane and solid PDMS Experimenting on tissues walls. The tissue was not in culture can facilitate drug constantly immersed in discovery because researchers fluid; rather the culture can systematically manipulate medium circulated within the tissue and test different the microchannel and passed drugs or drug combinations. through the semi-permeable However, when studying a whole membrane, which allowed system in which many cells proper gas exchange. interact with each other, it has It was challenging to find the been difficult to keep optimal settings. “Controlling the tissue ‘alive’ for more than the medium flow was difficult a few days. Tissue dries out because the microchannel that quickly and dies unless it is formed between the PDMS placed in a culture medium walls and the porous membrane containing appropriate was unusual,” Ota notes. nutrients. On the other hand, “However, we had success after immersing complex tissue in trial-and-error modifications fluid can damage it because to the porous membrane and An all-RIKEN team has developed a microfluidic system that can keep mouse the normal transfer of gases adjustments of the inlet/outlet brains (yellow tissue in image) viable in culture for almost a month. cannot occur. flow rates.” Now, Nobutoshi Ota and The team tested the device circadian activity. In contrast, The team is planning to use colleagues at the RIKEN Center using tissue from the mouse neural activity in tissue kept their system to observe the for Biosystems Dynamics suprachiasmatic nucleus—a in a conventional culture formation of blood vessels and Research have developed a complex part of the brain decreased by 6% after only cell movement during organoid microfluidic device made from that governs circadian rhythms. 10 hours. formation. The mice were knock-in In the short term, the system mice in which circadian will be useful for observing rhythm activity in the brain biological development and Reference was linked to the production testing how tissues respond 1. Ota, N., Kanda, G. N., The system will Moriguchi, H., Aishan, Y., be useful for of a highly fluorescent protein. to drugs. The long-term Shen, Y., Yamada, R. G., By measuring the level of benefits are also clear. “This Ueda, H. R. & Tanaka, Y. A observing biological bioluminescence from the method will also improve microfluidic platform based brain tissue, the researchers research into organogenesis on robust gas and liquid development and exchange for long-term were able to see that tissue through long-term culturing culturing of explanted testing how tissues kept alive by their system and observation, which is tissues. Analytical Science respond to drugs. stayed active and functional necessary for growing tissue 35, 1141–1147 (2019).

for over 25 days with nice and organs,” says Ota. LIBRARY PHOTO KING-HOLMES/SCIENCE JAMES ©

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EPIGENETICS Catching chromosomes changing their shape Movements of chromosomal domains between compartments have been captured during differentiation of mouse embryonic stem cells

IKEN geneticists have R observed how chromosomes change their shape during cell differentiation in detail using genomics-based approaches¹. The finding provides insights Compartment into changes in chromosome Nucleosomes organization on the scale of millions of base pairs—base Chromosomes pairs being the building blocks of the DNA double helix. The human genome consists of 46 chromosomes, which are each about 100–200 million base pairs long. Each chromosome contains nucleosomes—146-base-pair-long DNA strands wrapped around eight histone protein molecules. Recently, novel structural units called topologically associating domains (TADs) have TAD/loop been discovered on mammalian domain chromosomes, which are about one million base pairs in size. Multiple TADs assemble to form Geneticists at RIKEN have observed how structures known as compartments, which are made up of multiple topologically subnuclear compartments: TADs associating domains (TADs), change during the differentiation of mouse embryonic stem cells. with many active genes form A compartments, whereas TADs that switched their replication The team found that genomic epiblast-derived stem cells,” with few or no active genes form timing (the temporal order regions that switched from B to says Hiratani. B compartments. The positions of genomic DNA replication) A compartments did so one to “Our study is the first to clearly of boundaries between A and from early to late or vice versa, two days before gene activation demonstrate that changes in B compartments are known respectively. A to B compart- and replication timing varied chromosome conformation to change during differentia- ment changes were accompanied from late to early. This raises precede changes in DNA-based tion, but such changes had not by movement from the nuclear the intriguing possibility that transactions, such as gene been observed directly as they interior to the periphery and compartment changes might be expression and DNA replication occurred. gene repression, whereas B to a prerequisite for gene activation timing,” adds Hiratani. Now, Ichiro Hiratani of the A compartment changes were and replication timing changes. RIKEN Center for Biosystems accompanied by movement The findings suggest that A/B Dynamics Research and co- from the nuclear periphery to compartments change primarily Reference workers have observed changes the interior and gene activation. by the relocation of single 1. Miura, H., Takahashi, S., Poonperm, R., Tanigawa, between A and B compartments These results strongly suggest TADs facing the A/B compart- A., Takebayashi, S. & during the differentiation of that A/B compartment changes ment interface to the opposite Hiratani, I. Single-cell mouse embryonic stem cells. represent physical movements of compartment. “It’s possible DNA replication profiling The researchers discovered portions of chromosomes within that the accumulation of these identifies spatiotemporal developmental dynamics of many genomic regions that the three-dimensional nuclear compartment switching events chromosome organization. switched compartments, from A space, accompanied by changes may reflect or represent changes Nature Genetics 51, to B or vice versa, which corre- in gene expression and replica- in differentiation states such as 1356–1368 (2019).

From Ref. 1. Reprinted with permission from AAAS. lated well with genomic regions tion timing. from embryonic stem cells to

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QUANTUM MATERIALS

Searching for the These vortices emerged on applying a magnetic field. The detection of electronic states “The material possesses at a vortex core of a topological Majorana quasiparticle features of a trivial supercon- superconductor using the tip of a scanning tunneling microscope. A potential host of the Majorana quasiparticle— ductor in the bulk but has the features of a topological insulator a component of quantum computers of the at the surface,” says Machida. “As This observation is a vital clue for future—has been observed a result, topological supercon- the control of Majorana quasipar- ductivity, and hence Majorana ticles—namely that it is important quasiparticles in the vortex cores, to keep the magnetic field low. onditions appropriate Now, Tadashi Machida of the may be induced at the surface “In Majorana-based quantum C for generating a particle- RIKEN Center for Emergent without the need for any fabrica- computing, it is envisaged that like entity useful for quantum Matter Science and co-workers tion processes.” pairs of Majorana quasiparti- computing have been induced have found strong evidence that The imaging of the zero- cles function as fundamental by RIKEN physicists1. They have the zero-energy states in the energy state requires spectro- quantum bits and the compu- detected a zero-energy state in vortex cores of the iron-based scopic imaging with an ultrahigh tation can be executed by the a superconducting material, topological superconductor energy resolution. Specifically, exchange of their locations,” says bringing researchers closer to Fe(Se,Te) may host Majorana the energy resolution of the Machida. “Realizing this process realizing controllable Majorana quasiparticles. imaging must be lower than is the next challenge.” quasiparticles—particle-like the lowest energy of the trivial “Although there is a long way entities that are their own bound states, which are also to go, we believe that our finding antiparticles¹. “We believe that found in the vortex core of topo- is a first step towards moving The Majorana quasiparticle our finding is a logical superconductors. quantum computing from vision has recently been observed By using a spectroscopy to reality,” he adds. experimentally in various first step towards technique employing a scanning materials. The challenge now moving quantum tunneling microscope at ultralow is to create easily controllable temperatures, Machida and his Reference Majorana quasiparticles that can computing from colleagues achieved a high enough 1. Machida, T., Sun, Y., Pyon, S., Takeda, S., Kohsaka, Y., be used in quantum computing. vision to reality” energy resolution to detect the Hanaguri, T., Sasagawa, The quasiparticle is thought zero-energy state in the presence T. & Tamegai, T. Zero- to exist in vortices that form on of bound states (see image). energy vortex bound state superconducting materials since They used the tip of a scanning Only a fraction of vortices in in the superconducting topological surface state of several telltale signs hinting at the tunneling microscope to reveal Fe(Se,Te) host the zero-energy Fe(Se,Te). Nature Materials presence of Majorana quasiparti- the zero-energy states on the state, and this fraction increases 18, 811–815 (2019). cles in bound states have been seen. surface of vortices in Fe(Se,Te). with a decreasing magnetic field. Matter Science Emergent for RIKEN Center 2019 ©

24 RIKEN RESEARCH RESEARCH HIGHLIGHTS

CELL POLARITY A polarizing influence in cells A method for inducing polarization in cells will allow scientists to explore the real-time processes that occur during cell polarization

IKEN researchers have R found an intrinsic way to induce cell polarity—the asymmetry observed in the shape, structure, or organization of cells—in fruit fly cells¹. This method provides a useful means for studying the dynamics of cell polarization on a micrometer scale. Animals consist of many different types of cells, all of which originate from a single cell—the fertilized egg. To generate this huge diversity in cells, the egg and its descendants must divide unevenly to produce new cells with different fates. Thus, asymmetric cell division, which generates two different daughter cells, is a critical step in cell development. Cell polarity plays a crucial role in asymmetric division. Much work has been done on discovering the factors that drive A super-resolution micrograph of artificially polarized Schneider 2 cells, or S2 cells. cell polarity. In particular, the Par family of proteins has been than a decade, but work did not and dissociated with each other. this interesting problem,” found to play a crucial role in begin in earnest until graduate As these island structures Matsuzaki adds. establishing polarity. student Kalyn Kono took on this resemble patch-like features The team intends to explore “As our understanding of cell challenging project four years known to exist in the neural what determines whether the polarity advanced, we noticed ago. By investigating changes in stem cells of fruit flies, their Par-complex islands cluster that the Par complex operates the expression level of each of method appears to closely model asymmetrically or evenly. Going in a context-specific way,” the major components of the Par the autonomous process of beyond polarization, a future says Fumio Matsuzaki of the complex, the team hit on their polarization. goal is to reconstruct asymmet- RIKEN Center for Biosystems method for inducing polarity “Our success in polarizing S2 ric cell division. Dynamics Research. “This through overexpressing Par3— cells implies that, in principle, has made it difficult to study one of the three core proteins any cell can be polarized if a the general features of the cell of the Par family—in non-polar certain set of conditions is met,” Reference 1. Kono, K., Yoshiura, S., polarization process.” fruit fly cells called Schneider 2 comments Matsuzaki. Fujita, I., Okada, Y., To gain a better picture of cells, or S2 cells. A remaining question is Shitamukai, A., Shibata, polarization dynamics, the Using their reconstruc- why the Par-complex islands T. & Matsuzaki, F. team focused on generating tion system, the researchers do not appear to merge into Reconstruction of Par- Par-dependent polarity using observed clusters, or what they one large island under the dependent polarity in apolar cells reveals a non-polar cells. call Par-complex islands, that cell membrane, even when dynamic process of The idea behind this are composed of a meshwork polarized. “We have started cortical polarization. eLife approach had been simmering containing unit-like segments, collaborating with physicists 8, e45559 (2019).

WINTER 2019 25 FEATURES

DEEPENING OUR UNDERSTANDING OF SELFISH

BEHAVIORRIKEN researchers have identified distinct neural processes that occur when we make decisions for the benefit of others.

26 RIKEN RESEARCH FEATURES

s a selfish person just processing the decisions that result in rewards to others differently? Perhaps, suggests a recent RIKEN study. A RIKEN team, led by Hiroyuki Nakahara Iof the Laboratory for Integrated Theoretical Neuroscience at the RIKEN Center for Brain Science, discovered this when they examined 36 healthy volunteers aged between 20 and 32 years. Their aim was to find out which parts of the brain are activated when considering giving rewards to others. These volunteers were asked to choose one of two options, each with a baseline reward to themselves. One option then involved an extra financial This feature looks reward for the participants and the other, a reward to at the work of ‘others’—in this case a series of well-known charities. HIROYUKI NAKAHARA The group looked at the what happened when a person is giving an extra reward to one of the Hiroyuki Nakahara earned his PhD at the charities, using functional magnetic resonance University of Tokyo imaging (fMRI) and a computational modeling studying sequential method called a connectivity analysis. They dis- decision-making in covered that there is a three-stage cascade process biological systems. He involved. then joined Shun-ichi In the first stage, the brain detects a perceived Amari’s laboratory at benefit to others. The first stage was accompanied by the RIKEN Brain Science Institute (BSI), and later neural activity in the right temporoparietal junction started his own lab at (right TPJ) and the left dorsolateral prefrontal cortex BSI. His Laboratory for (left dlPFC)—regions that are well known to play a Integrated Theoretical role in attention and social interaction. Neuroscience aims The second stage involves understanding the to understand the impact of the offer of value on the outcome. This cor- computational principles that underlie the way responded to activity in the right anterior insula (right neural systems realize AI), a key node of a brain circuit called the salience adaptive behavior, network, which has been associated with empathy. decision-making, and The third stage is the actual decision-making associated learning; in process. Decision-making corresponded to activity particular, reward-based in the medial prefrontal cortex (mPFC), supporting learning and social decision-making. They findings from previous studies that have implicated build computational and the mPFC in strategic reasoning.

GETTY IMAGES GETTY mathematical models, Next, the team explored whether there might be while also using human any common patterns in the neural pathways involved functional magnetic in the choice to give to others in individuals who can resonance imaging (fMRI) broadly be described as either generous or selfish. For in combination with this, the team used a test established by social psy- quantitative approaches. chologist Paul A. M. Van Lange of Vrije Universiteit Amsterdam in the 1990s. The test enables scientists to gauge a person’s preference regarding the allocation of rewards to themselves and others. This social value orientation (SVO) test is widely used in social psychology and other disciplines, such as economics. The volunteers took the SVO test in the form of a questionnaire and were subsequently classified as either prosocial (i.e. having a tendency towards generous behavior) or individualistic (having a tendency towards selfish behavior). One of the most striking findings was that there was a distinct difference in the neural processes

WINTER 2019 27 FEATURES

MEDIAL RIGHT PREFRONTAL ANTERIOR CORTEX INSULA 1 3

RIGHT 2 TEMPOROPARIETAL

JUNCTION

RIGHT HEMISPHERE

LEFT 1 HEMISPHERE LEFT DORSOLATERAL

PREFRONTAL CORTEX

REGIONS OF individualistic subjects. This difference existed even THE BRAIN when the two groups chose similar things in the The right temporoparietal original task. junction and the left Nakahara considered it particularly intriguing that These multifarious factors “would certainly contrib- dorsolateral prefrontal cortex play a role in attention and prosocial subjects used a similar brain process for ute to shape more complex types of social behaviors,” social interaction. other-bonus and self-bonus choices, mediated via the Nakahara explains. “Through repeated experiences in left dlPFC–mPFC pathway. Individualist subjects, daily life, they would be built-in as part of the neural The right anterior insula has been associated with on the other hand, mediated the process of weighing circuitry of social behavior and decision-making. The empathy. up giving to others in a different way to the self-re- building blocks of the social conversion process would ward choice. In the second stage of the process, more then be modulated and integrated with those processes The medial prefrontal cortex has been implicated in ‘selfish’ subjects mediated the choice to give to others to produce a final behavior and decision.” strategic reasoning. by the right AI, which represents where the brain may Another promising research direction, albeit one digest the implications of the benefit-to-others option. that goes beyond the scope of the present study, would 1 Perceived benefits This isn’t all about selfishness and generosity, but be to look at the possibility that the process involved rather perceptions of value, emphasize the research- in giving to others might in some way be different in Impact of benefits 2 on the choice ers. Rather than being altruistic, a generous subject people with antisocial disorders. Such differences, if may be perceiving more value in social contributions identified, may contribute to understanding of the 3 Decision or be subject to predispositions such as inequity neural correlates of antisocial behavior. aversion and guilt. The team have called the process Nakahara’s team is continuing to work on uncov- Other benefits of deciding to give to others ‘social value conversion’. ering further insights into of social decision-making. (individualistic and social) In the paper, the team predicted that social value con- “One of our ongoing studies investigates how people version is actually a primitive computation that may seek to make better decisions by predicting the be essential for different forms of social behavior. decisions of others, and we are getting some Other benefits (social) The team’s findings provide building blocks for interesting results,” he says. investigating more complex forms of social decision-making. Exploring ideas about generosity REFERENCE Self benefits and selfishness would call into question the role of Fukuda, H., Ma, N., Suzuki, S., Harasawa, N., cultural and religious factors, and variations across Ueno, K., Gardner, J. L., Ichinohe, N., Haruno, M., countries and regions, for example, in accounting for Cheng, K. & Nakahara, H. Computing social value how we each perceive and take on board consideration conversion in the human brain. The Journal of

28 RIKEN RESEARCH PERSPECTIVES

WHY MAP EVERY CELL IN THE HUMAN BODY? RIKEN is spearheading Asia’s efforts for the Human Cell Atlas, a push to understand the regulatory networks that make human cells unique.

IERO CARNINCI: A highly standardized I am part of the original HCA Organization reference dataset of human cells is currently Committee with Jay W. Shin, a team leader for the being created under a project called the Laboratory for Advanced Genomics Circuit at the Human Cell Atlas (HCA). This international RIKEN Center for Integrative Medical Sciences. This Pconsortium aims to create a common database con- committee consisted of 31 scientists from 10 countries sisting of millions of single-cell data points in order to and established the guidelines and scientific policies map out all the cell types and their relationships. This to make the HCA database an accessible resource to will help better understand health and identify triggers the global community. As of September 2019, more that cause disease. The database aims to be open to than 1,000 research institutes and 1,500 scientists from the public to accelerate research for better medical 60 countries and regions are now participating as research, diagnostics and drug discovery.1 members of the HCA.

WINTER 2019 29 PERSPECTIVES

RIKEN IMS HUMAN CELL ATLAS TISSUES As one of its key aims, the consortium is collect- At the RIKEN Center for Integrative Medical Sciences, a ing data across broad ethnic and geographic regions number of researchers are charged with leading efforts to to provide an equitable and globally representative profile single-cell regulatory networks and identify new cell picture of the human body. RIKEN is one of four types within specific tissues, with the aim of feeding this information into the Human Cell Atlas. Executive Offices (EOs) that will regularly coordinate general HCA activities, alongside the Wellcome Sanger Institute for the United Kingdom, the Broad Institute of MIT and Harvard for the United States, and the Karolinska Institutet for the European Union. RIKEN will act as the EO in Asia.

FANTOM SYNERGY RIKEN was perfectly positioned to take part in this project. It already has decades of experience mapping the gene expression and regulatory networks that define the different types of cells through its lead- ership of the international consortium working SKIN from Keio University CHEST (BREAST) from on FANTOM (Functional Annotation of the St. Marianna University School of Medicine Mammalian Genome). Among the many findings of the FANTOM projects, we cataloged the genomic regions critical in controlling the expression of RNAs, known as promoters and enhancers, and measured their activities across the major primary cells and tissues.2 The FANTOM database allowed us to understand the interplay of the regulatory proteins that defines a cell type, known as transcription factors. We also created an atlas of non-coding RNAs (ncRNAs) and revealed their importance in human genetics and gene control. In fact, in the current sixth edition of

LUNG from National Cancer BLOOD from Toranomon FANTOM (FANTOM6), we are aiming to understand Center Japan and Juntendo Hospital and RIKEN the functions of long ncRNA.3 University Because of this history, there is a natural synergy with the HCA and we will work closely with them to build the atlas of promoters and enhancers at a single-cell resolution, as well as to profile millions of single cells across many tissues across populations.

TOWARD THE ANALYSIS OF SINGLE CELLS The HCA will start by sampling a comprehensive set of organs and tissues, followed by dissociating these samples into single cells or profiling gene expression within a tissue’s spatial context. The combined information will lead us to define the identity of THYMUS from the University INTESTINE from the National each cell, based on the level of RNA, chromatin of Tokyo Cancer Center Japan, Chiba states and to a certain extent protein expression. University and Keio University We will employ expert-guided curation and data- driven definitions to reach a consensus about the boundaries of how each cell should be classified by type and state, and this will create a common language for the global community. RIKEN has started with a project to analyze blood samples from multiple ethnic groups in Asia including those in South Korea, Singapore (India, Malay, Chinese), and Japan funded by a grant from the Chan Zuckerberg Initiative (CZI). The project

30 RIKEN RESEARCH PERSPECTIVES

expression signatures in immune cells and cross-ref- understand diseases. By looking at deviations erence them to their sources’ genetic background, from the baselines set by the HCA, we should also as well as to environmental factors, to identify the be able to ascertain drug efficacy and safety with causal regulators of the immune system. Several high precision. bioinformaticians are on board and will work The HCA will also help us look at diseases together with clinicians and ethicists to make the by revealing more cell subtypes. The brain, for data meaningful and accessible to the community. example, has many subtypes of neurons, and some In addition to the CZI grant, RIKEN is spear- may only be discovered by looking at gene expres- heading a Single Cell Medical Network where sion. In 2015, researchers at the Karolinska Institutet samples from clinical collaborators in Japan will be in Sweden discovered a much greater diversity of profiled using the latest single-cell RNA sequencing glial cells—a type of cell that supports and shields PIERO CARNINCI and spatial technology. neurons—by looking at gene expression alone. We Deputy Director of In FANTOM5, we profiled large numbers of also know that certain subtypes of neurons are the RIKEN Center for samples using CAP Analysis of Gene Expression particularly affected in Parkinson’s disease, so to Integrative Medical (CAGE), which was developed at RIKEN. The understand this type of disease, we must understand Sciences (IMS) CAGE method precisely determines where the gene the brain’s cell types and the expression levels that After arriving at RIKEN in is generated in our DNA, giving us a good sense of make them unique. 1995, Carninci played a how the gene is controlled. However, in FANTOM5, In addition, cell states are important—for critical role in many key we profiled bulk samples. Now, because of example, cells located near cancer cells may respond projects, including the advancing technologies, we’re able to profile RNAs to signals from them and change states, becoming FANTOM Consortium. at a single-cell level using a modified version of the directly involved in cancer progression and metas- In 2018, he became CAGE method that we recently developed. tasis. However, previous methods that relied upon deputy director of the IMS. He also leads the the averaged values for groups of cells could not Laboratory for Single Cell AY W. SHIN: Early in 2019, I led a team, help us understand changes in cell states. The new Technologies, which is together with Dr. Piero Carninci, to combine a single-cell CAGE could help us spot dynamic levels describing samples as microfluidic technique with CAGE to better and of RNA expression in cells in a disease state, as a populations of single cells more systematically profile RNA transcripts at means of early detection. For example, in Parkin- classified by RNAs. He is J an organizing committee the single-cell level. son’s disease, cells that produce the neurotrans- member of the HCA. We used a microfluidic platform called C1, which mitter dopamine are lost in specific regions of the isolates, processes and prepares individual cells for brain. As many as 70% of dopamine-producing cells analysis, and we integrated a highly sensitive version are lost by disease onset, implying that these cells of CAGE with this system, which we refer to as C1 must show some markers earlier than that. We have CAGE. The team compared the C1 CAGE method already found that the level of a certain ncRNA in with a standard protocol for profiling RNA's 5'ends the blood increases in the early phase of Parkin- in single cells and found it to be more sensitive, son’s disease, which may lead to a means for early detecting more genes including non-coding RNAs.4 detection. Many more RNA and protein biomarkers With the support of the HCA, we continue to are likely to be found in this way through the HCA. develop and benchmark RNA profiling methods Last but not least, a better understanding of in single cells as one of our key contributions to cells will very likely help us when we differentiate the HCA community. With these new technologies induced pluripotent stem cells into specific cells to JAY W. SHIN we can measure individual RNA molecules within replace and repair damaged or defective tissues in Team Leader at the single cells, enabling us identify rare cell types or the body. RIKEN Center for states in a sample with heterogeneous cell popula- Advances based on the HCA findings will likely Integrative Medical tions, which is particularly important for the inter- be quick. The first cell atlas that will be published in Sciences (IMS) pretation of disease pathology in clinical samples of a few years’ time will most likely be a draft of each complex tissues.5 healthy tissue and organ. New research can begin Shin studied computer The ultimate aim of the HCA is to help treat from the moment such an atlas is published, ranging science at Boston College in the United States diseases and improve diagnostics. There are many from research into the similarities and differences and gained a PhD in life ways we can approach this. For example, it has between Asian and American lung cells, to differ- sciences at Swiss Federal become apparent that the risk of disease onset is ences by sex and age. It is likely that this research Institute of Technology usually linked to changes in the genome through will also compare healthy tissues and organs charac- in Zürich, Switzerland. single nucleotide polymorphisms, which can terized by the HCA with the cells of disease tissues Today, he leads RIKEN’s influence the functions and expression levels of and organs, opening up a whole range of exciting Laboratory for Advanced Genomics Circuit, the proteins that cause diseases. Analysis of RNA new insights. co-leads the FANTOM6 expression in single cells should shed light on consortium and is an exactly how each polymorphism affects expression For a full list of references, please visit organizing committee

Intestine: STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY / Getty Images; Thymus: Ed Reschke / Getty Images levels and functions, helping us to vastly better RIKEN’s website. member of the HCA.

WINTER 2019 31 SCAN TO LEARN MORE! PROGRAMS FOR

INTERNATIONAL SPECIAL POSTDOCTORAL YOUNG RESEARCHERSPROGRAM ASSOCIATE RESEARCHERS PROGRAM International Program Associates (IPAs) are The Special Postdoctoral Researchers (SPDRs) graduate students that are jointly guided, for up program provides roughly 60 creative young sci- to three years, by RIKEN researchers, alongside entists with the opportunity to conduct independ- researchers from a partner graduate school or ent research on a topic of their own choosing, research institution. The latter are located in for up to three years. Applicants must have been either Japan or overseas. To apply, you must be a awarded a PhD within five years of application or non-Japanese doctoral student enrolled (or to be expect to be awarded a PhD by the date of hire. enrolled) at a university that has (or is expected to have) a Joint Graduate Program agreement FIELDS: Mathematical science, physics, chemistry, with RIKEN. biology, medical science and engineering ANNUAL RESEARCH BUDGET: ¥1,000,000 FIELDS: Mathematical science, physics, chemistry, MONTHLY SALARY: ¥487,000 and commuting biology, medical science and engineering and housing allowances SUPPORT: Living allowance of ¥5,200/day; free APPLICATIONS: February to April on-campus housing or housing allowance of up to LEARN MORE: riken.jp/en/careers/programs/spdr ¥70,000/month for off-campus housing; and one round-trip travel fare to and from RIKEN. APPLICATIONS: RIKEN researcher can apply to host a student in spring and autumn. Students JUNIOR RESEARCH ASSOCIATES should start by contacting the RIKEN researcher they would like to work with. Junior Research Assocites are given part-time LEARN MORE: riken.jp/en/careers/programs/ipa research positions for up to three years (or four years in some cases). These roles are aimed at young researchers enrolled in PhD programs in Japanese universities that have collaborative RIKEN HAKUBI FELLOWS PROGRAM agreements with RIKEN or are involved in joint research with RIKEN scientists. RIKEN Hakubi Fellows are junior principal investigator (PI) positions for up to seven years of FIELDS: Mathematical science, physics, chemistry, independent research by exceptionally talented biology, medical science and engineering individuals who are able to manage their laborato- SUPPORT: ¥164,000/month with a commuting ries as Principal Investigators. allowance APPLICATIONS: October–November SUPPORT: Research budget of ¥10 to 40 million PROGRAM START: 1 April or 1 October per year; salary of ¥910,000/month; commuting LEARN MORE: riken.jp/en/careers/programs/jra and housing allowances. LEARN MORE: riken.jp/en/careers/hakubi RIKEN’S CENTERS AND FACILITIES across Japan and around the world

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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 2019-023