October 2012
Vol.
1

Center for iPS Cell Research and Application, Kyoto University

CiRA
Newsletter

Shinya Yamanaka

Interview with Professor Jun Takahashi

Targeting Parkinson’s Disease Treatments with Pluripotent Stem Cells

The research group led by Professor Jun Takahashi of the Department of Cell Growth and Differentiation published papers in the scientific journals Journal of Parkinson’s Disease and Stem Cells. We asked Takahashi about his research findings.

What kind of research was involved in the studies?
Professor Jun Takahashi

Our focus is on intractable neurological diseases and especially Parkinson’s disease, for which we aim to develop cell transplantation therapy. In the research we presented in the Journal of Parkinson's Disease, we induced dopaminergic neurons*1 from human induced pluripotent stem (iPS) cells in a suspension cell culture without using feeder cells or other animal-derived materials. We also demonstrated that, when neurons generated from human iPS cells were transplanted into the brain of cynomolgus monkeys in which Parkinson’s disease had been artificially induced, the neurons survived for six months without forming tumors. We believe that this research has proved significant in the establishment of methods for confirming therapeutic effect and safety ahead of future preclinical studies.

Meanwhile, in the research presented in Stem Cells, neurons generated from human embryonic stem (ES) cells were again transplanted into a cynomolgus monkey model of Parkinson’s disease, and their safety and therapeutic effect tested. Improvement in symptoms was observed, with monkeys that had been unable to walk at the start regaining the ability over a number of months or becoming free of limb tremor and stiffness. The improvement was maintained for 12 months. This is the first time that the efficacy of human ES cells has been confirmed in primates.

What is distinctive about this research?

One major point to start with is that therapeutic effect was observed in a study using human ES cells in a primate model. I also believe that a major advance toward future preclinical studies is represented by our establishment of approaches based on non-invasive clinical course observation using MRI (magnetic resonance imaging) and PET (positron emission tomography) and on analysis of behavior using video and score evaluation.

MRI and PET make it possible to analyze whether transplanted neurons derived from iPS cells are functioning, that is, whether they are working to synthesize dopamine, release it from cells, and take it back up into cells. They also enable us to observe the survival and proliferation of transplanted cells in vivo over time. For analysis of behavior, video analysis equipment to objectively quantify monkey behavior was introduced. In conjunction with a cynomolgus monkey version of the score evaluation used for clinical assessment of Parkinson’s disease patients, this equipment was used to confirm therapeutic effect. These evaluation methods will also be available for use when actual clinical application is realized.

Will cell transplantation be used to replace other current therapies?

Parkinson’s disease is a progressive and intractable neurological disease in which a decrease in the number of dopaminergic neurons reduces the level of dopamine in the brain, producing limb tremor, stiffness leading to impaired movement and other symptoms. Up untill now, treatments have included use of drugs to stimulate dopamine synthesis and implanting of electrodes in the brain. However, although these therapies may produce a temporary improvement in symptoms, since they cannot halt the decline in dopaminergic neurons, the drugs gradually become ineffective. By combining the transplanted dopaminergic neurons we are currently researching with drug-based therapies, it is envisaged that the duration of drug efficacy can be prolonged and symptoms mitigated.

Publications:
“ Survival of Human Induced Pluripotent Stem Cell-Derived Midbrain Dopaminergic Neurons in Brain of a Primate Model of Parkinson’s Disease ” Journal of Parkinson's Disease (Tetsuhiro Kikuchi, Asuka Morizane, Daisuke Doi, Hirotaka Onoe, Takuya Hayashi, Toshiyuki Kawasaki, Hidemoto Saiki, Susumu Miyamoto and Jun Takahashi)

“ Prolonged maturation culture favors a reduction in the tumorigenicity and the dopaminergic function of human ESC-derived neural cells in a primate model of Parkinson's disease ” Stem cells (Daisuke Doi, Asuka Morizane, Tetsuhiro Kikuchi, Hirotaka Ono, Takuya Hayashi, Toshiyuki Kawasaki, Makoto Motono, Yoshiki Sasai, Hidemoto Saiki, Masanori Gomi, Tatsuya Yoshikawa, Hideki Hayashi, Mizuya Shinoyama, Refaat Mohamed, Hirofumi Suemori, Susumu Miyamoto and Jun Takahashi)

Notes:
1. Type of neuron. Acts as a neurotransmitter to express dopamine from cells. In many cases of Parkinson’s disease, degeneration of dopaminergic neurons in the substantia nigra of the midbrain is known to be the main cause of the disease.

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ISSCR Yokohama Report

International Society of Stem Cell Research (ISSCR) Annual Meeting

The 10th Annual Meeting of the International Society of Stem Cell Research (ISSCR), which brings together stem cell researchers from around the world, was held at the Pacifico Yokohama convention center in Yokohama City in June 13-16.

A sugoroku boardgame featuring iPS cells (under development) is displayed at the CiRA booth.

At this year’s meeting, held in Asia for the first time, researchers, students, and industry representatives from around the world gathered in Yokohama. Many CiRA researchers, including Director Shinya Yamanaka, president-elect of the ISSCR, took part in the event.

To present its research activities and raise its international profile, CiRA joined domestic and overseas enterprises and other institutions in setting up a booth in the exhibition area, at which publications were distributed. The CiRA booth was decorated with a tapestry themed on the CiRA facility and the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program), a program sponsored by the Cabinet Office in which Yamanaka has been selected as a core researcher. As well as our annual report, we gave out information on opportunities for further study as graduate students and practical skill training in the field of induced pluripotent stem (iPS) cells, while a projector was used to display images presenting CiRA and its activities.

CiRA sets up a booth at the exhibition area.

One section of the booth was devoted to a display showing a game of sugoroku (a kind of Japanese backgammon) featuring the appearance of iPS cells. The game is being developed by researchers as a school teaching material in the framework of the iCeMS/CiRA Classroom program.

At this year’s ISSCR meeting, a poster presentation session was held, with the presentation space divided up according to cell type studies and other aspects of research content. The fields with the largest number of presentations included hematopoietic stem cells, neurons, mesenchymal stem cells, embryonic stem (ES) cells, and iPS cells, with the last specifically accounting for more than 100 poster presentations. There were 29 posters for which a CiRA researcher was the lead presenter; including joint research projects CiRA researchers were involved in a total of 48 poster presentations, prominent among which were studies of iPS cell properties and safety.

CiRA Lecturer Kazutoshi Takahashi speaks during a press conference before his lecture.

On the afternoon of the 13th, a presidential symposium was held in the National Convention Hall, which has a capacity of 5,000. After lectures by three scientists who figure among the leading names in stem cell research –– Dr. Rudolf Jaenisch, Dr. Austin Smith, and Dr. John Gurdon –– CiRA Lecturer Kazutoshi Takahashi took the podium for a contribution entitled ``What is the Bug in the Program of Pluripotency?,’’ in which he presented research on comparative study of more than 50 iPS cell lines and ES cell lines. Yamanaka was absent while attending the Millennium Technology Grand Prize award ceremony in Finland, but was shown during the lecture in a slide, in which he was seen bowing his head in apology. This appearance was well received and provoked laughter in the auditorium.

ISSCR Report

Event to Mark the 10th Anniversary of ISSCR

Participants attend a lecture at the National Convention Hall
at Pacifico Yokohama. Photo Courtesy of ISSCR

On the afternoon of June 15, the International Society of Stem Cell Research (ISSCR), which celebrated the 10th anniversary of its foundation this year, held a ceremony and reception to mark the occasion at Pacifico Yokohama.

Left : Their Majesties, Emperor Akihito and Empress Michiko, attend the ceremony while CiRA Director Shinya Yamanaka serves as their escort. Photo Courtesy of ISSCR
Right : Their Majesties the Emperor and Empress have conversations with researchers at the reception.

The event was attended by their Majesties the Emperor and the Empress, with CiRA Director Shinya Yamanaka, who had just returned from attending the Millennium Technology Grand Prize award ceremony in Finland, serving as their escort. The commemorative ceremony, held in the National Convention Hall, was attended by around 2,000 participants from the Society’s annual meeting.

After the arrival of their Majesties, ISSCR founder Leonard Zon of Harvard University gave a talk on the background to the foundation of the ISSCR and the society’s academic activities to date. Next, congratulatory addresses were given by three guests: Senior Vice Minister of Education, Culture, Sports, Science and Technology Tenzo Okumura; Kanagawa Governor Yuji Kuroiwa; and Yokohama Mayor Fumiko Hayashi. Their Majesties also attended the reception held after the conclusion of the ceremony, where they conversed with stem cell researchers from around the world.

On the afternoon of the 16th, the last day of the annual meeting, Yamanaka gave a speech in his role as the president-elect, in which he declared his ambition as new president to drive forward the activity of the ISSCR based on a vision entitled ``Bring Stem Cells to Clinics.’’

Realizing stem cell-based therapies would, he said, require all the pieces of the jigsaw puzzle to be fitted together correctly, which could only happen when all the pieces from the various fields had been brought together. These fields ranged from ES/iPS cell-based regenerative medicine, drug discovery research, and cell engineering to patents, ethical standards, regulations, and education. Yamanaka emphasized the need for researchers in different fields to collaborate.

Participants in the annual meeting discuss at a poster session venue.
Photo Courtesy of ISSCR

This year’s annual meeting, which attracted more than 3,500 participants from over 55 countries and saw more than 1,400 poster presentations, was brought to a successful conclusion. Next year’s ISSCR annual meeting will be held in Boston.

On the 17th, an ISSCR public symposium entitled ``iPS Cells and Our Future’’ was held at Tokyo’s National Museum of Emerging Science and Innovation (Miraikan). Dr. Ian Wilmut, the ``father’’ of Dolly the cloned sheep, and Yamanaka respectively presented material from their research, explaining in detail the background to Dolly’s birth, and to the birth of iPS cells, respectively. Afterwards, with the participation of a science moderator from the museum, a three-way discussion on the potential of iPS cells took place.

Glossary

International Society of Stem Cell Research: a non-profit organization established in 2002 with Dr. Leonard Zon as the principal founder. Its headquarters are in the US state of Illinois. The annual meeting is held every year in June and is said to be the most influential in the field of stem cell research.

Patient Handbook on Stem Cell Therapies: published by the International Society of Stem Cell Research (ISSCR). Contains answers to frequently asked questions on stem cells and stem cell therapy and was conceived as an aid to medical professionals and patients when making medical treatment decisions.

ISSCR Guidelines for the Clinical Translation of Stem Cell Research: contains recommendations on scientific and clinical ethical behavior for researchers and regulatory authorities in the international community.

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Symposium Report

CiRA Hosts its First International Symposium

The CiRA International Symposium 2012, titled “ Advances in Nuclear Reprogramming and Stem Cell Research,” was held at Kyoto University on February 23, 2012.

This was the first international symposium organized by CiRA. In spite of the chilly and wet weather, approximately 270 researchers and students from inside and outside Japan participated.

The purposes of the symposium were to promote research by deepening ties with overseas researchers and to discuss the standardization of iPS cell technologies with a view to building a basis for global cooperation.

During the symposium, Professor Austin Smith of Cambridge University, an authority in the field of embryonic stem (ES) cell research, talked about his fundamental studies of ES cells and presented unpublished data. Another overseas guest speaker, Assistant Professor Marius Wernig of Stanford University, gave a lecture on his research into the direct reprogramming of fibroblasts into neuronal cells without use of iPS cells.

Other speakers were Professor Mitinori Saitou of Kyoto University, Professor Shinya Yamanaka of Kyoto University, Lecturer Masaki Ieda of Keio University, and Associate Professor Haruhisa Inoue of Kyoto University.

The one-day meeting concluded with a discussion on the theme “ iPS Cell Capability and Potential,” led by a panel consisting of all six speakers. The three topics addressed were: “ Pluripotent Stem Cells and Reprogramming Biology, ” “ Cell Fate Manipulation, ” and “ Reprogramming for Clinical Applications.”

In the discussion on the second topic, the panelists weighed up the advantages and disadvantages of two different approaches to generating somatic cells: iPS cell technology and direct reprogramming, which is a method of converting somatic cells of one type into somatic cells of a different type without using iPS cells. One view expressed was that, if such man-made cells become available for regenerative medicine in the future, it will be important to select the appropriate method for each particular disease.

The symposium was supported by the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST), Cabinet Office, Government of Japan.

Guest speakers discuss during the panel session.

The CiRA International Symposium 2012, titled “Advances in Nuclear Reprogramming and Stem Cell Research,” was held at Kyoto University on February 23, 2012.
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People at CiRA

A Man Who Wants To Use Massive Data To Solve the Cell Equation

We speak here with Professor Wataru Fujibuchi, who was appointed in April as principal investigator of CiRA's Department of Cell Growth and Differentiation, a post which he will combine with that of director of the Information Security Office.

Professor Wataru Fujibuchi
Professor Wataru Fujibuchi

I was born in Beppu, Oita Prefecture, and as an elementary school pupil I was an enthusiastic insect catcher and radio set builder. As a junior high school student, I regularly made the two-hour one-way trip by bicycle to a department store in the next town to use a computer, and taught myself BASIC and other computer languages.

At university I majored in zoology, which would have been difficult to do on a self-taught basis. The opportunity to undertake systematic and comprehensive study ranging from protozoan organisms to invertebrates was a valuable experience. While pursuing molecular biology for my graduation research, I realized that laboratory experimentation was not my strong point and would explore the living world through the medium of computers, so I transferred to an information-based laboratory.

In the early 1990s, when I entered graduate school, interest in bioinformatics* was beginning to reach Japan. As it was a completely new discipline, I was very excited about my research. After obtaining a Ph.D., I moved to the National Center for Biotechnology Information (NCBI) in the United States, the world center of bioinformatics, where I undertook postdoctorate studies and was also a full-time employee.

A turning point came after my return to Japan in 2007. I had just become the director of the cell function design team at the National Institute of Advanced Science and Technology (AIST) when I heard the report that human iPS cells had been successfully generated. Although I was disappointed that someone else had gotten there first, I also had the feeling that information analysis staff would soon be needed.

Partly thanks to my experience in cell database development and ES/iPS cell information analysis, I was selected to become a member of CiRA's faculty from April. I have two tasks to take on here. One is to build up an information base covering information security, research support, and other relevant areas. The second is to carry on the research done so far into expanding the human cell information database. By cataloging a wide of variety of cells, my goal is to derive a principle like the Schrödinger equation and to clarify the relative positions of iPS cells and other artificially induced cells.

I feel very lucky to be at CiRA, where I am surrounded by colleagues like Professor Yamanaka, who create a challenging but close-knit atmosphere like among a band of samurai adventurers. Now it's time for me to take a fresh outlook, put on my sword belt, and join combat through my research and support activities.

Captions:

*Academic discipline which seeks to resolve the issues of biology by applying computer science and related technologies. In recent years, the progress of computer science has led to an explosion in the amount of data available, and research in this field has become important in facilitating accurate data analysis.

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iPS Cell Research Fund

iPS Cell Research Fund Thanksgiving Meeting

CiRA held the first Kyoto University iPS Cell Research Fund Thanksgiving Meeting at its research building on May 14, 2012. Under bright early summer sunshine, the event was attended by some 100 people from all parts of Japan from Hokkaido to Kagoshima. We sent invitations to those who made donations to the iPS Cell Research Fund before the end of March 2012

A participant views iPS cells in the gallery on the first floor of the CiRA research building.

At 2.00 p.m., the auditorium on the first floor of the research building filled up with donors. To start the first part of the lecture meeting, CiRA Director Shinya Yamanaka once again expressed his thanks to those who had donated, saying that the receipt of generous donations from many individuals was a great encouragement to scientific and administrative staff in their work to further iPS cell research. Next, Yamanaka outlined the fundamentals of iPS cell research and its current state of progress, then went on to report on the the fund's income and expenditure and underline the need for the fund.

Following on, Professor Jun Takahashi of the Department of Clinical Application reported on the progress of iPS cell-based Parkinson’s disease research, while Professor Noriyuki Tsumaki of the same department gave a lecture on research into cartilage regeneration through a method known as direct reprogramming, which generates cartilage from skin cells without using iPS cells. Both lectures were presented in a readily accessible way using slides, and were followed by a short but lively question and answer session with participants.


CiRA Director Shinya Yamanaka gives a lecture.

After the lectures, the participants were joined in the entrance hall by more than 20 members of CiRA's scientific staff for an informal meeting. The participants put a range of different questions to researchers whose work interested them and took souvenir photographs, which helped them feel a direct connection with iPS cell research. The researchers, meanwhile, although somewhat nervous, clearly enjoyed the discussions and were further reinforced in their commitment by the opportunity to interact directly with the people who support their research. A space in the hall was set aside for microscope viewing of iPS cells, which at one point attracted a line of participants, indicating their strong level of their interest in iPS cells.

Next year again, we plan to send out invitations to people who make donations in academic year 2012 for a similar thanksgiving meeting.

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Taking on a Challenge

Yamanaka and Toguchida run the Kyoto Marathon!

CiRA Director Shinya Yamanaka and Deputy Director Junya Toguchida took part in the Kyoto Marathon held on Sunday March 11, 2012, to raise funds for Kyoto University iPS Cell Research Fund.

Yamanaka, one of the Cheer Ambassadors of the marathon, ran 42.195 km in 4 hours, 3 minutes, and 19 seconds, while Toguchida finished his first full marathon race in a time of 4 hours, 35 minutes, and 28 seconds.

As of March 14, the JustGiving Japan online site had raised over 10 million yen from more than 500 people along with messages to encourage the two scientists in their challenge. We sincerely thank you all for your warm support and donations.

On April 1, meanwhile, Professor Takashi Aoi ran the Naniwa Yodogawa Half Marathon, for which he also asked people to donate to the fund. Aoi completed the race in 1 hour, 49 minutes, and 14 seconds, raising 169,000 yen.

People look at posters showing messages from supporters who made donations to
CiRA via JustGiving Japan online site.
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Editorial Info

Publisher & Editor
CiRA International Public Communications Office
Email:cira-pr@cira.kyoto-u.ac.jp

Design & Photography
Jussi Panula

Design & Editting
Information Media Design INC.
URL:http://www.imd-net.com/

This newsletter is produced with the support of the Funding Program for the World-Leading Innovative R&D on Science and Technology (FIRST Program).

Copyright © 2012 Center for iPS Cell Research and Application, Kyoto University
No part of this publication may be reproduced by any means under any circumstances without written permission of the Center for iPS Cell Research and Application, Kyoto University.

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