Stem Cell Technologies

Transcription

www.gscn.org
Stem Cell Technologies
Annual magazine of the GSCN
2014/15
in Germany
zur deutschen Version p bitte wenden
ISSN (Print) 2198-7831
ISSN (Online) 2198-784X
IMPRINT
German Stem Cell Network e.V.
Annual Magazine 2014/15
© 2015 GSCN
Publisher
German Stem Cell Network
c/o Max Delbrück Center for Molecular Medicine (MDC)
Robert-Rössle-Str. 10
13125 Berlin
Tel.: +49 30 9406 24-87/-88
Fax: +49 30 9406 2486
E-Mail: [email protected]
Web: www.gscn.org
Editors
Stefanie Mahler, Dr. Daniel Besser, Ulrike Papra (Central Office GSCN)
Dr. Philipp Graf (BIOCOM AG)
Translation
English Express, Berlin
Design & Layout
Unicom Werbeagentur GmbH, Stephen Ruebsam
Print
Buch- und Offset-Druckerei H. Heenemann
Circulation: 900
Copyright
The magazine is part of the public relations work of the GSCN and funded by the
German Federal Ministry of Education and Research (BMBF). It is supplied for
a protective fee of 2€ (inclusive postage) and must not be resold. Reprint only
with permission by the editors.
ISSN (Print) 2198-7831
ISSN (Online) 2198-784X
WELCOME NOTE | THOMAS RACHEL
Welcome Note
S
tem cell research has
become firmly anchored at biomedical
research laboratories because not only are stem cells
the key to understanding
fundamental development
and regeneration processes,
they also open up fascinating
possibilities in the study and
treatment of diseases. Diagnostic procedures based on
stem cells are also becoming more and more relevant
in clinical practice. This area of research holds great hope
of generating new treatments but also bears scientific and
ethical concerns.
This highly dynamic yet sensitive area of research demands,
more than ever before, an intensive dialogue among stem
cell researchers, and this is why the Federal Ministry of Education and Research (BMBF) initiated the development of
the German Stem Cell Network (GSCN). The GSCN acts as a
central platform at national level as well as an institution
which will help to further build the profile of German stem
cell research at international level.
Annual GSCN Magazine 2014/15 The GSCN has grown successfully since its foundation two
years ago. It has developed into a lively platform which
more strongly consolidates the know-how available in research and industry. This success is owed as much to the
scientific and strategic working groups as it is to the great
interest of participants in the GSCN Annual Conferences
which have developed into a high-profile event for young
researchers and companies alike. The German Stem Cell
Network is well on its way to establishing itself as a cornerstone institution of the country’s research community.
This issue of the GSCN Annual Magazine reports on the activities of the past year and provides an overview of how
new technologies are further advancing stem cell research
in Germany. I am delighted about the commitment of all the
stakeholders from science and industry, who are ensuring
ever-improving cooperation in Germany’s network of stem
cell researchers.
Thomas Rachel, MdB
Parliamentary State Secretary of the Federal Ministry
of Education and Research
3
PREFACE | THOMAS BRAUN
T
he German Stem Cell Network (GSCN), now in the
third year of its existence,
is still a relatively young organization. It would therefore be premature to attempt to evaluate its
impact at this stage. One thing
that can be stated with confidence, though, is that thanks to
the generous support of the Federal Ministry of Education and
Research (BMBF), we have been able to establish a lively
network that reflects the landscape of German stem cell research in all its diversity and vitality. The German Stem Cell
Network brings together scientists and doctors working in
stem cell research and regenerative medicine and helps us
master the immense challenges that we face. These include
not only the increasing complexity of a dynamically growing scientific field – a complexity that is burgeoning as a result of new insights, methods and techniques – but also the
expectations placed on stem cell research to come up with
new treatment methods. The network links researchers in
different disciplines whose work focuses on stem cells; it is
committed to supporting young researchers by providing
them with a forum and with opportunities to communicate,
and it acts as a contact point for global activities and cooperative ventures at European and international level. Public
relations and establishing contact with researchers in industry are other important aspects of its work.
4
Our annual conferences have proved highly successful in
bringing together German and international stem cell researchers and encouraging the exchange of scientific ideas.
The conferences in Berlin (2013) and Heidelberg (2014)
were attended by over 400 delegates. Preparations are
under way for the next conference in Frankfurt in 2015,
which will again demonstrate the importance of the network for German stem cell research. In addition, the activities of various working groups within the network enable
current problems to be tackled jointly and new initiatives
to be developed within a narrower framework outside the
large-scale meetings.
Photo: MPI for Heart and Lung Research
Preface
In this annual magazine we report on the latest developments in methods and laboratory techniques in stem cell
research in the core facilities, which vary from region to
region. We focus on state-of-the-art technology in genetic
engineering, in model organisms from the axolotl to the zebra fish, and in the measurement of stem cells. In addition,
we address considerations relating to the quantitative and
high-quality production of stem cells and the development
of stem cell archives.
The progress of stem cell research is breathtaking. The list
of scientific breakthroughs compiled annually by American journal Science places two stem cell-related achievements in the top ten, immediately after the landing of the
Rosetta probe on the Churyumov-Gerasimenko comet. Not
(yet) on the list is the first clinical trial of iPS cells to treat
Stem Cell Technologies in Germany
PREFACE | THOMAS BRAUN
macular degeneration, taking place in Japan. The outcome
of this study is bound to have a significant effect on how
quickly iPS-based treatment methods are introduced elsewhere. However, speed in the application of research findings must never come at the expense of diligence. In the
past year, unfortunately, there have also been less pleasant
sides to stem cell research. The withdrawal of a report on
a new method of generating iPS cells and the
subsequent accusations of fraud that led
to the tragic suicide of a Japanese stem
cell researcher who was only peripherally involved in the study
Heart muscle tissue of a mouse,
remind us of the need to nip
Sca1 positive stem cell (green)
negative developments of this
sort in the bud. This can only
be achieved with high levels of transparency and an
emphasis on the exchange
of scientific ideas – values
to which the German Stem
Cell Network is committed
and against which it can be
measured.
Included with our annual magazine is the annual report of
GSCN e.V. What we have achieved
would not have been possible without
the tireless commitment of our found-
Annual GSCN Magazine 2014/15 ing president Oliver Brüstle and of Andreas Trumpp, who
took over from him last year. We are also very grateful for
the outstanding dedication of GSCN’s Central Office and
the many members who have helped shape the Stem Cell
Network in the past months and years. We may not yet
have reached every stem cell researcher in Germany, but
the majority is actively involved in the life of GSCN. GSCN
sees itself as a dynamic network that is able to learn and is
constantly improving. We depend on input from our members – especially the younger ones – to enable continuous
self-renewal and optimization. Central Office and the executive board are always open to suggestions.
I hope you enjoy reading the GSCN annual magazine as
much as I have done and that it will give you new insights
into German stem cell research, its prospects, opportunities and resources.
Best wishes,
Thomas Braun
Acting President
5
INDEX
Welcome Note
Thomas Rachel (BMBF)�� 3
Preface
Thomas Braun,
acting GSCN-President�� 4
8
The GSCN conference is where the stem cell community
comes together
Interview with Thomas Braun and Andreas Trumpp�� 8
GSCN-News
from Central Office�� 12
12
All about Stem Cells
2nd International Annual Conference of the GSCN�� 14
14
Model organisms 20
Learning from masters
of regeneration
24
Measuring stem cells 24
Deciphering the stem cell code
Bioinformatics analysis 28
Navigating a sea of digital data
6
28
Photos: GSCN; EuroStemCell / Katia Hervey; MDC / Cecile Otten / Himsel; TU Dresden / Ingo Röder
20
INDEX
32
Genome Editing 32
Designer cuts in the genome
Stem cells from the factory 37
Cranking up cell production
37
Photos: MDC / Cecile Otten; Life & Brain; Fotolia / pp77; MDC / Julian Heuberger; GSCN
Archiving stem cells 42
Cell treasures from a catalog
42
Bioprinting 46
Tissue from the
laser printer
50
46
GSCN Annual Report 2014�� 50
7
GSCN | INTERVIEW WITH THOMAS BRAUN AND ANDREAS TRUMPP
New president of the German Stem Cell Network (GSCN)
“The GSCN conference is where the
stem cell community comes together”
The German Stem Cell Network (GSCN) is a dynamic network. The trend established in 2014 continues unbroken
as member numbers keep growing. The increasing number
of conference participants is an expression of the growing
stem cell community in Germany, and the BMBF (German
Federal Ministry of Education and Research) has approved
funding for the next three years. These are among the successes achieved by President Andreas Trumpp together with
Daniel Besser and the GSCN Central Office during the past
year. This discussion with Trumpp and new GSCN president
Thomas Braun addresses the GSCN’s challenges, goals and
plans for 2015.
GSCN Annual Magazine: In a few words, how would
you describe the German Stem Cell Network (GSCN)?
Andreas Trumpp: The German Stem Cell Network brings
together scientists and clinicians from academic research
institutes and from pharmaceutical and biotech companies
that work with stem cells. The members of the GSCN represent research in fields as diverse as embryonic stem cells
and iPS cells, the stem cells that control foetal development
and the development and regeneration of our organs, and
the stem cells that play a role in degenerative diseases and
cancer. And of course they also work with stem cells that
can be used in future therapies. At the GSCN annual conference, all new results and trends from the past year in
Germany and other countries are presented, discussed and
critically analyzed.
Thomas Braun: The GSCN is a lively, dynamic organization.
Many professional associations rely heavily on involvement
by established scientists, and they are sometimes dominated by a few personalities. We are trying to take a different
route. For example, new people regularly move into the executive committee. It is primarily younger people who have
a say, which reflects the relatively young character of a research field that is still gathering momentum.
Andreas Trumpp, what was the past year like for you
as president of the GSCN; what were the highlights?
8
Andreas Trumpp: 2014 saw the systematic continuation
of the first three years of collaboration with Oliver Brüstle, Daniel Besser and many other scientists on building
up the organization. We founded the GSCN and convinced
the BMBF to support our young, vibrant network. The first
presidency was characterized by efforts to transform the
network that existed on paper into an active community. The highlights during my time as president were the
BMBF’s agreement to continue funding the GSCN for three
more years and the organization of the second annual conference. And it’s been worth it, as our membership has
risen greatly in just that one year, from 250 to almost 350.
We are already running into problems with space at the
annual conference because so many people want to participate. Significantly more companies have also applied to be
exhibitors at our annual meeting in Heidelberg. These are
clear signs that our network is well received by both scientists and companies.
What new goals are on the GSCN agenda?
Thomas Braun: An important area that will involve a great
deal of additional work is setting up long-term project
funding, including for translational research projects that
cannot be completed within a three-year cycle. Of course,
we also hope to be able to convince the BMBF to support
such a strategy so that specific stem cell research projects
can be funded as well as the network itself. There have already been some small-scale initiatives in the past, but the
resources that have been made available are quite limited
in international comparison. Moreover, some programs are
being cut or not renewed in favor of funding for the German Health Research Centers, meaning that additional
flexibility is very difficult to come by. We therefore face the
question of whether we might not be better able to achieve
success and obtain project support by cooperating with the
Health Research Centers.
Andreas Trumpp: I also think that showing the ministry
that we are a strong, successful community is one of the
most important goals of the GSCN network. We are successful internationally, we are certainly one of the leading
nations with regard to stem cell research, and of course we
also need financial support for research on stem cells here
in Germany.
As far as you have seen, is the political discussion
changing in Germany with regard to stem cell
research?
Thomas Braun: You have to differentiate. There are certainly still strong prejudices related to embryonic stem
cells. With the establishment of induced pluripotent stem
cells, however, the mood has become more matter of fact
and less emotional. Public educational efforts are necessary in order to dissolve the absurd Frankenstein-like image of our research field that many people still have.
How have the professional groups within the GSCN
worked out?
Andreas Trumpp: In my cancer stem cell working group,
meeting up with our colleagues from the DKTK (German
Andreas Trumpp (left) and Thomas Braun in discussion with Stefanie Mahler, GSCN Central Office
Photo: GSCN
Cancer Consortium, one of the German Health Research
Centers) program on “Stem cells in oncology” for joint research weekends has worked out well. On those occasions,
clinicians and researchers from all over Germany come together to present and discuss their projects and findings.
I would wish that all the working groups could have this
type of meeting.
On the topic of women in science, would you say
the stem cell community is fairly male-dominated?
Andreas Trumpp: It depends what level you’re looking at.
Among doctoral students and postdocs there actually tend
to be more women than men, but for working group chairs
the ratio is reversed, and there are very few female professors. However, there are some very successful women in
top positions who also fulfil important roles in the GSCN
and are possible candidates for the presidency as well. Of
course we hope that there will be more of them as time
goes on and that our network can help with that.
Thomas Braun: In our “Somatic stem cells and development” working group, we had a kick-off meeting for a new
research association, which was really good. But it should
also be noted that the working groups are all different,
and it’s in the nature of our bottom-up structure for some
groups to be more active than others. We should offer even Thomas Braun: The women who are in top positions are
more incentives for all the groups to develop a high level of always asked to take on far too many roles. This in turn
leads to excessive administrative duactivity. With a 40-percent increase
ties and restricts time for research.
in membership, our organization is
“We are a bottom-upThat’s absurd. Young female working
still very young. We are still in the
organization with a democratic and
group chairs in particular risk being
early days, but a great deal has altransparent structure.”
assigned representative administraready been achieved during a very
tive roles because there are fewer of
short period of time.
them than of their male colleagues. That is a huge burden
Andreas Trumpp: The GSCN is also planning meetings in for them.
the future just for our young doctoral students and postdocs. When working group leaders and professors are not After they complete their doctorates, women are confrontpresent, they have fewer inhibitions about discussing their ed with the family dilemma. Until then, there are actually
research openly, and the discussion is more intense. The more qualified female doctoral candidates than male, but
GSCN’s bottom-up approach comes through here as well, as then come children, who need their parents’ time, and unyoung scientists have almost as much influence as the old fortunately that is not equally distributed between the two
parents. Our system is unforgiving in that regard, and it
guard, which makes our network very dynamic.
would be good if we could finally make the paradigm shift
Thomas Braun: The approach of requiring young peo- so that the life of a researcher permits breaks and re-entry
ple to take responsibility for setting up and running these from time to time. Currently, ever more linear résumés are
meetings can in itself be an excellent motivating factor. The expected, and if you take a break for a year or two, it really
GSCN funds these research weekends for the individual kills your chances, which takes an especially heavy toll on
women.
working groups and supports their organization.
Annual GSCN Magazine 2014/15 9
Thomas Braun: The GSCN
board has recently made a
brand-new resolution to
present a Female Scientist
Award for 2015. The prize
is intended to encourage our
younger female colleagues to
remain in the field of science
despite the difficult working conditions. The prize money can be used to
make family life easier.
Andreas Trumpp: Of course, a prize like this also looks
good on your résumé if you are a junior working group
chair applying for a permanent position.
but also practicing scientists, doctoral students and postdocs. For them in particular, this is an especially important
meeting, and these conferences lead to an extraordinary
number of interactions and joint activities.
How is the GSCN’s relationship to the business world
developing?
Andreas Trumpp: It’s going really well. In Heidelberg, we
hardly had enough room for all the industry exhibits. From
the very beginning we made sure to involve industry, and
at the conference we even had a special industry session
where companies could present their latest instruments
and products, technologies and research results. We got
very positive feedback from both industry and researchers
about this opportunity to have more direct contact with
each other.
Thomas Braun: Naturally, big pharmaceutical companies
are not very interested, because stem cell products are not
large-scale, easy-to-store products for a broad market. I
Has the Stem Cell Network succeeded in its efforts
think we need to spark the pharmaceutical industry’s into bring together all researchers throughout the
terest in order to get research results out of academia and
community?
into the realm of practical application. For this, we need
Andreas Trumpp: Yes, that is just what has happened. Our to interact with clinicians in particular so that we can get
annual meetings are organized differently than traditional cell-based therapies to patients. However, we are also seeing larger pharmaceutical manufacturconferences. Junior scientists present
ers being increasingly motivated to get
research results, while well-known pro“The GSCN is now creating a
into stem cell areas, which should be
fessors chair sessions and lead discusfemale scientist award.”
encouraged even more. The closer we
sions. And in the GSCN’s second year,
you can already see that all leading stem cell researchers get stem cell research to the realm of practical application,
are coming to our conference. It is THE stem cell meeting in the greater the interest of industrial partners will be in the
Germany, the meeting you have to come to in order to meet future.
colleagues and see the directions the various fields are taking. There is also much discussion of new German political
developments, funding guidelines and steps and, of course, Does the GSCN want to enter the public arena more
current research. When it comes to the GSCN annual meet- in the future, with statements on current topics in
stem cell research?
ing, one rule applies: You have to be there!
Thomas Braun: After all, it’s not just directors of institutes
and departments who communicate with each other here,
Thomas Braun: Well, we already did that last year; I am
referring to our petitioning against the One-of-Us initia-
Photo: GSCN
How can the GSCN help
make the situation easier
for female researchers?
Max Planck Institute for Heart and Lung Research
MPI-HLR
The Max Planck Institute for Heart and Lung
Research, located in Bad Nauheim, investigates
developmental processes of organs in the cardiovascular system and the lung.
A second focus is molecular and cellular processes during the formation of diseases in heart,
blood vessels and lung, including remodeling
processes in these organs. Scientists at the institute search for new approaches to support repair
and regeneration of the affected organs.
The MPI closely cooperates with universities in
Frankfurt, Gießen and Marburg. It has become
10 a major part of various federal and state excellence
initiates and contributes to two “Gesundheitsforschungszentren”.
Max Planck Institute for Heart and Lung Research
W.G. Kerckhoff-Institut
Ludwigstr. 43
61231 Bad Nauheim
www.mpi-hlr.de
tive on the EU level. We will definitely speak out publicly
on relevant, fundamental problems, for example on animal
experiments. Often, stem cells can only be studied in their
natural environment. For this we need animal models, and
so we have to take a position on that. However, the GSCN
won’t be issuing statements at every possible opportunity.
Recently, some highly scrutinized papers have been
withdrawn, in Japan as well as in Germany. Does that
also play a role in the GSCN’s discussion culture?
Thomas Braun: Of course, but I have to reiterate that from
the very beginning my colleagues viewed many of the studies in question very critically. As I see it, most of my colleagues viewed the studies very skeptically from the get-go,
but journals and experts determined that they were good.
So perhaps we need to call into question the policies of the
international journals.
Photo: GSCN
Do you mean that the science community quickly saw
that the studies were not okay, and that generally good
scientific practice is the rule?
Andreas Trumpp: In science, you generally know after a
short time which publications and which results are really
accurate and which are problematic. Some ground-breaking studies are referred to thousands of times and have
been repeated by various working groups, and the results
have been confirmed. That’s why Dr. Yamanaka received
the Nobel Prize so quickly for his research on reprogramming mature skin cells into pluripotent stem cells. After he
showed how the induced pluripotency method works, the
techniques were quickly repeated in numerous labs with
the same results, and that proved definitively that the results were accurate.
Transparency is an important quality criterion in research,
and the GSCN meetings are especially well suited for that.
Each presentation receives feedback, is called into question
or praised, and that is extremely important.
What are the next steps for
the GSCN?
Thomas Braun: In 2015
we will strengthen the individual working groups
and ask that they present
a recurring curriculum
including such things as
retreats and continuing education opportunities. Now
that the 2014 conference is over
we are already organizing the 2015
conference.
Andreas Trumpp is head of the Division of Stem
Cells and Cancer at the German Cancer Research
Center (DKFZ) in Heidelberg and managing director
of HI-STEM, a non-profit public-private partnership
between the DKFZ and the Dietmar Hopp Stiftung.
A primary focus of his research is the functional and
molecular characterization of normal and abnormal somatic stem cells. Another focus is identifying
metastasis-inducing stem cells of various carcinomas.
Trumpp is one of the founders of the German Stem
Cell Network (GSCN) and was Acting GSCN President
in 2014.
Thomas Braun is director of the Department of
Cardiac Development and Remodeling at the Max
Planck Institute for Heart and Lung Research in Bad
Nauheim and Professor at the Justus Liebig University
Giessen. He is an MD PhD interested in the molecular
mechanisms governing stem cell functions as e.g.
self-renewal, maintenance and differentiation of stem
cells. His research focuses on the regeneration of striated muscles, the cardiovascular system, and the lung.
He has published more than 200 papers in leading
international journals.
German Cancer Research Center (DKFZ)
Research for a life without cancer
The German Cancer Research Center (Deutsches
Krebsforschungszentrum, DKFZ), located in
Heidelberg, is a member of the Helmholtz-
Association and is the largest biomedical
research institute in Germany.
At the DKFZ, more than 1,000 scientists work
together in order to develop novel strategies
aimed at improving the prevention, diagnosis and treatment of cancer. Several research
laboratories investigate normal and cancer stem
cells (CSCs) as well as their respective niches.
The goal is to develop strategies to monitor and
Annual GSCN Magazine 2014/15 target CSCs in primary cancers and metastasis.
Together with the Dietmar Hopp Foundation, the
DKFZ is a shareholder of HI-STEM, the nonprofit
Heidelberg Stem Cell Institute and organizes the
biannual Heinrich-Behr-Conference on „Stem Cells
and Cancer“, which attracts international experts in
the field.
With the Heidelberg University Clinic, the DKFZ has
established the National Center for Tumor Diseases
(NCT), to clinically translate innovative basic cancer
and stem cell research discoveries into clinical
therapies.
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
www.dkfz.de
11
GSCN | FROM CENTRAL OFFICE
GSCN-News
A highlight of 2014 was undoubtedly the promise of the
German Federal Research Ministry (BMBF) to continue
supporting us financially for another three years. This will
enable us to establish our network on a sound footing and
pursue its expansion carefully and sustainably. We are delighted to be receiving this support!
New at Central Office: Stefanie Mahler takes over
communication for the GSCN
Since July 2014, Stefanie Mahler, a trained
journalist, has been responsible for communication at GSCN Central Office. She was
thrown into the job at the deep end: as an
introduction to the subject of stem cells she
produced three films on stem cell research
that were shown at the end of the Second Annual Conference in Heidelberg and can now be
viewed on the Internet. She thoroughly enjoyed
getting up close to stem cells right from the start.
Science has long been close to Mahler’s heart: in 2000 she
joined TV network 3sat as an editor and film-maker for the
magazine program nano. Her aim at the GSCN is to develop lots of new films, documents, forms of communication,
working groups and materials on stem cell research and to
strengthen and expand interaction within the network.
From Central Office: Conference date moved
All the preparations had been made; everything was
planned and booked for the 3rd Annual Conference in
Frankfurt. Then came the unexpected hitch: a press
preview of the International Motor Show (IAA) sent
hotel prices soaring at exactly the time of our conference. After much frenzied activity and frantic
telephoning, GSCN Central Office came up with a
new plan: a great new location was found, five days
earlier and a little further from the center of Frankfurt. The 3rd Annual Meeting of the GSCN will be held
on 9 – 11 Sept. 2015 on the Riedberg Campus in Frankfurt/Main. We’re looking forward to it!
New GSCN working group “Basic, Translational and Applied
Hematopoiesis” seeks members
The number of scientific working groups has risen to seven:
at the 2nd Annual Conference in Heidelberg, Claudia Waskow
(Dresden) and Timm Schroeder (Basel) launched the new
scientific working group on hematopoietic stem cells.
12 Anyone interested in joining should contact GSCN Central
Office at [email protected]
Meetings between peers: Launch of non-PI meetings
Who would be interested in organizing a small conference, and in talking to working group members from other
institutes – with no pressure and without PIs on board?
The GSCN seeks to promote even stronger networking between its members and to encourage personal and professional dialog. It is therefore inviting two of the more junior
scientists from each working group to organize a non-PI
meeting with a conference-like structure. The GSCN will
cover the costs of accommodation, food and the conference location. You will select the topics and encourage
people to attend.
If you are interested, please contact GCSN Central Office at
[email protected]
New group: “Communication on Stem Cell Research”
Public relations work is an indispensable part of stem cell
research. Its tasks are many and varied; they include explaining the content and methods of research to the general
public, setting up experiments for schoolchildren, training
teachers, devising educational materials, and making films
and cartoons. The GSCN has now set up a group dedicated
to communication on stem cell research that will bring science communicators together once a year. What happens
at these meetings? People discuss their experiences, produce materials, consider new types of event, and debate
the handling of new issues such as lobbying and the use of
social media. The first meeting, held in Hannover in September 2014, was attended by delegates from a range of
Germany wide institutes who engaged in detailed discussion of the methods and materials used when working
with school groups. A meeting in Berlin is planned
for 2015.
GSCN gets social
Carefully, cautiously, but confidently: this is how
the GSCN is approaching social media. We are now
on Twitter at twitter.com/gscn_office.
We look forward to interesting input and lots of followers!
GSCN films on stem cell research
As a networking organization, the GSCN sets out not only
to link stem cell researchers but also to inform the public
transparently, openly and proactively about stem cell research. In 2014 we therefore produced three films about
different research institutions and scientists in the field of
stem cell research. The films are available on YouTube and
on our website. You are welcome to view, use and share
them.
Photo: GSCN
From Central Office: Research Ministry funds GSCN
for another three years
GSCN | FROM CENTRAL OFFICE
Photos: GSCN; EuroStemCells / Katia Hervey
Dinner in Hydra
Reports on GSCN activities
Travel Awards for Hydra X,
the European Summer School
on Stem Cells & Regenerative
Medicine
The GSCN granted Travel Awards
to Katarzyna Osetek, Ronan Russell
and Sukhdeep Singh to enable them to attend the European Summer School Hydra X on the Greek island of Hydra
from 7 – 11 Sept. 2014. The three participants thoroughly enjoyed the stimulating yet relaxed atmosphere of the
Summer School – the tenth organized by EuroStemCell –
as well as the interesting discussions and the
opportunity to forge new contacts. More
than 50 postdocs and PhD students
from 19 countries attended the various lectures and seminars on a range
of issues relating to stem cells and
regeneration. The organizers had
invited 27 experts on stem cells,
aging, cancer and tissue generation. The opening lecture was given
by Connie Eaves (Vancouver) – in almost complete darkness as the result
of a power cut. Also informative were the
small group sessions which discussed both professional issues and ways in which scientists might convey
information about their work with stem cells to a wide audience.
The GSCN is planning further Travel Awards to international conventions next year. Information can be found on the
GSCN website closer to the time.
DGTI session and workshop
The 47th Annual conference of the German Society for
Transfusion Medicine and Immunohematology was also
a milestone in the partnership between the DGTI and the
GSCN, which is reflected in reciprocal membership. At the
conference, the GSCN organized a session on stem cells in
regenerative therapies. Tobias Cantz (Hannover) opened
the session with a lecture on “Stem cell based cellular therapies – perspectives and limitations” in which he reviewed
stem cell research in general and its application in Germany. He specifically explored pluripotent stem cells and
quoted the latest data from his own research. In a
presentation entitled “Epigenetic rejuvenation
of MSCs derived from iPSCs,” Wolfgang Wagner
(Aachen) considered the engineering of mesenchymal stromal cells (MSCs) from induced
pluripotent stem cells. MSCs derived from iPS
cells have greater homogeneity and a rejuvenated epigenetic program in comparison with
Annual GSCN Magazine 2014/15 primary MSCs from patients. “The hidden stem cell
of the liver” was the title of the lecture by Michael
Ott (Hannover). The engineering of liver cells from
stem cells is a key concern of his working group.
The symposium closed with a talk by Toni Cathomen
(Freiburg) on “Targeted gene editing in pluripotent
stem cells – from disease modeling towards therapy.” He
described the growing range of genome engineering options emerging also from his laboratory. The article “Designer cuts in the genome” in this issue (page 32) outlines
the great progress being made in this field.
At the DGTI conference, the GSCN also helped organize the
event “ATMPs – How to bring cell-based medicinal products successfully to the market” hosted by the Committee
for Advanced Therapies (CAT) of the European Medicines
Agency. The regulations governing clinical trials of advanced therapy medical products (ATMP) were explored in
detail at this half-day seminar.
Stem cells are a Tour-de-Force in Dresden
The symposium Neural Stem Cells in Evolution was held on
8 July 2014 during the 5th International Congress on Stem
Cells and Tissue Formation in Dresden. Elly Tanaka, Director of CRT Dresden, and Federico Calegari brought ten international scientists together for this event; among them
was Oliver Brüstle, founding president of the GSCN. The
lectures focused on brain development in various model
organisms as a basis for deciphering the evolutionary development of neural stem cells and their differentiation.
The aim is to understand the evolutionary history of the
most complex human organ, the brain. Federico Calegari’s
detailed report of the symposium is available on the GSCN
website.
Front row, from left to right: Tadashi Nomura, Kyoto, Japan; Colette
Dehay, Lyon, France; Nancy Papalopulu, Manchester, UK; Elly Tanaka, Dresden, Germany; Yoichi Kosodo, Kurashiki, Japan.
Back row: Victor Borrell, Alicante, Spain; Stefan Thor, Linköping,
Sweden; Oliver Brüstle, Bonn, Germany; Federico Calegari, Dresden,
Germany; Daniel Besser, Berlin, Germany.
13
GSCN | 2 ND ANNUAL CONFERENCE
2nd International Annual Conference of the German Stem Cell Network
All about Stem Cells
The GSCN’s annual conference brought 450 scientists
together at the German Cancer Research Center (DKFZ) in
Heidelberg from 3 – 5 Nov. 2014. For three days, everything
revolved around stem cells.
Andreas Trumpp, conference president, GSCN president
for 2014, and Heidelberg-based stem cell researcher, was
very pleased with the outcome: “The GSCN is only in its
second year, but already we have become the most important forum for the stem cell community in Germany.” The
numbers say it all: GSCN membership was up by more than
30 percent from its previous year, and the 2014 conference
had more participants, exhibitors and posters than the 2013
event in Berlin.
F
ollowing a welcome by Otmar Wiestler, chairman of
the DKFZ, Andreas Trumpp took to the stage and used
his opening speech to chart the positive course that
the GSCN had taken in 2014. The German Federal Ministry of Education and Research (BMBF) also provided positive feedback on the network. The scientific program then
began with a keynote presentation by Eduard Batlle (IRB,
Barcelona), in which he discussed his laboratory’s latest
findings on the formation and maintenance of stem cell
niches in the intestines, and on the deregulation of these
processes in tumorigenesis. Studies conducted in his labo-
ratory show that human colorectal
cancers have a similar organization to healthy tissue.
Many intestinal cells in
tumors also differentiate
and thereby lose their
immediate danger. The
exact opposite happens with the cancer
stem cells. In this scenario, the TGF-ß and
BMP signaling pathways control the transcription factor GATA6 in
both healthy and degenerated cancer cells. Another international highlight came in the form
of the keynote speech given by Parisian surgeon Philippe
Menasché (Hospital Georges Pompidou), in which he discussed his experiences of using stem cell patches on hearts
damaged by myocardial infarction. He described the first
clinical trial on humans using a cell population of human
embryonic stem cells that have the early cardiac genetic
marker Isl-1. His findings clearly prove that the positive
effects observed could not be ascribed to the direct installation of the transplanted cells, but to the way the foreign
cells support the body’s own regeneration processes. Menasché’s talk demonstrated a key feature of the conference:
rather than being solely a platform for mainly young scientists, it also focuses on exchange and contact between basic
research and its application.
With this in mind, collaboration with industry was an important part of the conference. “We had very many registrations from industry,” reported Daniel Besser, managing
director of GSCN, referring to the 22 exhibition stands
booked by various companies. “The industry stands are an
important part of the event for us because they present the
latest developments and give the scientists access to crucial partners.”
14 In three to four parallel sessions, researchers presented
and discussed the latest data and results from stem cell
research being conducted in Germany and abroad. Disease
modeling using stem cells, state-of-the-art genetic engineering methods, and 3D-printed cells were all big topics.
Once again, the participants were very interested in the
latest findings on reprogramming and transprogramming
somatic cells. A new feature of this year’s sessions was
that each chairperson gave an introduction to the topic of
their session. This approach received very good feedback
both during the conference itself and in the online survey
that was conducted afterwards. The three-day conference
Photos: GSCN
The scientific talks
GSCN | 2 ND ANNUAL CONFERENCE
“Anyone who chooses not to present their latest data to fellow scientists and make them available for valuable feedback only has oneself to blame. This event covers almost
the entire field in Germany,” said Trumpp, praising the diverse program.
Eduard Batlle
Jürgen Knoblich
Photos: GSCN
i ncluded 44 talks selected from 250 submitted abstracts in
the following fields:
• Stem cells in regenerative therapies
• Stem cells in diseases: cancer stem cells
• Computational stem cell biology
• Somatic stem cells
• Stem cells in disease modeling and drug development
• Programming and reprogramming
• Hematopoietic stem cells
• Pluripotency and embryonic stem cells
• Stem cells in development
What follows is a selection of the many excellent talks that
were given during the parallel scientific sessions. During
the Stem Cells in Development session, Achim Breiling
(DKFZ, Heidelberg) presented data on the function of the
three ten-eleven translocation enzymes (TET1-3) in embryonic stem cells. The findings show that the TET-dependent processing of 5-methylcytosine to
5-hydroxymethylcytosine protects DNA
from hypermethylation. It is likely that
uncontrolled hypermethylation deactivates genes that are important for
development. These findings were
confirmed by embryonic stem cells
from which TET 1 and 2, or TET 1,
2 and 3 were removed. Speaking in
the Programming and Reprogramming session, Lamia’a Bahnassawy
Philippe Menasché
(University of Luxembourg) spoke
about her study into identifying factors
that intervene in the regulatory circuit that
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Annual GSCN
Magazine
2014/15
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15
KAPITEL 1 | LEBENDER KOLUMNENTITEL
A joint presentation
by Michael Ansorge
(Leipzig University) and
Axel Krinner (TU Dresden)
examined cell migration. In the
two-part talk during the Computational Stem Cell Biology session, Ansorge showed in vitro
results of cell migration experiments, which Krinner then
evaluated and compared with in vivo data using computer-based analytical methods. Their collaboration allowed
the researchers to answer, in a simple 2D context, fundamental questions about how hematopoietic stem cells
(HSC) interact with relevant regulators in the stem cell
niches and about what role they play in the migratory behavior of HSC. The back-to-back presentation impressively
highlighted the advantages of combining computer-based
investigations with in vitro and in vivo studies. Speaking
in the Hematopoietic Stem Cells session, Daniel Klimmeck
(DKFZ, Heidelberg) gave a talk on the regulatory networks
that control HSCs in their undifferentiated state and during
their transition to progenitor cells. He presented studies
on proteome, transcriptome and methylome analyses that
involved comparing purified HSCs to the multipotent progenitors generated from them. His encyclopedic data facilitate that, in future, it will be possible to carry out easier,
faster and more comprehensive analyses of the molecular,
cellular and epigenetic processes that control the hematopoietic hierarchy.
16 During the Clinical Trials and Regulatory Affairs session,
Ulrich Martin (Hannover Medical School) gave a talk on
using stem cells in regenerative therapies. He discussed
studies conducted in Hannover on developing heart muscle
cells from induced pluripotent stem cells for cardiac therapies. Although the therapeutic application of these types
of cells remains a very lengthy process, the studies have
produced positive results. Nico Lachmann, also of the Hannover Medical School, participated in the Stem Cells in Regenerative Therapies session by presenting new studies on
transplanting macrophages into the lungs to treat pulmonary alveolar proteinosis (PAP), a hereditary lung disease.
The studies used macrophages from undifferentiated stem
cells. The trials have so far been carried out on mice serving as humanized disease models for PAP. The researchers
hope that it will be possible to use durable cells from the
blood system to treat patients in future.
This year’s conference included workshops for the first
time. “We want to develop close relationships with application and industry as frames of reference for basic research
and as prospects for scientists,” said Daniel Besser, explaining why this format had been introduced. “The workshops
were well attended and were rated positively in the online
survey.” Participants could choose between workshops on
the following topics: biobanks of human pluripotent stem
cells (Andreas Kurtz / Joana Namorado); the clinical relevance of animal models (Georg Duda / Frank Emmerich,
Regenerative Medicine Initiative Germany (RMIG)); and
the differing expectations of the pharmaceutical industry
and stem cell research (Oliver Brüstle / Ira Herrmann, Stem
Cell Network North Rhine-Westphalia). Also new to the
GSCN conference were the scientific meeting and general
assembly of the German Society for Stem Cell Research.
The two poster sessions attracted a great deal of interest.
Participants literally stood on tiptoe so that they could see
and discuss the 200 posters on display. The work provided
good insight into the current status of stem cell research.
“The research and presentation were of an extremely high
standard. I really struggled to pick three posters,” said Ingo
Röder (Dresden), describing his task as part of the jury for
the poster awards. Franziska Zickgraf (Heidelberg) was delighted to have participated: “I’m really pleased to be presenting my poster here. It’s helping me connect with interesting people and hear their thoughts and experiences,” she
said, discussing the outcome of her work.
The following participants won awards, provided by
Peprotech, for their posters:
• Debojyoti Chakraborty, TU Dresden: A novel lncRNA
protein interaction characterizes mouse embryonic stem
cell fate
• Peggy Matz, Düsseldorf University: Endodermal progenitor cells derived from integration-free iPSCs as an in vitro
model for dissecting endodermal cell fate decisions
• Janine Müller, Bielefeld University: Intrastriatal transplantation of adult human neural crest-derived stem cells
improves functional outcome in rat model of Parkinson’s
disease
• Roman Reinartz, University of Bonn: Modeling poly
clonal dynamics in glioblastoma
Photos: GSCN
maintains pluripotency. Within
this process, the
TRIM32 factor regulates at least two
of the factors – c-Myc
and Oct4 – that control the undifferentiated
state in stem cells. TRIM32
is not, however, needed to
maintain this state, but
rather to interrupt the
regulatory circuit during differentiation by
helping degrade the
pluripotency factors
via the process of
ubiquitination.
The GSCN would also like to take this
opportunity to congratulate the recipients of GSCN Travel Awards:
Cantas Alev (Japan), Janine Müller
(Bielefeld), Susann Rahmig (Dresden) and Yuval Rinkevich (USA).
Photos: GSCN
Strategic working groups
The Public Outreach working group tried out
its educational materials on the conference participants,
who swapped their lunch hour for hopping over pictures
of cells and arranging magnets of human organs. “It’s really
important that we explain stem cell research to the public.
Doing so will allow us to discuss the ethical implications
and present our work to a large audience,” said Ira Herrmann (Düsseldorf) and Tobias Cantz (Hannover), explaining their aims as leaders of the working group. The workshop was a good opportunity for conference participants to
acquaint themselves with the diverse materials so that they
could use them during future open days or for laboratory
tours at their respective institutes.
The strategic working group sessions focused on career
development, funding, clinical trials and stem cell technologies. It is especially important that young researchers
Annual GSCN Magazine 2014/15 receive support in developing their career prospects and in
exploring the opportunities open to them. Other much-discussed topics at the conference addressed the fast and effective reprogramming of cells. The focus was on new quality assurance technologies and on methods for increasing
the quantities of the new stem cells required.
The strategic working groups also included a new format
that functioned rather like an intensive workshop: ten registered scientists gathered in the canteen to engage with
a distinguished expert on a specific investigative method.
These “meet-the-expert” events saw Claudio Mussolino
(Freiburg), Boris Chichkov (Hannover) and Micha Drukker (Martinsried) meet with a small group of participants
17
Meet-the-expert-table
with Claudio Mussolino
Wednesday brought the conference to a close with more
highlights from international research in the form of talks
by Shahragim Tajbakhsh (Institut Pasteur, Paris) and Jürgen
Knoblich (IMBA, Vienna). Tajbakhsh presented his laboratory’s latest findings on the molecular regulation of muscle stem cells during development and regeneration. The
Notch signaling pathway performs a special control function in this system. While the pathway is active in dormant
muscle stem cells, it is deactivated very quickly when a cell
begins to divide, e.g. after muscle injury. In dormant stem
cells, Notch is particularly important for the interaction
between the cells and their niche, and preserves stem cell
identity. Knoblich’s talk was part of a joint symposium on
neural stem cells, which was also the sixth meeting of the
BMBF-funded independent young researcher groups in
neuroscience. Knoblich presented his laboratory’s data on
the 3D culturing of human brain cells. His team succeeded
in producing organoids (“mini-brains”) that are structured
in a similar way to the human brain. The new technology
allowed the scientists to shed light on the genetic defect
involved in a form of microcephaly. If the microcephaly
protein CDK5RAP2 is not present or has a genetic defect,
this results in accelerated and therefore premature
neural development. The tissue remains smaller than usual because fewer progenitor cells
form. When the researchers repaired the
defect, the mini-brains grew almost normally. The hope is that these cell culture
systems will help scientists understand
other human diseases for which studies
in animal models are either impossible
or too complex. The symposium also featured a talk by Amelia Eisch (University
of Texas, Dallas) on the mechanisms underlying the formation of new nerve cells
in adults, and one by Sebastian Jessberger
(University of Zurich) on the function of
neural stem cells and the processes that occur in these cell populations during the aging
process. The Neural Stem Cell Symposium held
on Thursday, 6 Nov. 2014, featured more high-level
talks from outstanding international researchers.
18 Participants also enjoyed the conference’s networking
event – and views over Heidelberg – on the Tuesday
evening. The relaxed atmosphere in the Molkenkur restaurant was the perfect setting for continuing discussions and
a celebratory atmosphere. The online survey shows that the
participants were extremely satisfied with the conference,
its content, and the organization. “Next year we will make
sure we have enough space for the poster exhibition so that
we don’t have to put it in a separate marquee. Thankfully,
that will be easy in Frankfurt,” said GSCN managing director Daniel Besser, commenting on some of the criticisms
expressed in the survey. Andreas Trumpp was delighted with the event: “The conference was a huge success. I
liked the dynamic and lively exchange between researchers of all ages and industry representatives, the intensive
networking and the high quality of the contributions. This
is exactly what we want to support.” Last year, the GSCN
secured a three-year extension of its BMBF funding. “That
was a highlight for us last year. Now our efforts are concentrated on enabling the network to run independently,” said
Thomas Braun, setting out the GSCN’s plans for the future.
As the new GSCN president, Braun, who is director of the
Max Planck Institute for Heart and Lung Research in Bad
Nauheim, will be inviting stem cell researchers to the 2015
GSCN conference, which will be held in Frankfurt am Main
in mid-September.
The 2014 conference was the first to close with a public
event at the end of the three days. Using GSCN-produced
films from the laboratories of Andreas Trumpp, Magdalena Götz and Anthony D. Ho, as well as a panel discussion,
it presented the reality of and prospects for stem cell research. Attracting 120 guests, the event, which received
support from the Ernst Schering Foundation, was well attended and reflected the public’s keen interest in finding
out about the latest stem cell research and how the findings
can be applied in therapeutic contexts.
The GSCN films about the stem cell researchers and the film
of the 2014 conference are available on the GSCN website.
Photos: GSCN
to discuss their
processes in the
fields of genetic
engineering, laser
printing, and reprogramming. A number
of participants provided
feedback to the GSCN Central
Office, saying that the events had
produced extremely effective and useful discussions. Andreas Bosio, head of the Stem Cell Technologies working group, was delighted with the positive
responses: “We really want to include the expert sessions
again in 2015. It’s an unusual format and seems to work
extremely well.”
3rd International
Annual Conference
of the German Stem Cell Network (GSCN)
9 – 11 September 2015
Campus Riedberg, Otto Stern Center
Goethe University
Frankfurt/Main
Photos: Otto Stern Center © Goethe University Frankfurt/M.; Skyline Frankfurt/M. © Tourismus+Congress GmbH Frankurt/Holger Ullmann; Scientific picture © FMP/Schmoranzer; Conference pictures © GSCN/Steffen Weigelt, Yan de Andrés
www.gscn.org
International keynote speakers
Andras Nagy (Toronto) · Paul Riley (Oxford)
Hans-Willem Snoeck (New York) · Lorenz Studer (New York)
Presidential Symposium
Oliver Brüstle (Bonn), GSCN Awardees: Young Investigator,
Female Scientist, Publication of the Year
Abstract submission deadline for oral presentations: 31 May 2015
Oral presentations chosen from the best abstracts
Scientific sessions
•
•
•
•
•
Pluripotency and embryonic stem cells
Programing and reprograming
Somatic stem cells
Hematopoietic stem cells
Stem cells in development
• Stem cells in diseases: cancer stem cells
• Stem cells in regenerative therapies I
• Stem cells in regenerative therapies II:
Mesenchymal stem/stroma cells
• Stem cells in disease modeling and drug development
• Computational stem cell biology
Program committee
Daniel Besser (Berlin) · Thomas Braun (Bad Nauheim) · Ulrich Martin (Hannover) · Michael Rieger (Frankfurt) · Elly Tanaka (Dresden) · Andreas Trumpp (Heidelberg) · Harald von Melchner (Frankfurt)
Supported by
Annual GSCN Magazine 2014/15 Collaboration with
19
Photo: MDC / Cecile Otten
Presentation of the mobility of the embryos of zebrafish
(red:
20 before; green: afterwards)
STEM CELL TECHNOLOGIES IN GERMANY | MODEL ORGANISMS
Model organisms
Learning from
masters of regeneration
Tissue stem cells are the driving forces behind growth and
regeneration in humans, animals and plants. To gain an
understanding of the fundamentals of stem cell biology,
developmental biologists are taking a close look at model
organisms with amazing self-healing abilities. Axolotl,
flatworm and zebrafish are among the species that could
be described as masters of regeneration. Researchers have
spent years acquiring expertise on these creatures and
developing infrastructures for their study. For biomedical
research, mice, rats and larger animals are continuing to
gain importance, but bioartificial “model organisms”, or
multi-organ chips, are also opening up new paths for health
research.
A
dult stem cells are the regeneration reserves for tissues and organs. They ensure that new cells are generated when old cells deteriorate or are injured. Developmental biologists therefore naturally focus on these
cells. “There is a robust community of developmental biologists in Germany, and a number of them are interested in
stem cell research,” says Thomas Braun, acting president of
the German Stem Cell Network (GSCN) and director of the
Max Planck Institute (MPI) for Heart and Lung Research in
Bad Nauheim in the state of Hesse.
Certain model organisms, both animals and plants, have
proven to be ideal objects for studying regeneration processes. They can be used to study key mechanisms such as
the maintenance of stem cells or phenomena like proliferation and differentiation. A whole range of organisms including flatworms, the round worm C. elegans, the fruit fly
Drosophila, zebrafish, hydra, amphibians as well as Arabidopsis thaliana serve as models for stem cell researchers
in Germany. Many resources have been set up for studying
them in recent years. Complete genome information is now
available even for exotic model organisms, and new molecular biological tools are opening up entirely new avenues
for developmental biologists. For Thomas Braun, diversity
is especially important here: “Researchers should not focus
too heavily on investigating mammals. We need a sensible
mix of model organisms to learn more about stem cells.”
Planarians: Compact packages of stem cells
The species most favored by stem cell biologists include the
planarians. These flatworms, measuring just a few centimeters in length, are easy to overlook in their natural habitats – seas and rivers. But they are truly exceptional when it
comes to regeneration. Severed heads and tails grow back
rapidly, and an amputated body part can even produce a
complete, viable organism. This is actually not so surprising, since planarians are really just little packages of stem
cells. Even the adults consist of about 30 percent neoblasts.
The thing that fascinates developmental biologists is the
fact that many of the neoblasts are pluripotent, meaning
Annual GSCN Magazine 2014/15 that a single transplanted cell can generate all the organism’s cell types. But how is this pluripotency controlled and
maintained? What molecular programs underlie the phenomenon?
Kerstin Bartscherer’s team at the MPI for Molecular Biomedicine in Münster is taking a close look at a planarian
species called Schmidtea mediterranea. However, planarian
cells cannot be reproduced in a Petri dish. For Bartscherer,
this deficit constitutes one of the system’s great strengths.
“For us, the planarians are a kind of in vivo Petri dish,” she
says, “meaning that pluripotent stem cells can be observed
and manipulated in their natural environment.” The researchers use flow cytometry to isolate the pluripotent
cells and thereby determine the molecular profile of the neoblasts. In addition to gene activity studies, Bartscherer’s
team is using quantitative mass spectrometry to determine
the protein fingerprint of the versatile flatworm cells. In
this way, the Münster-based developmental biologists have
already tracked down several pluripotency factors.
Zebrafish, an elegant model for geneticists
The zebrafish (Danio rerio) is one of the most popular model animals for foundational researchers. The animals are
transparent during early embryonic development, meaning that cell structures and movements can be observed
directly using a microscope. In addition, they are very well
suited for genetic experiments. The zebrafish has therefore
quickly become the preferred vertebrate model for studying organ development. And these fish have impressive
self-healing powers. Even mature animals are able, thanks
to active neural stem cells, to regenerate brain injuries.
Parts of the heart muscle and fins can also grow back.
Ever since Christiane Nüsslein-Volhard, a researcher at the
MPI in Tübingen and 1995 Nobel Prize laureate, brought
the zebrafish to popularity as a model for developmental
geneticists, scientists at many other locations in Germany
have been actively furthering zebrafish research. For example, several groups of researchers at the Center for Regenerative Therapies Dresden (CRTD), a DFG research center,
have focused on regeneration of the central nervous system. Didier Stainier’s working group at the MPI for Heart
and Lung Research is among those researching blood stem
cell biology. The team recently found out that interferon
gamma, a signaling molecule usually involved in inflammatory processes and infections, also plays a key role in the
genesis of blood stem cells in embryos. The researchers
even assume that these findings could help simplify production of blood stem cells in Petri dishes.
Using genetic screens or genetic engineering experiments,
biologists in Germany and elsewhere have generated thousands of zebrafish lines. These are valuable resources that
21
stable way, genes necessary for regeneration. Thus there
now exists a powerful tool for unraveling the further secrets of the miraculously regenerating axolotl.
Small rodents and large animal models
Flatworms, fish and salamanders may be unique models
for researching universal mechanisms in stem cell biology,
but when it comes to gaining insights relevant to human
biology and medicine, mice and rats are indispensable
model systems. Here as well, researchers are
pinning their hopes on the new designer
The axolotl, poster child of
nucleases. Such nucleases make it posregeneration medicine
sible to modify or switch off genes in
Zebrafish
a targeted way in a much shorter
The axolotl is another verteperiod of time and thereby learn
brate famed for its spectacular
about their functions. “This
self-healing abilities. These
does make it possible to accelMexican salamanders are conerate the production of knocksidered nature’s best tissue
out mice,” says Braun, “but
engineers. If their limbs are
keeping the animals is still a
severed or their spinal cord
lot of work.” The regulatory
badly damaged, they can genburdens for animal experierate a completely functional
ments, such as the documentareplacement. Nerves as well
tion requirements, have grown
as skeletal and muscle tissue all
enormously in recent years due
grow back perfectly. Elly Tanaka is
to new EU directives. Therefore,
the director of the CRTD in Dresden
central resources have become all
and a member of the extended board of
the more important here as well. The
the GSCN. She has been studying the axoGerman Mouse Clinic at the premises of
lotl’s self-healing powers for many years. Tanaka
Helmholtz Zentrum München is an important
and her team have already developed a number of special platform, with many thousands of mouse lines available.
methods for uncovering the molecular programs behind That facility was built with support from the Federal Minsalamander regeneration. Molecular genetic experiments istry of Education and Research (BMBF). The EU-funded
in amphibians are an extremely difficult undertaking, but European Mouse Mutant Archive (EMMA) is also housed
great progress has been made in recent years. Designer there.
nucleases are universal molecular tools that allow genetic
modifications to be carried out in a targeted way, regard- Animal models like mice and rats as well as larger animals
less of the species (see chapter on Genome Editing, page like goats, sheep and pigs are important tools for the in32). Tanaka’s team in Dresden has also successfully used vestigation of diseases, but in many cases there are serious
the CRISPR-Cas genome editing system to switch off, in a limitations on how findings can be medically applied.
Photo: Fotolia / mirkorrosenau4
must, however, also be archived. Since 2012, the Karlsruhe
Institute of Technology (KIT) has housed one such zebrafish archive. Called the European Zebrafish Resource Center
(EZRC), the archive is a central facility with over 3,000
aquariums for the maintenance and distribution of zebrafish lines. It is funded by the Helmholtz Association and the
Klaus Tschira Foundation. GSCN president Thomas Braun
believes that central collections like the EZRC are extremely useful. “These reliable resources make our work much
more efficient and much faster,” he says. “They are particularly important for smaller research teams.”
The Collaborative Research Center SFB 873
Maintenance and Differentiation of Stem Cells
The Collaborative Research Center SFB 873
“Maintenance and Differentiation of Stem Cells
in Development and Disease” at Heidelberg University works towards defining the regulatory
principles underlying the balance between maintenance, expansion and differentiation of stem
cells in diverse systems on a mechanistic level.
To this end the SFB873 studies a wide spectrum
of experimental models ranging from plants to
human to elucidate the inherent properties of
specific stem cell systems, but also to uncover
common and divergent principles behind regulatory regimes and molecular signatures.
22 Our consortium brings together internationally
recognized researchers, with unique scientific
strengths in cell biology, biophysics, developmental
biology, molecular medicine or modeling. With our
research we hope to advance our understanding of
principles underlying stem cell function and lay the
foundation for translational approaches.
Centre for Organismal Studies (COS)
69120 Heidelberg
www.sfb873.de
Photo: Fotolia / kazakovmaksim
Multi-organ chips – humans on the specimen slide
The hope is that many animal experiments could become
superfluous due to technological progress in regenerative
medicine. To this end, this field of research is now producing miniature model organisms. Tissue engineers hope to
shrink human tissue and organs to the size of a specimen
slide so that important metabolic processes can be simulated in the lab. Pharmaceuticals could then be tested on
them and clearer predictions made for the development
of active substances. Researchers working with Uwe Marx
and Roland Lauster at TU Berlin, funded by the GO-Bio program of the BMBF, are developing such organ chips in order
to replicate important physiological processes. To do this,
they are breeding organ-like structures on a microscopic
scale in tiny chambers. The mini-organs consist of only a
few cell types, but these already make up their own functional unit. Multiple organ systems have thus been successfully combined with one another within a very small space.
The chambers of the multi-organ chip are supplied by a micro-fluid system. The researchers’ long-term goal is, ideally,
to pack the entire human organism onto a microchip as a
modular collection of organ-like structures. A human test
dummy on a chip the size of a specimen slide – that’s how
the bioartificial model organism of the future may look.
Text: Philipp Graf
AMSBIO is a long-established supplier of high quality tools and
technologies to support stem cell research. Our extensive product
portfolio supports every facet of stem cell research ranging from
stem cell sources, iPSC reprogramming agents, and ready-to-use
feeder cells to advanced xeno-free culture medium components
and GMP grade cryopreservation media.
Together with a comprehensive range of stem cell characterization
products, differentiation reagents, and unique assay platforms
AMSBIO is proud to offer the industry’s largest selection of 2D
and 3D natural and recombinant extracellular matrices, including
Cultrex BME 2 organoid growth matrix to enable the development
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Annual GSCN Magazine 2014/15 Axolotl
At the very heart of AMSBIO’s core principles are quality and
innovation, constantly seeking out new and innovative products
to accelerate your stem cell research programme. We back our
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Visit www.amsbio.com
or contact us [email protected]
23
Chen, Chen 1 20080429_Series041_z02
Heart muscle cells derived from mouse embryonic stem cells
24 Photo: MDC / Chen Chen
STEM CELL TECHNOLOGIES IN GERMANY | MEASURING STEM CELLS
Measuring stem cells
Deciphering the
stem cell code
Thanks to highly sensitive measuring instruments, researchers are learning more and more about the special characteristics of stem cells. High-performance sorting procedures
can help to isolate specific cell types. High-throughput analytical techniques make it possible to decipher the molecular
signatures of stem cells. The interplay among biomolecules
can now be tracked even in single cells. The stem cell as a
system can be analyzed more precisely than ever before.
The question of which internal and external factors give a
stem cell its special characteristics is one of the key questions being addressed by stem cell researchers around the
world. However, decoding stem cells’ molecular signatures
has proven to be quite a challenge. After all, phenomena
like self-renewal or differentiation are based on very complex, dynamic biological programs. Moreover, stem cells,
whether pluripotent stem cells or tissue stem cells, take
many different shapes.
Photo: Goethe-University
Luckily, increasingly sensitive analytical techniques are
providing stem cell researchers with tools that enable them
to constantly improve their analyses of the objects they are
studying. Such instruments are the focus of the strategic
working group on “Stem cell technologies” of the German
Stem Cell Network (GSCN), headed by Frank Emmrich of
Leipzig University and Andreas Bosio, Head of R&D in the
stem cell division of Miltenyi Biotec GmbH in Bergisch Glad-
bach. “In our group, we want to discuss the wide range of
new techniques and promote dialogue about them,” says
Bosio. He says another goal is influencing and even helping to determine the future development of important cell
technologies.
Bringing order into the cell mix
Anyone wishing to take a closer look at specific stem cell
types needs samples that are concentrated and as pure as
possible. “The basic problem in working with tissue stem
cells is that we are dealing with heterogeneous cell populations,” says blood stem cell specialist Michael Rieger of the
LOEWE Center for Cell and Gene Therapy at the University
Hospital in Frankfurt am Main. Furthermore, these cells are
rare. In the bone marrow, there is one hematopoietic stem
cell (HSC) for every 100,000 cells.
Cell sorting procedures are used to bring order to this mix
of cells. In flow cytometry, cells flow rapidly past optical or
electrical detectors. They are sorted on the basis of characteristic molecules on the cell surface called markers. Fluorescence-activated cell sorting, FACS for short, has become
indispensable for research labs. Miltenyi is banking on
magnetic cell sorting, which has been widely used for many
years. In that process, magnetic nanoparticles are conjugated with antibodies that dock selectively at markers on
Analysis of FACS data in the laboratory
A new cell sorting system from Bergisch Gladbach, on the
other hand, is based on micro-fluidics. “We developed a
micro-chip with tiny channels and switches that can, on
the basis of fluorescence markers, sort cells that are flowing through even more quickly and more gently than is the
case with conventional flow cytometers,” Bosio explains.
This is also possible under sterile conditions, which constitutes a clear advantage for possible use in regenerative
therapies.
Omics technologies
Using omics technologies, molecular
biologists can look at cells with an
unprecedented degree of precision. Omics technologies are
high-throughput bioanalytical techniques that permit
parallel,
comprehensive
testing of biomolecules
from a biological sample
using a largely automated
process and in a relatively
short period of time.
The speediest development
without a doubt has been
in DNA sequencing. Breakthroughs in microsystems technology and nanotechnology have
accelerated DNA decoding by a factor
of millions and correspondingly reduced
the costs.
“In recent years, omics techniques have become so sensitive that you can work with very little cell material,” says
Michael Rieger, a member of the extended board of the
German Stem Cell Network (GSCN). He sees the most recent technological progress in transcriptome analysis as
especially relevant. This involves using a transcribed RNA
molecule to measure the activity level of genes in defined
cell types. Until recently, transcripts were read using DNA
microarrays. “But now RNA sequencing is on the rise,” says
Rieger. With the RNA-seq technique, the identity and quantity of RNA molecules that are present can be determined
very precisely.
Exploring the RNA universe
Another benefit is that this technique opens up a completely new view of the cell’s RNA universe, which has
scarcely been explored. This also makes it possible to investigate functional classes of RNA
molecules that are not translated into
a protein. These include short microRNAs and long non-coding
RNAs (lncRNAs). More and
more researchers are now
working to determine what
role these molecules play
in stem cells.
Epigenetic changes, or
chemical modifications
of DNA, make for another
level of genetic regulation. Modern sequencing
techniques have made it
possible to optimize epigenome analyses, such as
studies of DNA methylation
patterns. Recording the complete
repertoire of protein molecules in a
cell (proteome analysis) is likewise indispensable for gaining a precise understanding of biomolecular processes. Thanks to the development
of highly sensitive mass spectrometry (MS) techniques,
even proteins that are present only as tiny traces can now
be identified and even quantified.
Photo: MDC / Himsel
stem cell surfaces. The main advantage is that by using a
magnet, it is possible to fish out the desired cells from large
quantities of cells very gently and under sterile conditions.
The technique is already used routinely in clinics.
Heidelberg Institute for Stem Cell Technology and Experimental Medicine
HI-STEM gGmbH
HI-STEM gGmbH is a non-profit public-private
partnership between the German Cancer
Research Center (DKFZ) and the Dietmar Hopp
Foundation (DHS).
Located within the DKFZ in Heidelberg, HI-STEM
performs cutting-edge research on stem cells with
the aim of translating these results into novel clinical applications. This includes the development
of novel diagnostic tools and innovative therapies
to monitor and target leukemic and solid tumor
stem cells as well as metastatic disease.
26 Professor Dr. Andreas Trumpp and four Junior
Group Leaders direct an international research
team of more than fifty employees.
The HI-STEM Research Groups:
•Hematopoietic and Leukemic Stem Cells
(A. Trumpp)
•Experimental Hematology (M. Milsom)
•Stress induced activation of HSCs (M. Essers)
•Cancer Stem Cells and Metastasis
(A. Trumpp & M. Spick)
•Metastatic Niches (T. Oskarsson)
HI-STEM gGmbH
German Cancer Research Center (DKFZ)
69120 Heidelberg
www.hi-stem.de
Scrutinizing blood stem cells
Scientists in Heidelberg, at the German Cancer Research
Center (DKFZ) and the European Molecular Biology Laboratory (EMBL), recently published a study in the journal
Cell Stem Cell that documents the intensive use stem cell
researchers in Germany have already made of omics technologies. In this study, coordinated by Andreas Trumpp,
senior president 2015 of the GSCN, hematopoietic stem
cells (HSCs) and precursor cells were analyzed molecularly
in unprecedented detail. The researchers closely examined
the transcriptome, the proteome and the methylome of the
various cell types. The combination analysis brought to light
about 500 transcription factors and about 700 lncRNAs that
show varying patterns of activity in the cell types examined.
Michael Rieger, who was not involved in the study, considers the Heidelberg publication a valuable data resource for
all blood stem cell researchers around the world. “Now we
need to make biological sense of the multiple levels of this
information and develop hypotheses from them.”
Photo: MDC / Torben Redmer
3D organization of the genome
How does the molecular program of a stem cell work? Molecular biologist Frank Buchholz and his team at TU Dresden’s medical faculty are using genome-wide functional
screens to hunt for important molecular actors that are
necessary for stem cell maintenance. The Dresden-based
researchers are using RNA interference technology to systematically shut off the genes in cells and test the effects
of this intervention. Designer nucleases, the new precision
tools of genetic engineering, are also inspiring genome researchers (see chapter on Genome Editing, page 32). “It is
also becoming more and more important to consider the
spatial organization of the genome in cells,” says Buchholz.
Buchholz counts the chromosome conformation capture
method as one of the hottest topics in molecular cell biology.
Single-cell analysis becoming possible
The omics technologies have become so powerful and sensitive that analysis is even possible at the level of individual
cells. Stem cell researchers can
benefit enormously from such
single-cell analyses. Andreas
Bosio sees great potential in
this technique, especially for
cancer research. In the study
of extremely rare cancer stem
cells, for example, testing single
cells can provide valuable insight
into tumorigenesis. “The technique
is still quite cumbersome for broad
application,” says Bosio, “but linking it
with cell sorting can make things significantly easier.”
Tracking the fate of a cell
For Frankfurt-based researcher Michael Rieger, however,
examining the molecular profile of cells is not enough. To
understand how stem cells work, he says, it is also necessary to take a close look at their external form and their behavior. For this purpose, in recent years he has developed
a single-cell tracking system in cooperation with Timm
Schroeder, who now conducts research at ETH Zurich in
Basel. “This system makes it possible to follow the fate of
stem cells over long periods of time with a video microscope.” Using time-lapse epifluorescence microscopy, individual cells are photographed continuously in a Petri dish.
If the cell divides, the tracking software assigns numbers
to the daughter cells and then follows their trajectories in
real time. Essentially, this constitutes a biopic of the stem
cell. “We know about their relationships, their locations,
the circumstances of the neighborhood, and the degree of
differentiation of each cell,” says Rieger. Therefore, he says,
the system is ideally suited for studying the influence of external factors on stem cell behavior.
The arsenal of analytical instruments keeps getting more
powerful, and the information that is available keeps getting denser. Thus German researchers are getting closer
and closer to their goal of deciphering the complex code
that makes stem cells so special.
Text: Philipp Graf
Fraunhofer Research Institution for Marine Biotechnology EMB
Innovative research & development at the new institute building of the Fraunhofer EMB in Lübeck
On the 15th of December 2014 the Fraunhofer
EMB has moved to the new institute building
on the Lübeck BioMedTec Science Campus. The
newly constructed building has got modernly
equipped laboratories, aquaculture facilities, a
food technology center and biobanks with fully
automated state-of-the-art technology covering
a total area of 8 292 m2 (BGF).The technical
re-equipment includes a X-ray microscope, a
non-invasive small animal MRI as well as several
3D printer of the latest generation, which are
used for the development of novel laboratory
appliances.
Annual GSCN Magazine 2014/15 “With these excellent research capacities we look
forward to strengthening the life science expertise of
the Fraunhofer-Gesellschaft. The new research building gives us the opportunity to explore promising
topics for applied research and to promote existing
business areas with the most modern equipment”
concludes Prof. Charli Kruse, director of the Fraunhofer EMB.
The Fraunhofer EMB works on industry-related
research topics with focus on life sciences. Here, novel
technologies, procedures and instruments for cell
isolation and exploitation were developed. Moreover, the scientists from the EMB work on innovative
aquaculture systems and on the utilization of
aquatic raw materials for food engineering. With
the “Cryo-Brehm” the EMB maintains one of the
largest archives for cell cultures from wild animals.
Fraunhofer Research
Institution for Marine
Biotechnology EMB
Mönkhofer Weg 239a
23562 Lübeck
www.emb.fraunhofer.de
Contact: [email protected]
27
Photo: Fotolia / kentoh
28 Stem Cell Technologies in Germany
STEM CELL TECHNOLOGIES IN GERMANY | BIOINFORMATICS ANALYSIS
Bioinformatics analysis
Navigating
a sea of
digital data
High-throughput molecular technologies and high-definition imaging are generating enormous amounts of data in
stem cell biology. This large volume of data cannot be handled without computer support. Big data not only has great
potential, it can also cause problems. Systems biologists and
bioinformatics scientists are trying to use mathematical
models to extract some insights from the mountains of data.
To be able to predict stem cell characteristics, it is essential
to look at important details as well as at the big picture.
Photo: TU Dresden / Ingo Röder
High-throughput molecular analyses, so-called omics technologies, and digital imaging techniques have significantly
altered biomedical research and are opening up entirely
new insights into vital functions. But they are also generating enormous amounts of data, of which only a fraction can
currently be analyzed. This is referred to as the “big data
problem”, since the growing amount of data does not automatically mean that greater insights are obtained.
Stem cell researchers also face the challenge of extracting
the information that is relevant to their topics from the
mountains of digital data before they can analyze it. Then
there is the next step of making the data and the findings
derived from that data available to the scientific community through suitable networks.
Differing approaches
Ingo Röder of the Institute for Medical Informatics and Biometry (IMB) at TU Dresden has been working for years
on the mathematical modeling of stem cell systems. Using
computer simulations and statistical methods, he is getting
closer to understanding complex phenomena like the pluripotency of embryonic stem cells (ES cells).
Computer-based analysis of biological data
Researchers from around the world have now compiled an
enormous amount of molecular data on this topic. For the
analysis, two approaches to developing computer-based
models dominate. “Some researchers are looking at huge,
overarching regulation networks, while the others are limiting themselves to analyzing smaller partial systems,” says
Ingo Röder. There is good rationale for both approaches,
he says. While the approach driven by large amounts of
data tries to identify complex relationships, it often does
not move beyond the descriptive level. “Biological regulation networks are extremely complex and therefore very
difficult to describe quantitatively in their entirety.” With
their mathematical description, they are currently asking
primarily “What?” questions. “This provides an important
overview of regulatory structures but in many cases does
not provide mechanistic explanations,” says Röder.
Max Planck Institute for Molecular Genetics
MPIMG
Research at the Max Planck Institute for Molecular Genetics (MPIMG) concentrates on genome
analysis of man and other organisms to contribute to a global understanding of many biological
processes in the organism, and to elucidate the
mechanism behind many human diseases.
It is the overall goal of all MPIMG’s groups to gain
new insights into the development of diseases
on a molecular level, thus contributing to the
development of cause-related new medical
treatments. In this context, stem cell research is
Annual GSCN Magazine 2014/15 MPIMG
gaining increasing importance. In particular, MPIMG
researchers are working on a better understanding
of gene regulation networks for tissue formation
and homeostasis, as their dysfunction may result in
numerous diseases
Max Planck Institute for Molecular Genetics
Ihnestraße 63-73
14195 Berlin
www.molgen.mpg.de
29
de
nt
ify
dru
g ca
ndid
ates
The approach of only considering portions of a biological system is quite
different. Here, the question of “Why?” is foregrounded. “Using such
models, it becomes easier to really understand
underlying mechanisms,
and to then check them
experimentally on the basis of specific model predictions,” explains Röder. Once
i
to
partial systems have been unre
a
w
Scr
eens
soft
derstood, he says, they can be fitted
out
hot of t
he CellFateSc
back into the larger puzzle.
Looking at single cells
Modern technologies help make it possible to look at details. Single-cell analysis has become an important source
of data for systems biologists and mathematical modelers. Even cells within defined cell populations, like stem
cells or differentiated cells, are often not homogeneous,
as they differ from one another in terms of their specific
properties. A precise view of individual cells is important
for recognizing heterogeneities and their influence on the
organization of the system.
Single-cell analysis can, for example, be used to analyze all
RNA molecules and thus gene activity in a single cell. But
it is not only molecular data that can be recorded. “We are
also looking at the behavior of cells, at their communication with neighboring cells, and at the influence of spatial
structures,” says Röder. Such functional single-cell analyses, using techniques such as high-resolution imaging, produce enormous amounts of data. In the
area of theoretical stem cell
biology, the Dresden-based
researchers are joined
in evaluating single-cell
analyses by Fabian Theis and his colleagues
at Helmholtz Zentrum
München. The scientists
have developed statistical
methods that make it possible to simplify and improve
analysis.
Photos: IBIMA Rostock / Georg Füllen,
TU Dresden / Ingo Röder
DISTRIBUTED IN AUSTRIA. GERMANY AND
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t
Photo: TU Dresden / Ingo Röder
Solutions (ScaDS) is emerging under the direction of TU
Dresden and Leipzig University. Röder reports that ScaDS
will focus on informatics-based strategies for dealing with
huge amounts of data from the life sciences. In addition to
setting up efficient data structures, this also involves questions such as: How can specific knowledge be extracted
from the data? How do we deal with changing data?
Setting up new facilities
In Germany, researchers are still in the early stages of
working with big data and setting up the appropriate facilities. The Federal Ministry of Education and Research
(BMBF) is currently funding the development of two competence centers for Big Data. The Berlin Big Data Center
(BBDC) is being set up under the direction of TU Berlin,
and the Competence Center for Scalable Data Services and
In the future, stem cell researchers could also benefit from
the German Network for Bioinformatics Infrastructure (de.
NBI), for which the BMBF is likewise providing €22 million
in funding. This virtual association will seek to improve
and sustainably secure the availability of both hardware
and bioinformatics tools in the life sciences. Six research
centers have been selected: the DKFZ in Heidelberg, the
universities in Bochum, Tübingen and Freiburg, the Leibniz
Institute of Plant Genetics and Crop Plant Research (IPK) in
Gatersleben, and Bielefeld University, which is coordinating the efforts. The group will begin work in March 2015.
To date, Röder has observed a very pragmatic approach to
working with Big Data, one that focuses primarily on storing the large amounts of data rather than on creating value
creation or managing the life cycle of data. “In this regard,
we are still beginners,” he observes.
Text: Philipp Graf
Modeling
neurodegenerative disease
“Eureka, it worked!!!!”. Albert, in an ecstatic state, ran into his boss’s office nearly smashing the door against his desk. “You were right, your idea
worked beautifully. I could differentiate the iPSCs into neuronal stem
cells quickly and easily. Better still, I was able to derive various neuronal
subtypes from different brain regions, such as GABAergic,- dopaminergicand motor-neurons, from these neuronal stem cells! Take a look!” There
was a slight tremble in Albert’s voice as he contemplated a possible Nature paper, the Nobel Prize or, even better, a pat on the back from his boss! “And guess what – I got this job done so quickly, it was even faster than
baking a cake…. at least faster than if I’m baking it…” With a broad smile on
his face he reflected on the past few days work in his lab from reprogramming fibroblasts into iPSCs in only 14 days using the new CytoTune®-iPS
2.0 Sendai Reprogramming Kit, to culturing isolated iPSC colonies under
feeder-free conditions using Essential 8™ Medium, and characterizing
colonies for pluripotency and differentiation potential using the TaqMan®
hPSC Scorecard™ Assay. This had actually been Albert’s first step into the
wonderful world of qPCR, which he hadn’t trusted himself with in earlier
times. He admitted that he didn’t really understand qPCR, but who cares –
with ScoreCard™ and the cloud-based data analysis software he could get
much more out of the beige-blue boxes than in the past. He could now also
proudly add the first meaningful qPCR data to his lab notebook.
Using the Gibco® PSC Neural induction Medium he was able to quickly and
easily differentiate his iPSCs into a population of NSCs, and all without
having to undergo the tedious process of generating embryoid bodies or
picking neural rosettes which the lab seemed to have been doing for what
felt like 250 years! “This stuff is like packet soup” – he told his wife one
evening when he came home from the lab. “Just add it to your iPSCs, wait
7 days and, voilà you have your population of NSCs.” “And you wont believe
Annual GSCN Magazine 2014/15 the efficiency!” He had never dreamt that there could be such a simple method to
achieve a 20-fold expansion in final NSC count from the iPSC starting material
he had added to the Neural Induction Medium just 7 days prior. With so much
material available he could even afford to differentiate his NSCs towards, not
just one, but three different neuronal cell types, GABAergic,- dopaminergic- and
motor-neurons in parallel. Albert had already spent quite enough time developing a medium to induce NSC differentiation from iPSCs. So now, following a
thorough search of the literature, he decided to use conventional protocols to
differentiate his NSCs towards the desired neuronal-subtype for his research
work. Admittedly this took him some time, but in the end he succeeded and his
wife, his boss and also Albert himself were happy at the outcome. His boss, because once again his ideas and concept had come to fruition, Albert, because he
could go home in the evening at a reasonable hour, and his wife, because Albert
took her out for dinner – to the fish and chip shop on the corner of their street… Please visit lifetechnologies.com/stemcells
to receive more information.
31
Stained stem cells (red) and nerve system (green) of the head fragment of a planarian regenerating a new tail
32 Photo: MPI for Molecular Biomedicine / Hanna Reuter
STEM CELL TECHNOLOGIES IN GERMANY | GENOME EDITING
Genome Editing
Designer cuts
in the genome
They’ve only been around for a few years, but designer
nucleases have rapidly become indispensable tools for
molecular biologists. These “molecular scissors” can be used
to make quick, precise changes to the genome, opening up
a wide range of possibilities for biotechnology and health
research. The German stem cell community has been quick
to adopt the new technology. “Genome editing” can be used
to improve stem cell-based models of disease, while the
proponents of molecular medicine are already dreaming of
new, even safer routes to gene therapy.
Photo: Fotolia / molekuul.be
S9
-CA
SPR
CRI
Molecular biologists have long dreamed
of being able to modify the genome of
an organism quickly and precisely,
but up to now they have lacked
the necessary tools to do so. Instead, researchers wanting to
introduce defined changes into
a genome have for decades had
to rely on the complicated and
time-consuming process of
homologous recombination in
embryonic stem cells (ES cells).
manipulation and rearrangement of the DNA “text” in this
way has come to be known as “genome editing”.
Revolution in genetic engineering
This represents ground-breaking progress for many, including professor Toni Cathomen, Freiburg-based specialist in molecular medicine. “After restriction enzymes in
the 1970s, there is no doubt that we are now experiencing the second revolution in gene engineering,”
says Cathomen, director of the Institute for
Cell and Gene Therapy at the University
Medical Center Freiburg. The revolution has taken place in three phases, which Cathomen has followed
from the very beginning. Zinc
finger nucleases (ZFNs) were
developed about ten years
ago, and TAL effector nucleases (TALENs) followed in 2011.
“Then, in 2013, the really big
breakthrough for the field came
with the CRISPR-Cas system,”
says Cathomen. “Since it is simple, economical and universally apn
plicable, it spread through the world
ge
o
y
sp
of research like wildfire.”
ccu
es
.
In recent years, the field of DNA
ge
ne
technologies has been progressing
ed
itin
in leaps and bounds. “Designer nucleg co
mplex from Streptoco
ases” have enabled biotechnologists to
All three designer nuclease formats work on
create the precision instruments needed to
a similar principle. The protein molecules can be properform genome engineering. Using these newly discovered molecular scissors, it has become possible for the grammed to recognize a particular target sequence in the
first time to alter the genome with absolute precision, to genetic material. The molecular scissors are activated at
introduce mutations or whole DNA segments at a specif- the targeted location in the genome and the cut leads to a
ic location, or even to correct such mutations. The precise double-strand break in the DNA. “This activates the repair
Chair Tissue Engineering and Regenerative Medicine (TERM)
Artificial Vascularized Tissues
Implants with autologous cells are engineered
by Tissue Engineering methods which minimize
the body´s own implant rejection. The hereby activated self-healing mechanisms result in tissue
regeneration (Regenerative Medicine).
We develop human test systems as alternative
tissue models to animal trials. Tissue specific
bioreactors providing culture conditions of the
cell´s natural microenvironment in the body are
created to ensure in vitro functionality of the
used cells. A biological vascularized scaffold,
the BioVaSc, is applied to generate vascularized
Annual GSCN Magazine 2014/15 tissue in vitro. Tissue models as well as models for
cancer or (infectious) diseases have successfully
been set up.
Chair Tissue Engineering and Regenerative
Medicine (TERM)
Universtiy Hospital Würzburg
Röntgenring 11
97070 Würzburg
www.term.ukw.de
Tissue-specific bioreactors and incubators.
33
Reprogramming and Genome Editing
response in the cell, which can then be used to bring about
the intended modifications,” explains Cathomen.
Simple and efficient
Because ZFNs and TALENs use purely protein-based DNA
recognition systems, their engineering is relatively complicated and expensive. A degree of expertise in protein design is also called for. That is not the case with the CRISPR
system. In this equivalent of an adaptive bacterial immune
system, a special RNA molecule is all that is needed to focus
the Cas9 enzyme onto a particular target. “The system can
be engineered and introduced into cells using basic techniques available in any molecular biology laboratory,” con-
firms Cathomen. “After one week, you can already expect
a customized result with CRISPR-Cas,” he adds. “It works
extremely well.”
Other researchers are also fascinated by this precision and
speed. “It’s quite amazing,” says bioengineer Frank Buchholz of the medical faculty at TU Dresden. “This is a bacterial system that can be efficiently transferred to other
cells, regardless of species.” An additional benefit is that
multiple locations in the genome can be processed at the
same time. The prestigious publications that appear almost every week demonstrate the extent to which the new
molecular scissors are fuelling the imagination of genetic
researchers.
Graphic: The Korean Association of Internal Medicine, Stanford University / Sebastian Diecke
DFG Research Center for Regenerative Therapies Dresden (CRTD)
CRTD
At the DFG Research Center for Regenerative
Therapies Dresden (CRTD), Cluster of Excellence
at the TU Dresden scientists are seeking to understand the mechanisms of regeneration using
model organisms to translate the results to man
and to develop novel regenerative therapies for
thus far incurable diseases. The center’s major
research areas are focused on hematology/immunology, diabetes, neurodegenerative diseases,
bone regeneration and technology development.
Currently, seven professors and ten group leaders are working at the CRTD. They are integrated
into a network of over 80 member labs at 7
34 different institutions in Dresden. In addition, 21
partners from industry are supporting the research
projects. The synergies in the network allow for a
fast translation of results from basic research to
clinical applications.
CRTD / DFG Research Center for Regenerative
Therapies Dresden – Cluster of Excellence
Fetscherstraße 105
01307 Dresden
www.crt-dresden.de
The scope of application for genome editing is extremely
broad. “Genetically modified organisms can now be produced relatively easily and quickly,” says Buchholz. For example, it is possible in this way to develop better animal
models for human diseases. He even sees CRIPR-Cas as a
promising tool for functional high-throughput genomic
screens as it allows the precise up- or down-regulation of
gene activity.
Controls for disease models
The German stem cell community has also been quick to
adopt the designer nucleases. One of the great benefits in
this area arises from combination with another new and
powerful technology – that of cell reprogramming (see the
chapter Stem cells from the factory, page 37). In this way,
biomedical researchers can, for example, develop better
“disease in a dish” models. “Either you introduce a mutation into the genome of induced pluripotent stem cells (iPS
cells) of healthy individuals and investigate disease features in the cell types derived from them, or you use the
nucleases to correct mutations in the iPS cells derived from
patients,” explains Toni Cathomen. An additional advantage of genome editing is the generation of what are called
isogenic iPS cell lines: two lines that share an identical
genotype with the single exception of the edited sequence.
“These are the ideal controls, because they have the same
genetic background,” explains Christine Klein, a neurogeneticist at the Lübeck University Medical Center. This ensures that like is being compared with like. Klein is using
genome editing in nerve cells derived from iPS cells for her
research into the molecular causes of Parkinson’s disease.
This approach leads to significantly more robust models,
even if a degree of biological and technical variability cannot be completely excluded with iPS cells.
Opportunities for gene therapy
The new super-scissors are also inspiring researchers to
consider entirely new applications in personalized medicine. In gene therapy, for instance, the techniques of molecular biology are brought to bear in the treatment of hereditary gene defects. Until now, this has usually involved the
compensation of a molecular defect by using gene ferries to
introduce an additional, healthy copy of the gene into the
patient.
The designer nucleases now enable researchers to work
with surgical precision, correcting only the original mutation in a targeted fashion. Blood stem cells and T-cells
are currently the focus of gene therapeutic strategies of
this sort. Researchers in the U.S. have already conducted
Capturing rare events in iPSC
reprogramming.
Continuous monitoring of cell growth and behaviour can greatly enhance the
validity of any tissue culture process or cell based assay. iPSC laboratories
continue to work towards more efficient methods of deriving cells but stem cells
and somatic precursors can be fragile and inspection under the hood can be
arduous. The IncuCyte high throughput microscope is uniquely placed to allow
remote monitoring – without removing cells from the incubator. Simplifying
and automating key elements of inspection with the IncuCyte reduces the time
spent in non-ideal conditions for both the cells and the operator and provides a
major key to success. Now work often done in a TC hood is done at your desktop
PC, images from multiple wells and multiple flasks are delivered, without disturbing
the cells, straight to any suitably networked remote location. Software tools allow
colony tracking and marking, and plate marking tools reduce the burden of relocating colonies during maintenance. With continuous monitoring unique insights to
the emergence of new, rare and unforeseen events can be found.
For more information visit
www.essenbioscience.com or contact Dr Peter Djali, European Sales Manager,
[email protected]
The CellPlayerTM Kinetic Stem Cell Application using the IncuCyte ZOOMTM Live Content Imaging System. Seven days after
reprogramming fibroblasts with CytoTune®, transitioning cells are re-seeded onto feeder cells. Colony emergence over time was
observed. Here, representative images taken day 7, 12 and 17 during reprogramming show a colony’s evolution.
www.essenbioscience.com
Annual GSCN Magazine 2014/15 Live Content Imaging Within Your Incubator
35
Frank Buchholz’ team is also working on an HIV therapy
based on genome editing. He, however, is using a different
group of high-tech tools called “tre-recombinases”. “They
cut viral genetic material out of infected cells very precisely, and they also glue the DNA strands back together
accurately after the procedure,” says Buchholz. This, he explains, makes the system very safe. Based on encouraging
preclinical data, the researchers in Dresden are now working hard with their colleagues in Hamburg to test this therapeutic concept in early clinical studies.
Avoiding the misses
Despite their popularity, designer nucleases are not entirely error-free. They occasionally miss the target, and the
molecular scalpels then make their cuts at other locations
in the genome. These off-target effects must be excluded
as far as possible if the technique is to be used for medical applications such as gene therapy. Based on studies
performed in his lab, Toni Cathomen is reassuring on this
point: “With the doses of TALENs we have used and with
CRISPR-Cas, we have observed a high degree of cutting efficiency and scarcely any off-target effects.”
Meanwhile, biotechnologists are tinkering with ways to
make the nucleases even more reliable and user-friendly.
One of the limitations that need to be addressed concerns
the relatively large genetic blueprint of the Cas9 nuclease.
This makes it difficult to pack as freight into gene ferries
for delivery to living cells. However, there are already innovations here that promise to help solve the problem. The
genetic engineering revolution is clearly moving ahead full
steam. Text: Philipp Graf
Editorial note:
The fascinating possibilities in the techniques of genome editing, in particular by the CRISPR-Cas9 system,
should facilitate the genetic tailoring of cell and tissue
therapeutics in the future but raise far-reaching ethical
issues. These methods would allow rapid intervention
in the human germ line leading to the inheritance of
both targeted and unwanted genetic alterations introduced into the genome. Accordingly, a group of leading
scientists, including an inventor of the CRISPR system,
published a statement in March 2015 in the journal
Science warning against germline alterations in human
beings and calling for a worldwide moratorium. They
recommend that scientists should “strongly discourage,
even in those countries with lax jurisdictions where it
might be permitted, any attempts at germline genome
modification for clinical application in humans, while
societal, environmental, and ethical implications
of such activity are discussed among scientific and
governmental organizations.” *The International
Society for Stem Cell Research (ISSCR) also supports a
moratorium on interventions in the human germline by
genome engineering in reproductive medicine.
*Original source: Science Journal: Baltimore et al.
„A prudent path forward for genomic engineering and
germline gene modification, 19 March 2015.
Fraunhofer Institute for Cell Therapy and Immunology
Photo: MDC / Cecile Otten
successful early-stage clinical studies
using zinc finger nucleases, the small
size of which make them particularly well suited for clinical applications. These researchers succeeded in using genome editing to
achieve a gene alteration in HIV
patients that made them at least
temporarily immune to the HIV
virus in their bodies. Cathomen’s
team at the University Medical
Center Freiburg is also working on
therapies to cure HIV patients as well
as patients with other chronic immune
defects. And, he is convinced, “It is just a
question of time before the most recent technology platforms, like TALENs and CRISPR, follow suit and
find their way into clinical application.”
Fraunhofer IZI
The Fraunhofer Institute for Cell Therapy and
Immunology IZI investigates and develops
solutions to specific problems at the interfaces
of medicine, life sciences and engineering. One of
the institute’s main tasks is to conduct contract
research for companies, hospitals, diagnostic
laboratories and research institutes operating in
the field of biotechnology, pharmaceuticals and
medical engineering. The Fraunhofer IZI develops, optimizes and validates methods, materials
and products for the business units Drugs, Cell
Therapy, Diagnostics and Biobanks. Its areas
of competence lie in cell biology, immunology,
36 drug biochemistry, bioanalytics and bioproduction
as well as process development and automation.
In these areas, research specifically focusses on
the indications oncology, ischaemia, autoimmune
and inflammatory diseases as well as infectious
diseases and regenerative medicine. The institute
works in close cooperation with hospital institutions and performs quality tests besides carrying
out the GMP-compliant manufacture of clinical test
samples. Furthermore, it helps partners obtain
manufacturing licenses and permits.
The Fraunhofer IZI together with the TRM Leipzig is organizing the WCRM 2015.
www.wcrm-leipzig.com
Fraunhofer Institute for Cell Therapy and
Immunology IZI
Perlickstr. 3, 04103 Leipzig
www.izi.fraunhofer.de
Photo: MDC / Jochen Meier
Annual GSCN Magazine 2014/15 Stained cells of the brain tumor of a mouse
37
STEM CELL TECHNOLOGIES IN GERMANY | STEM CELLS FROM THE FACTORY
Stem cells from the factory
Cranking up
cell production
The reprogramming technique and sophisticated procedures for generating particular cell types have revolutionized stem cell research. And the field is becoming increasingly institutionalized: many research centers in Germany are
now setting up special laboratories or core facilities for cell
production. Furthermore, thanks to automated state-of-theart bioprocess engineering, stem cells are turning into an
industrial commodity. With factory-produced cell types, applications in regenerative medicine are becoming a reality.
The engineering of human induced pluripotent stem cells
(iPS cells) and cell types derived from them is now at the
heart of the activities of many stem cell researchers. The
iPS technique has revolutionized stem cell research in just
a few years. Using the process first described by Shinya
Yamanaka in 2006, molecular biologists can revert cells to
a quasi-embryonic state simply by introducing four specific reprogramming factors. The resulting pluripotent stem
cells can be propagated almost indefinitely and can theoretically give rise to every other cell type in the body.
The potential of these artificially produced stem cells is
vast: cells from patients can now be propagated in the
Petri dish and used to study the molecular mechanisms of
disease. Such stem cell-based disease models are promising tools for drug research. iPS cells are also viewed as an
important source of material for cell-based therapies. The
first clinical study to be based on iPS cells was launched in
Japan in 2014.
iPS technology as a service
The techniques and processes used in the generation of
iPS cells are becoming increasingly robust and productive.
However, there is still great demand for expertise in dealing with stem cells and for the right laboratory equipment.
More and more major biomedical research institutions in
Germany have started to set up in-house core facilities for
stem cell production.
For example, with the opening of the Berlin Institute of
Health (BIH), Berlin will be home to an international center
of excellence for translational and system medicine that
pools the strengths of Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine
(MDC). The work of this new “super institute” is supported by seven technology platforms. One of them is the Stem
Cell Core Facility. At the MDC’s site in Berlin-Buch, biologist
Sebastian Diecke and his team of four are in the process
of setting up this special laboratory. Biotechnologist Harald
Stachelscheid is in charge of the counterpart facility at the
Charité campus Virchow-Klinikum. “Our task is to support
basic and clinical research by providing all the technology for the use of human iPS cells,” explains Diecke. He arrived in 2014 from Stanford University in California, where
alongside his post-doc activities he worked for a similar
service facility funded by the California Institute of Regenerative Medicine (CIRM).
The mission of the core facility at the BIH, which is initially
funded until 2018, is broad and includes derivation, differentiation, characterization and distribution of the iPS cell
lines. “A technique that is increasingly in demand is that of
genome editing,” says Diecke (see the chapter on Genome
Editing, page 32). In this field, too, the researchers possess
expertise and experience. The BIH experts also plan to
store important cell lines in a biobank. In essence, the staff
at the Stem Cell Core Facility do not simply see themselves
Institute of Reconstructive Neurobiology
From disease modeling to stem cell therapies
The Institute of Reconstructive Neurobiology at
the University of Bonn Medical Centre focuses
on the use of pluripotent stem cells for the study
and treatment of neurological disorders. Based
on a broad technology portfolio including cell
reprogramming, neural differentiation, direct
cell fate conversion, stem cell industrialization and neurotransplantation, the Institute
develops stem cell-based model systems for
disease-related research and drug development
as well as novel cell therapy regimens. It closely
interacts with LIFE & BRAIN GmbH, a transla38 tional hub of the University of Bonn providing stem
cell products and services for pharma, biotech and
academia.
Institute of Reconstructive Neurobiology
LIFE & BRAIN GmbH
University of Bonn
Sigmund-Freud-Straße 25
53105 Bonn
www.stemcells.uni-bonn.de
Robot arm in the StemCellFactory
as service providers; they want to be on hand to support
the work of researchers with advice and practical assistance. “We provide standardized protocols and techniques,
advise on projects, and offer regular practical courses in
the various methods,” says Diecke.
Reprogramming in a joint effort
Photo: Life & Brain
Micha Drukker is in charge of the core facility – the hiPS Cell
Unit – in the Institute of Stem Cell Research at Helmholtz
Zentrum München. This, too, is an experimental platform
where patients’ iPS cells can be cultured, scrutinized and
differentiated into particular cell types. The main function
of the core facility is to serve researchers from the Helmholtz Association, but research partners in the Munich area
can also make use of it. Among other things, the researchers of the Drukker group have specialized in a reprogramming technique based on artificial mRNA molecules.
Another unit, the Stem Cell Unit – Göttingen is a non-commercial facility of the University Medical Center Göttingen
(UMG) that is funded by it and the German Center for Cardiovascular Disease (DZHK). The director of the unit is stem
cell researcher Kaomei Guan-Schmidt, who also leads her
own research group. At the Stem Cell Unit, patient-specific
iPS cells are derived, characterized and provided to the Göt-
tingen research facilities
and DZHK partners. The
Göttingen researchers
specialize in disease
models of heart failure
and the differentiation
of iPS cells into heart
muscle cells.
There are other core
facility initiatives for iPS
production in Aachen, Bonn,
Hamburg and Münster, and similar facilities are planned in Dresden
and Hannover. Another iPS initiative covers university sites
within the Bavarian research network ForIPS. “Each site
has of course developed special knowledge in particular
fields,” says Sebastian Diecke. He and his colleagues Harald
Stachelscheid and Micha Drukker have launched a scheme
aimed at strengthening the links between core facilities
in Germany and improving the exchange of knowledge.
The idea is that combining expertise will make it easier to
compare the different facilities’ standards in producing the
cells and datasets. The purpose is also to discuss and share
protocols and new techniques and prevent the creation of
redundant structures.
Hexcell Berlin GmbH sells biological products, especially products
Hexcell – Berlin Fetal Bovine Serum Berlin:
for cell culture, with particular attention to the sales of fetal calf
crude serum exclusively from the associated collection in Brazil.
Each manufactured batch is strictly controlled, from the collection of serum, in all phases of treatment and production to final packaging in the
company of Hexcell – Berlin GmbH. Each batch comes with a certificate
of analysis.
The sterile fetal calf serum is stored in the refrigerator at -20 ° C
We provide free samples on request.
serum for the customers. In order to be a particularly credible, reliable and affordable source of fetal calf serum, Hexcell obtains the
and shipped in Styrofoam boxes with dry ice to customers.
Hexcell – Berlin Human Serum:
Our pharmaceutical biotechnology customers use our products
in basic scientific research, in the pharmaceutical industry and in
stem cell therapy.
NEW:
Coming soon a new development of Hexcell – Berlin
GmbH will be included in the program.
The Hexlysat is required for stem cell research and
stem cell therapy.
Visit our website: www.Hexcell-Berlin.de
Annual GSCN Magazine 2014/15 Human serum is prepared from human plasma by adding of calcium
chloride. This leads to coagulation of the plasma.
We get our blood plasma from recognized German blood banks.
A complete traceability from the donor is possible at any times.
All donors are free of
HBsAg, HIV 1/2 , HCV, HCV – NAT, HIV – 1 NAT, ALT.
For each serum a certificate of analysis is delivered.
We provide free samples on request.
Products at a glance:
• Fetal Bovine Serum EU approved, Fetal Bovine US origin,
AB Human Male (off the clot),
• HSA, human serum albumin 20 % therapeutic grade Inject.
39
Bioreactors for mass production
Pluripotent stem cells are an important basis for the production of defined cell types. However, enormous quantities of
such cells are needed for tests in industry, regenerative cell
therapies, and the generation of replacement tissue in vitro.
The team headed by Robert Zweigerdt of the Leibniz Research Laboratories for Biotechnology and Artificial Organs
(LEBAO) at Hannover Medical School (MHH) is working on
the mass propagation of pluripotent stem cells. In recent
years, the team has used and refined bioreactor systems that
work on the same principle as the stirred-tank reactors used
in biopharmaceutical production. “Unlike in a conventional
2D culture, the cells float in a 3D suspension culture and are
stirred,” says Zweigerdt. “As a result, the culture conditions
are highly homogeneous and we can observe the cell growth
continuously online.” The researchers have tweaked several aspects of the process, adapted the media, defined the
culture conditions, and adjusted the stirrers. In matters of
bioreactor technology, the researchers from Hannover have
worked closely with Eppendorf subsidiary DASGIP.
Stem cells cling to one another
The stem cells floating in the bioreactor definitively cling to
one another. “They form pure cell aggregates; that makes
upscaling easier,” says Zweigerdt. In their bioprocess, the
researchers can track the formation of the cell clumps
and control their density and size. In the bioreactors from
Hannover this enables undifferentiated cell aggregates to
be produced from human embryonic stem cells (ES cells)
or iPS cells. Through the exchange of culture media these
differentiate in the bioreactor into cell types such as heart
muscle cells and endothelial cells.
“We can currently produce up to 50 million cells in a volume of 100 milliliters,” says Zweigerdt. The researchers are
now aiming to move to a larger scale. “We want to produce
around a billion cardiomyocytes in a one-liter bioreactor.”
That is roughly the quantity that is destroyed and therefore needs to be replaced in a heart-attack patient. The researchers also aim to produce other cell types needed for
regeneration of the heart. The team working with Zweigerdt and LEBAO research director Ulrich Martin are already
planning the next step for the heart muscle cells from the
bioreactor; preclinical cell therapy studies in large animal
models are due to start soon. The Hannover team is also
involved in one of the large European consortiums for iPS
production, StemBANCC (see the chapter on Archiving
Stem Cells, page 42). A key aim here is to provide heart
muscle cells in large quantities for cell-based test systems
in drug research and safety pharmacology.
Biological Industries Releases Human Mesenchymal
Stem Cell Differentiation Kits for Health Therapies
Biological Industries (BI), a worldwide leader in the design and manufacture
of life science products for the biopharmaceutical industry, has launched innovative hMSC differentiation kits for research and stem cell based therapies.
“This is a unique line of serum-free and xeno-free differentiation kits, providing
the ability to efficiently differentiate hMSC from various sources into adipocytes,
chondrocytes and osteoblasts,” said David Fiorentini, Director of Research &
Development.
All three kits are serum free and xeno free:
MSC Go Osteogenic XF ™ – Rapid differentiation of osteogenic
(Complete, ready-to-use)
MSC Go Adipogenic XF™ – Basal medium and supplements mix
MSC GO Chondrogenic XF™ – Basal medium and supplement mix
“The Differentiation media contain all the growth factors and
supplements necessary for the direct differentiation of hMSC,”
Fiorentini said.
The kits are designed to be user friendly with all necessary ingredients included. They offer a complete system for multipotency evaluation of hMSCs and reliable induction of hMSCs into adipocytes,
chondrocytes and osteoblasts/osteocytes. No adaptation is required
from cell expansion cultures using MSC NutriStem® XF Medium.
The kits were validated for hMSC from various tissues including
BM-hMSC, AT-hMSC, and UCT-hMSC.
BI’s previous release was the MSC NutriStem® XF Medium,
a gold standard serum-free, xeno-free medium developed for the
growth and expansion of human mesenchymal stem cells (hMSC)
isolated from a variety of sources including bone marrow, adipose
tissue and umbilical cord tissue; BM-hMSC, AT-hMSC, UCT-hMSC.
Left: Generation of heart muscle cells monitored by the activation of a fluorescent reporter gene. The cell aggregates in the bioreactor emit
green light. Right: The generated heart cells show the typical cross striations (red) around the nucleus (blue).
Photo: MHH / Robert Zweigerdt
Automated stem cell factory
The proliferation of cell products on an industrial scale
for drug-testing purposes is a vision that is becoming reality at the LIFE & BRAIN research center in Bonn, where
Oliver Brüstle is scientific director. In collaboration with
the Fraunhofer Institute for Production Technology (IPT),
RWTH Aachen, the MPI for Molecular Biomedicine in Münster, HiTec Zang, and Bayer Technology Services (BTS), the
facility that has recently been set up focuses on the automated culturing of iPS cells and differentiation of those
cells into nerve and heart muscle cells. “The Stem Cell Factory is a fully automated production line that reproduces
the entire process from skin cell to finished iPS cell in one
facility,” explains Simone Haupt, who heads the Bioengineering Segment at LIFE & BRAIN.
The roughly five-meter-long production line is a closed
system: once the skin cells have been introduced, reprogramming, picking of clones, and cultivation proceed automatically. The finished product is ready in ten weeks.
“The big advantage is that iPS cells from a large number
of patient samples can be cultivated here simultaneously,”
states Haupt. The follow-on project Stem Cell Factory II
was launched in 2014, once again with the involvement of RWTH Aachen, Fraunhofer IPT in Aachen, HiTec
Zang GmbH, and the MPI in Münster. The state of North
Rhine-Westphalia is providing funding of €1.2 million for
the project, which will see additional modules added to the
facility. For example, the bioengineers are developing an
automated genome editing process that will enable them
to make specific modifications to the stem cell genome
(see the chapter on Genome Editing, page 32). For another, external module, researchers are working on creating
three-dimensional cell clusters and organoids – such as
small particles of human brain or heart tissue – from differentiated cells. In addition, there are plans to develop the
stem cell factory into a commercial facility, with the spinoff of a company dealing with the automation of cell culture. “We have already had a very positive response from
the biobank scene,” says Haupt.
The artificial creation of stem cells has found a firm place in
biomedical research facilities in Germany. And biotechnologists and engineering scientists are continuing to explore
how knowledge from stem cell laboratories can be translated into industrial practice.
Text: Philipp Graf
Max Delbrück Center for Molecular Medicine (MDC)
Located in Berlin-Buch, the MDC carries out
high-quality, interdisciplinary research on basic
mechanisms and applications in major human
health threats including cancer, cardiovascular
and metabolic diseases, and disorders of the
nervous sytem. These thematic research areas
are supplemented by the Berlin Institute for
Medical Systems Biology (BIMSB) at the MDC
and the MDC-Charité partnership in the Berlin
Institute of Health (BIH).
Annual GSCN Magazine 2014/15 Professor Mathias Treier, senior group leader at the
MDC, states: “Opportunities for partnerships with
clinical groups, a range of cutting-edge technology
platforms, and superb animal facilities for diverse
model organisms make the MDC an excellent site
for stem cell research.” Recently, MDC and BIH have
created a stem cell core facility to offer expertise to
derive and manipulate iPSC lines for MDC groups or
BIH projects. Alongside assisting groups, the facility
is putting an emphasis on training, says Sebastian
Diecke, head of the facility.
Max Delbrück Center for Molecular Medicine
(MDC), Berlin-Buch
Robert-Rössle-Str. 10, 13125 Berlin
www.mdc-berlin.de
41
Photo: MDC / Jochen Meier
Neuronal network in an area of the brain affected by epilepsy
STEM CELL TECHNOLOGIES IN GERMANY | ARCHIVING STEM CELLS
Archiving stem cells
Cell treasures
from a
Pluripotent stem cells are important resources for the medicine of the future. If the vast range of existing stem cell lines
is to be tracked and made available for practical use, these
lines must be tested, cataloged and stored in a central location. Cell archives thus become important treasure troves
for stem cell researchers. Using state-of-the-art cryogenics,
researchers from Germany are involved in the development
of systematic online catalogs and biobanks.
It is in the nature of stem cells that they have permanent
characteristics: once obtained, pluripotent cells can be cultivated and propagated almost indefinitely. Stem cell lines
are therefore valuable biological resources that are predestined to be shared among researchers and users and made
available in central collections. This is particularly true of
embryonic stem cells (ES cells), the acquisition and use of
which is governed by different legal conditions in different
countries. In addition, the technique of reprogramming has
led to the engineering of induced pluripotent stem cells
(iPS cells) on a significant scale in recent years. A major issue for science and industry in this context is the quality
and comparability of engineered cell lines. This has given
rise on the European level to a number of initiatives with
German participation.
Stem cell register: Online catalog of ES cells
To obtain human ES cells, the embryos must usually be destroyed. This ethically problematical step triggered intense
and controversial debate in the early years of this decade.
In Europe, this resulted in a patchwork of stem cell regulations, with conditions covering the entire spectrum from
liberal to restrictive.
Photo: Fotolia / pp77
The European Human Embryonic Stem Cell Registry (hESCreg) was created in 2007 to provide an overview of existing human ES cell lines from European laboratories. “In
setting up this public information portal, the European
Commission particularly wanted to create transparency
and place research on a sound ethical foundation,” says
Andreas Kurtz, one of the hESCreg coordinators at the Berlin-Brandenburg Center for Regenerative Therapies (BCRT)
at the Charité. Other partners are the Stem Cell Bank of Barcelona at the CMR[B] and the UK Stem Cell Bank in South
Mimms, north of London.
The data catalog records where the cells originated and are
stored, and describes their biological and “ethical” profile.
This enables stem cell researchers to answer questions
such as: “Where is there a suitable cell line?”; “Are the cells
actually pluripotent?”; “Were they obtained under conditions that are ethically acceptable for my research?”
The number of entries in the stem cell register has grown
quickly – and it includes data from outside Europe. “We
Annual GSCN Magazine 2014/15 catalog
are now the leading global register of pluripotent stem cell
lines,” states Kurtz. He estimates that there are more than
2,000 ES cell lines in the world, of which around 800 are
now recorded in hESCreg.
The most important global directory of pluripotent cells
For a time, the data portal had to manage without EU funding, but since 2013 EU money has again been contributing
to development of the stem cell register. This has enabled
its task spectrum to be significantly expanded. For example,
iPS cell lines obtained from patients with a specific disorder
are now recorded. From an ethical perspective, this poses
additional challenges. “The cell donors are still alive. Their
consent forms must therefore be available, and sensitive
data must be appropriately protected,” explains Kurtz. At
the German Stem Cell Network (GSCN), Kurtz heads a strategic working group “Clinical trials and regulatory affairs”.
Stem cell researchers are already benefiting from the
changes at hESCreg: on the occasion of the 2nd GSCN annual conference in Heidelberg in November 2014 the completely revised website (www.hescreg.eu) went online. The
search templates of the new version enable researchers to
comb through the cell lines in more detail than before. “And
external users can now also enter cell lines online,” says
Kurtz. Moreover, hESCreg is to take on a further function.
According to the plans of the EU Commission, cell lines
will not in future be considered for EU project funding unless they are included in hESCreg. The coordinators of the
stem cell register are also to assume a monitoring role in
the future. “We are currently developing a tracking system
for this purpose,” says Kurtz, who is based in Berlin where,
together with three members of staff, he has particular responsibility for coordination, IT and information management of the online platform.
Biobank boom
Stem cell registers such as hESC
reg are simply collections of
data; the cells themselves
are stored in refrigerators at individual research
laboratories.
This makes exchange
difficult, especially as
the quality of the cells
may vary widely. The
logistic requirements
stretch many laboratories to their limits.
The advance of iPS technology in laboratories has further
Storage in a freezer
at -80 degree Celsius
43
Dopaminergic neurons from iPS cells derived from
a patient with Morbus Parkinson
million, is a consortium of 26 organizations coordinated
by pharmaceutical
corporation Pfizer.
Seven German partners are involved.
The central biobank
will be set up on the
In consequence, researchers from academia and industry Babraham
Research
are calling ever more loudly for central cell archives or Campus in Cambridge, UK.
biobanks. These provide an infrastructure for testing and A special feature of the constoring cells in accordance with defined standards. The sortium is a “mirror bank” that
systematically cataloged lines can then be sent all over will store a complete equivalent of the EBiSC collection
the world in response to orders. In Europe, the Innova- as a backup. The mirror bank is located in the Saarland in
tive Medicines Initiative (IMI) has backed the creation of Germany. The Fraunhofer Institute for Biomedical Engitwo research alliances that plan to set up central biobanks neering (IBMT) is setting up the necessary infrastructure
for iPS cells. IMI is a public-private partnership between in the town of Sulzbach, where a team led by Julia Neubauthe European Commission and the European Federation er is responsible for freezing the cells, for automating cell
of Pharmaceutical Industries and Associations (EFPIA). cultivation, and for the logistics of the biobank. The IBMT
German stem cell researchers are heavily involved in both researchers use a technique that involves carefully cooling
organizations.
the stem cells to minus 130 degrees Celsius: the stem cells
can remain adherent to the culture surface if they are froThe EBiSC European iPS bank
zen with nitrogen gas. In the Fraunhofer facility the stem
cells are then stored in cryotanks with special protective
An IMI consortium launched in 2014 plans to set up a cen- hoods. The hoods prevent other samples being affected
tral European Bank for induced Pluripotent Stem Cells when cell samples are removed and ensure that the cool
(EBiSC) over the next three years to
chain remains unbroken. In other
systematically archive well-characrespects, too, the cryopreservation
“An ambitious target:
terized iPS cells from all over Europe.
technology used is state of the art:
1500 cell lines from 500 patients
It envisages a collection of 1,000
both the automated freezing process
with various diseases”
defined and characterized cell lines
and the storage are computer-confrom patients with specific diseases, tailored to the needs trolled. The EBiSC researchers have already deposited the
of the pharmaceutical industry and health research.
first iPS cell lines in their cell bank; it is anticipated that
potential users will be able to start requesting cell lines in
These requirements include sufficiently large cell quanti- 2017.
ties – 100 million cells per line are planned – that are ready
to use in drug screenings. Once it has been established, StemBANCC: Focus on neurological disorders and diabetes
both the scientific community and industry will have access to the non-commercial biobank, which will eventually An European IMI consortium is behind another five-year
support itself financially. EBiSC, which has a budget of €35 project on iPS cells, StemBANCC, which was launched back
Photo: University of Lübeck
complicated the situation. Reprogramming makes it possible to generate human cell lines that carry a patient’s genome. This lays the foundation for patient-specific disease
models. Tracking down the molecular causes of a disease
requires a large number of cell lines from as many patients
as possible. For their drugs tests, pharmaceutical researchers are already dreaming of creating large patient groups
– available at any time in the form of iPS cells in the Petri
dish.
Berlin-Brandenburg Center for Regenerative Therapies
BCRT
The Berlin-Brandenburg Center for Regenerative Therapies (BCRT) is an interdisciplinary
translational center with the goal of enhancing
endogenous regeneration by cells, biomaterials,
and factors which can be used to develop and
implement innovative therapies and products.
At the BCRT clinicians and researchers are
working closely together on a personalized
medicine that depends on the early recognition
of patients‘ individual healing potential. The
primary focus of the BCRT is on diseases of the
immune system, the musculoskeletal system, the
cardiovascular system and the kidney for which
44 currently only unsatisfactory treatment options are
available. Early cooperation with industry, health
insurers and regulatory authorities as well as other
external partners boosts the chances of exploiting new methods and provides access to flexible
financing options.
BCRT · Charité – Universitätsmedizin Berlin
Augustenburger Platz 1
13353 Berlin
www.b-crt.de
in 2012. StemBANCC is coordinated by Swiss pharmaceutical company Roche; the leading academic partner is the
University of Oxford. Nine of the 35 partners are from Germany.
The consortium, which has a budget of €55 million, aims
to establish high-quality iPS cell lines from healthy subjects and patients that can be used for biological disease
models and toxicology tests. “The focus is on widespread
diseases such as neuronal and neurodegenerative disorders and diabetes,” says Christine Klein of the Institute
of Neurogenetics at the University of Lübeck. Her team
coordinates patient recruitment for the consortium; they
work with other clinical centers in Europe to select patients and obtain skin samples. The target is ambitious:
the consortium partners plan to collect skin samples from
500 patients with the various diseases and generate 1,500
cell lines from them. Progress varies on different fronts:
“At our location we have already completed recruitment
of Parkinson’s patients and control patients,” says Klein.
The iPS cells will be generated and characterized in the
UK under standardized conditions. They will also be cataloged there and deposited in a biobank so that they will
be available to researchers all over the world in the future.
A special biobank with cells from Lübeck
At Lübeck University Hospital, a center for research into
rare diseases, neurogeneticist Christine Klein and her
team have exclusive access to patient material that is of
great interest for health research and disease models in
the Petri dish. Moreover, her team has built up considerable expertise in iPS technology in recent years. To utilize
this potential, Klein and five colleagues have developed
a business idea that is now coming to fruition: the company iPS-HL is due to be launched in Lübeck this spring.
“We won’t only have a special selection of iPS cell lines
from patients available but will also be able to offer customers the improved end products, such as differentiated
cell types,” explains Klein. From the many enquiries she
receives it is clear that the majority of researchers want to
get going on relevant cell types straight away.
Whether for use in cell-based tests or in innovative therapies, standardized and reliable sources of stem cells are
essential in regenerative medicine. The biobanks and registers that are now being set up all over the world play a
crucial role in this.
Text: Philipp Graf
RetroNectin® can save your cells!
Target cell
RetroNectin Reagent enhances viral transduction by
promoting the co-localization of lenti- or retrovirus with
target cells. It has been used with great success in
sensitive and hard-to-transduce cells such as
hematopoietic cells, B cells and T cells.
RetroNectin is a recombinant human fibronectin
fragment containing three functional domains,
two for cell binding and one for binding viral particles.
Cell binding
domain
Lentivirus or retrovirus
(C-domain)
RetroNectin
Heparin binding domain
(H-domain)
CS-1 site
(binds to VLA-4 integrin receptor)
Highly efficient in hard-to-infect cells
RetroNectin Supports
High-Efficiency Gene Transfer1
• Improves gene transfer efficiency in hard-to-infect
cell types and stem cells
• Multivalent molecule simultaneously binds
virus particles and cell surface proteins,
maximizing cell-virus contact
• Low toxicity allowing a high cell survival rate
Efficiency of
Gene Transfer (%)
Cell Type
www.clontech.com/retronectin
Human CD34+ CD38– BMC2
95.5
Human PBMC3
91.2
TF-1
97.9
SupT1
97.3
Jurkat
80.1
K-562
90.4
HL-60
86.1
Monkey CD34 BMC
72.0
Monkey CD4+ T-cell
85.0
+
1
2
3
Annual GSCN Magazine 2014/15 Viral receptor
VLA-5
(integrin receptor)
Transductions were performed using the RetroNectin-Bound Virus (RBV)
Method of transduction.
Bone marrow cells.
Peripheral blood mononuclear cells.
45
Photo: MDC / Julian Heuberger
Mucin secreting cells in the small intestine of the mouse
STEM CELL TECHNOLOGIES IN GERMANY | BIOPRINTING
Bioprinting
Tissue
from the
laser printer
Using living cells to print out tissue in 3D is no longer such
a distant dream, thanks to bioprinting. Here in Germany,
as elsewhere, engineers are working on production systems
that use bio-inkjet printers or laser-based systems. Bioprinting is of interest not only in connection with tissue replacement in clinical applications but also for stem cell research.
A freshly printed organ, cell layer after cell layer made in
the laboratory, still sounds like science fiction. But scientists are convinced that this will be possible in future. Additive manufacturing processes, also known as “3D printing”,
are becoming ever more sophisticated and less expensive.
They have been in use for some time in innovative industries such as solar technology, consumer goods manufacturing, and the automotive sector.
But how well can biological materials be printed? Bioprinting is the branch of research in which tissue engineers seek
to construct biological structures through printing. The applications are many and varied and either involve printing
cells directly onto surfaces or manufacturing scaffolds and
biomaterials onto which cells can be seeded.
The right printing technique
Photo: Fraunhofer ILT, Aachen
There are three main ways of printing cells directly. One is
the inkjet technique, which works like a commercial inkjet printer. A mix of cells and a hydrogel – the “bio-ink” –
is dispensed through a fine nozzle in the form of minute
droplets. Another widely used process uses an extrusion
technique: the material is gradually built up as a continuous bead, as though from a tube. The third method involves
a laser-based process. It is a 3D laser printing technique of
this sort that physicist Lothar Koch and his team have developed. Koch heads the Biofabrication Group at the Laser
Zentrum Hannover (LZH). “We have taken a technique that
has been used for some time in the production of solar cells
and transferred it to living cells,” he explains.
The laser-based printer used in Hanover works by mixing
the cells with a viscous hydrogel, which is applied in a layer
beneath a glass slide. Between the glass slide and the biomaterial is another layer that can absorb the energy of a laser beam. When the laser is focused on this absorbing layer,
it vaporizes explosively in the form of a bubble. The expansion gives the biomaterial a sudden impetus, accelerating it
precisely onto a surface.
Cells survive unharmed
This may sound like a turbulent process, but it is completely harmless for the cells: “No matter what cell type they are,
the cells are not affected at all by the process; the survival
rate is 99 percent,” says Koch. The genetic material also remains intact and cell behavior is completely normal. The
results are significantly better than with other bioprinting processes. “In addition, the laser process enables us to
work with high cell densities and viscous gels and also at
a high resolution,” continues Koch. This means that cells
can be printed in the density at which they actually occur
in tissues.
With all bioprinting techniques there is still a need for
considerable research into the optimum bio-ink mixture.
LIFTSYS-facility (laser induced forward transfer system) of the Fraunhofer ILT for the selective transfer of biogenic material
STEM CELL TECHNOLOGIES IN GERMANY | BIOPRINTING
New cells on a scaffold after
two-photon-polymerization
For example, a team headed by Kirsten Borchers at the
Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB) in Stuttgart is working on inks based
on natural substances such as gelatin. This has enabled
them to print cartilage replacement tissue with their inkjet printers.
However, there is still a long way to go before complete organs can be engineered in the laboratory: so far, the laser
printing specialists in Hanover have produced only relatively simple fragments of skin tissue and “band aids” from
heart muscle cells. Such tissue fragments could someday be
used for test purposes in the pharmaceutical and cosmet-
ics industries. In the past, attempts to
engineer more complex organs have
failed because they have been unable to replicate a functioning blood
vessel system.
“Printing a heart would take several
hours. Then a vascular system would
have to be immediately capable of
supplying the printed heart muscle,” says
Koch. In collaboration with biomedical experts
in the REBIRTH Cluster of Excellence (“From REgenerative
BIology to Reconstructive THerapy”), the researchers have
also experimented with adult and induced pluripotent
stem cells (iPS cells).
Stem cell niche products
Another laser-based technique is 3D two-photon polymerization: in the hands of the researchers this has proved particularly useful for generating scaffolds for tissue engineering. “With this we can produce structures with a resolution
of less than 100 nanometers,” says Koch. That will enable
scientists to fine-tune the structuring of pores in biomaterials and replicate particular microenvironments of stem
cells, known as niches, in order to observe and influence
their behavior.
A group of bioprinting specialists led by Michael Gelinsky
at the Centre for Translational Bone, Joint and Soft Tissue
Research at TU Dresden is investigating how such printed
niches could improve the cultivation of adult stem cells.
Stroboscopic recording of the hydrogel beam/- Jets
The REBIRTH Cluster of Excellence
Bioprinted cell products thus have great potential. And
there is no lack of ideas: in a talk at the 2nd GSCN annual
conference in Heidelberg, Boris Chichkov of the Laser Zentrum Hannover explained that the number of cells that can
be printed and the size of the printed products is theoretically unlimited. “With our technology it would take two
hours and 47 minutes to print a complete person in 3D,”
he grinned.
Text: Philipp Graf
Photos: Laser Zentrum Hannover / Lothar Koch
A powerful, laser-based method for printing biomolecules
and cells has also been developed by the team of Dominik
Riester and Martin Wehner from the Fraunhofer Institute
for Laser Technology (ILT) in Aachen. Prior to transfer,
each cell can be analyzed microscopically. The so called
system LIFTSYS is therefore designed to target individual
cells and print them with high yet gentle precision in high
rates on surfaces. This allows in-vivo-structures to be replicated in the laboratory. Thus, fibroblasts and endothelial
cells have already been arranged in predetermined patterns with LIFTSYS.
From Regenerative Biology to Reconstructive Therapy
REBIRTH has, under the nationwide Excellence
Initiative, been funded as a cluster of excellence
since 2006. The aim of the internationally
renowned centre for regenerative medicine is
to develop innovative therapies for the heart,
liver, lungs and blood, and to translate these
into clinical use. This involves collaboration – in
Hannover and at participating partner institutions – between physicians, physicists, chemists,
biologists, engineers, legal professionals and
ethicists, the main research priorities being stem
cell biology, the reprogramming of cells for cell
therapy, disease models and tissue engineering.
48 Participating Partners:
•Hannover Medical School
•Leibniz University of Hannover
•Hannover Laser Centre
•University of Veterinary Medicine Hannover,
Foundation
•Helmholtz Centre for Infection Research
Braunschweig
•Max Planck Institute for Molecular Biomedicine,
Münster
•Institute of Farm Animal Genetics, Friedrich Loeffler Institute, Mariensee
•Fraunhofer Institute of Toxicology and
Experimental Medicine, Hannover
Cluster of Excellence
REBIRTH Cluster of Excellence
Hannover Medical School
Carl-Neuberg-Straße 1, 30625 Hannover
www.rebirth-hannover.de
Photo: University of Lübeck
Annual GSCN Magazine 2014/15 Cholinergic neurons of the forebrain differentiated from induced pluripotent stem cells
49
GSCN | ANNUAL REPORT
GSCN
Annual Report
Boards
Executive Board
According to Section 8 (1) of the statute of the German Stem Cell Network (GSCN), the Executive Board
comprised of the Acting President (Chair), the Senior President (1st Vice Chair), the Designated President
(2nd Vice Chair), the Treasurer, and an Assessor. During the reporting period (Nov. 2014 – Sept. 2015), the
Executive Board is made up of the following members:
Acting President
(Chair)
Senior President
(1st Vice Chair)
Designated President
(2nd Vice Chair)
Treasurer
Assessor
Prof. Dr. Dr. Thomas Braun
(Max Planck Institute for Heart and Lung Research, Bad Nauheim)
E-mail: [email protected]
Prof. Dr. Andreas Trumpp
(German Cancer Research Center Heidelberg, DKFZ)
Prof. Dr. Ulrich Martin (Hannover Medical School)
Dr. Michael Cross (University of Leipzig)
Prof. Dr. Frank Emmrich (TRM & University of Leipzig)
Executive Board during 2014
50 The GSCN offers its sincere appreciation to the members of the Executive Board during 2014
(Nov. 2013 – Nov. 2014). The Founding President Oliver Brüstle left the Executive Board due to rotation
principle and was elected into the Extended Board.
Photo: GSCN
Executive Board: (from left) Ulrich Martin, Thomas Braun, Andreas Trumpp, Frank Emmrich, Michael Cross
GSCN boards and members of the Central Office
Extended Board
Photo: GSCN
According to Section 9 (1) of the statute of the German Stem Cell Network (GSCN), the Extended Board
consists of up to 15 members. In the reporting period, the Extended Board is made up of the following
members:
Prof. Dr. Oliver Brüstle (University of Bonn)
PD Dr. Tobias Cantz (MH Hannover)
Dr. Micha Drukker (Helmholtz Zentr. München)
Prof. Dr. Hartmut Geiger (Ulm University)
Prof. Dr. Magdalena Götz (LMU Munich)
Ira Herrmann (Stem Cell Network NRW)
Prof. Dr. Jürgen Hescheler (Uni. Hospital Cologne)
Prof. Dr. Ana Martin-Villalba (DKFZ Heidelberg)
Prof. Dr. Albrecht Müller (University of Würzburg)
Prof. Dr. Michael Rieger (Goethe Uni. Frankfurt)
Prof. Dr. Ingo Röder (TU Dresden)
Prof. Dr. Hans R. Schöler (MPI for Mol. Biomed.)
Prof. Dr. Elly Tanaka (CRT-Dresden)
Prof. Dr. Mathias Treier (MDC Berlin)
Prof. Dr. Claudia Waskow (TU Dresden)
Working group initiators
Scientific working groups
Pluripotency and
reprograming
Dr. Micha Drukker
Prof. Dr. Hans Schöler
Prof. Dr. Mathias Treier
Basic, translational and applied hematopoiesis
Prof. Dr. Timm Schroeder (ETH Zurich, Basel)
Prof. Dr. Claudia Waskow
Somatic stem cells and
development Stem cells in diseases
(cancer stem cells) Stem cells in regenerative
therapies Stem cells in disease modeling
and drug development
Computational stem cell
biology Prof. Dr. Dr. Thomas Braun
Prof. Dr. Elly Tanaka
Prof. Dr. Thomas Brabletz (Uni. Medical Center Freiburg)
Prof. Andreas Trumpp
Dr. Michael Cross
Prof. Dr. Ulrich Martin
Prof. Dr. Oliver Brüstle
Prof. Dr. Karl-Ludwig Laugwitz (Uni. Clinic r.d.I., Munich)
Prof. Dr. Georg Füllen (IBIMA Rostock)
Prof. Dr. Ingo Röder (TU Dresden)
Funding programs
and policies
Prof. Dr. Ulrich Martin
Prof. Dr. Albrecht Müller
Acting GSCN President (ex-officio)
Clinical trials and
regulatory affairs
Dr. Andreas Kurtz (BCRT, Berlin)
Prof. Dr. Torsten Tonn (Inst. F. Transfus. Med., Dresden)
Prof. Dr. Hans-Dieter Volk (BCRT, Berlin)
Patient information
(stem cell therapies)
Dr. Gisela Badura-Lotter (Ulm University)
Ira Herrmann
Career development
Public engagement and
outreach activities
Stem cell technologies
52 Prof. Dr. Hartmut Geiger (Ulm University)
Prof. Dr. Jürgen Hescheler
Dr. Insa Schröder (GSI, Darmstadt)
PD Dr. Tobias Cantz
Ira Herrmann
Dr. Andreas Bosio (Miltenyi GmbH, Bergisch Gladbach)
Prof. Dr. Frank Emmrich
Facts and figures
Meetings
Executive Board meetings
The Executive Board of the GSCN regularly holds meetings and telephone conferences. These meetings are
coordinated and organized by the Central Office. The following Executive Board meetings took place in the
reporting year:
• Video conference (15 July 2014)
• Meeting, 3 Nov. 2014, in Heidelberg
Extended Board meeting
• 3 Nov. 2014, in Heidelberg
General Assembly
• 3 Nov. 2014, in Heidelberg
Overview of members in 2014
Total no. of members
Natural persons
Legal persons
344
Full members
197
Junior members
122
Research institutes
14
Companies with more than 20 full-time staff
3
Companies with fewer than 20 full-time staff
7
Partner societies
1
Membership cancelations in 2014
27
Members of the working groups
Scientific working groups
Pluripotency and reprograming
187
Somatic stem cells and development
149
Basic, translational and applied hematopoiesis
Stem cells in diseases (cancer stem cells)
140
Stem cells in regenerative therapies
187
Stem cells in disease modeling and drug development
127
Computational stem cell biology
52
20
Funding programs and policies
124
Career development
125
Clinical trials and regulatory affairs
104
Public engagement and outreach activities
62
Patient information (stem cell therapies)
17
Stem cell technologies
184
Last updated 26.03.2015
Institute members
Company members
• Berlin-Brandenburg Center for Regenerative Therapies (BCRT)
• AMS Biotechnology
(Europe) Ltd.
• Center for Regenerative Therapies Dresden (CRTD)
• German Cancer Research Center (DKFZ), Heidelberg
• Fraunhofer Research Institution for Marine Biotechnology
(Fraunhofer EMB), Lübeck
• Fraunhofer Institute for Cell Therapy and Immunology
(Fraunhofer IZI), Leipzig
• Leibniz Institute for Age Research / Fritz Lipmann Institute (FLI),
Jena
• Max Delbrück Center for Molecular Medicine (MDC), Berlin-Buch
• Max Planck Institute for Heart and Lung Research (MPI-HLR),
Bad Nauheim
• Max Planck Institute for Molecular Genetics (MPIMG), Berlin
• REBIRTH Cluster of Excellence, Hannover Medical School
• Collaborative Research Center SFB 873, Department of Medicine V,
Heidelberg University Hospital
• Tissue Engineering und Regenerative Medicine (TERM), University
Hospital of Würzburg
• Biological Industries
• Eppendorf AG
• Essen BioScience Ltd.
• Hexcell Berlin GmbH
• HI-STEM gGmbH
• Life Technologies GmbH
• PELOBiotech GmbH
• PeproTech GmbH
• Takara Bio Europe S.A.S.
Partner Societies
• Deutsche Gesellschaft
für Transfusionsmedizin
und Immunhämatologie
(DGTI) e.V.
GSCN General Assembly
Members’ meeting 2014
54 Photos: GSCN
Ninety-seven members attended the second General Assembly of the GSCN, held on 3 Nov. 2014 during the
2nd Annual Conference in Heidelberg. The minutes of the assembly and the presentation that formed part of
it can be downloaded from the members’ area of the website. The Executive Board and the Extended Board
were re-elected (see above) and the auditors formally approved the actions of the association. President
Andreas Trumpp urged GSCN members to be more active in exercising their democratic rights – only 21
percent (73 out of 349 members) had voted in the online elections.
Activities in 2014
In 2013, its first year, the German Stem Cell Network
(GSCN) moved from an idea to reality, becoming an
association with a central office, a successful annual
conference, and a network of working groups based
on a clear vision of the GSCN’s mission.
In 2014 the task was to add vitality to this structure.
And the initial verdict must surely be that this has
been achieved. Crucially, the Federal Ministry of Education and Research (BMBF) approved funding for
the next three years. During this time, the GSCN will
demonstrate how it intends to place this independent, wide-ranging, growing and successful network
on a firm footing. Growth was the watchword for
2014 – membership of the GSCN grew by a quarter.
The number of institutes and companies involved in
the network also rose. The activities of the GSCN in
2014 are summarized below, divided in accordance
with the association’s objectives into network activities and communication.
The network
Conferences are the ideal place for networking. They
form a meeting place for large numbers of scientists
and represent an opportunity to exchange newly
gathered data, discuss exciting findings, present the
results of time-consuming work, learn about unfamiliar methods and ways of thinking – and make
contact with friendly and inspiring people. The second GSCN conference was perfect proof of this: from
3 – 5 Nov. 2014 some 450 scientists came together
in Heidelberg and discussed stem cells from every
perspective. This gathering of stem cell researchers demonstrated that even at this early stage the
GSCN’s annual conferences have become valuable
and useful focal points for scientists (see detailed
conference report, page 14).
The GSCN not only held its own annual conference
but was also represented at many conferences and
symposiums of other organizations. For example,
a symposium on neural stem cells, organized jointly with the BMBF-funded Independent Research
Groups in Neurosciences, was held immediately
after the GSCN annual conference (5 – 6 Nov. 2014)
and was attended by 150 delegates. The working
groups of the GSCN were also involved in satellite symposiums and sessions at other conferences
in 2014. At the 5th International Congress for Stem
Cells and Tissue Formation, Elly Tanaka and Frederico Calegari of the “Somatic stem cells and development” working group organized a satellite symposium on “Neuronal Stem Cells in Evolution” (8
July 2014, Dresden). At the annual meeting of the
German Society for Transfusion Medicine and Immunohematology (DGTI) in Dresden on 9 – 12 Sept.
2014, the “Stem cells in regenerative therapies”
working group organized a satellite session on stem
cell research in Germany, and the “Clinical trials
and regulatory affairs” working group supported a
Annual GSCN Magazine 2014/15 workshop on advanced therapy medical products (ATMP) run by the European Medicines Agency (EMA).
At the 2014 ISSCR Annual Meeting (18 – 21 June,
Vancouver), the second GSCN Meet-up Hub was
held for the attending GSCN members and guests.
Daniel Besser attended the ISCI/ISCBI workshop of
the International Stem Cell Forum (ISCF) on the
standardization of pluripotency in Vancouver (22
June 2014) on behalf of the GSCN. The institutional
network also grew: collaboration with other organizations expanded further in 2014. For example, the
Regenerative Medicine Initiative Germany (RMIG)
ran a workshop on animal models in stem cell
research, and the German Society for Stem Cell Research (GSZ) held a scientific session and its general
assembly at the GSCN Annual Conference 2014.
Throughout the year there was close collaboration
with the Stem Cell Network North Rhine Westphalia,
EuroStemCell, and the ISSCR. For example, the Stem
Cell Network North Rhine Westphalia and the GSCN
joined forces to run a workshop on the subject
“Big pharma and the stem cell field – matching
expectations?” at the 2014 GSCN Annual Conference. The partnership with EuroStemCell involved
contribution of content, translation, proofreading,
and improvements to teaching materials. The working group “Computational stem cell biology” organized a workshop on mathematical and computer-based methods of model development in modern
stem cell research 1 – 2 Dec. 2014, Dresden). Attendees devised methods for modeling large quantities
of data.
The working groups give structure to the GSCN’s
networking activities. In 2014 Claudia Waskow
(Dresden) and Timm Schroeder (Basel) set up a new
scientific working group – now the association’s
seventh – on “Basic, translational and applied hematopoiesis”. Overall, the working groups are very
active. Nevertheless, the involvement of the individual groups could be strengthened. Therefore, starting
from 2015 there will be non-PI meetings at which
the members of a working group can get together
informally in a central location in Germany, with
presentations by participants. The aim is to stimulate one-to-one contact and professional dialogue
between peers and to encourage the development
of other bottom-up network structures. In 2014, the
Travel Award scheme, which defrays the costs of
attending a conference, was operated via the working groups and the GSCN Central Office. Three young
scientists received awards for travel to the Hydra X.
Summer School in Greece and reported enthusiastically on their experience (see “GSCN News”, page 12).
Communication
The GSCN aims to function publicly as an interface
between science, policy-making, education and
society in all matters of stem cell research. In July
55
Methods through which the GSCN can reach a broad
public include not only films, digital and print media but also events, study groups and collaborative
ventures. For example, on 16 – 17 Sept. 2014 the
strategic working groups “Public engagement and
outreach activities” and “Patient information” organized a two-day workshop in Hannover at which
20 science communicators discussed stem cell research materials and ways of communicating with
schools and interested members of the public. For
this meeting a leaflet entitled “Explaining stem
cells” (in German) and detailing selected materials
that explore the biological, social and ethical aspects
of stem cell research was produced and distributed
throughout Germany. The meeting triggered the formation of the group “Communication on Stem Cell
Research”, a dialog and support network whose
members will meet annually. A key concern of all
members is to maintain a flow of new, improved and
purpose-specific activities and information for the
interested public.
At the Long Night of the Sciences in Berlin, Daniel
Besser and his team presented “A journey into the
world of stem cells”, which had visitors hopping enthusiastically through EuroStemCell’s cell differentiation game, picking up information materials, and
positioning organs and associated cell types on a
magnetic game board (10 May 2014).
Public outreach is always tailored to particular target groups, and students in schools are an important such group, since they are the citizens and decision-makers of the future. But another reason for
targeting them is that stem cell research is covered
in only a very rudimentary fashion in textbooks and
curricula. Daniel Besser’s talk on stem cell research
at the youth science competition “Jugend forscht“
(25 Sept. 2014) was addressed to gifted young people interested in the natural sciences, while teachers took part in a training session on stem cells and
the current state of research at the German Bundestag (4 Dec. 2014). Further activities included also a
science event at the gymnasium Erkner (28 Jan.
2015), an event “Ethics forum: stem cell research
and reproduction biology” with the education
center “Haus Kreisau” (29 Jan. 2015) and participation in the “Hauptstadtforum 2015” of the MINTEC, an excellence network of schools in Germany.
Communication via social media is another topic of
discussion within the GSCN. In accordance with its
wish to communicate via a variety of channels, it has
set up a Twitter account and developed its own mobile app GSCN Navigator. The app was launched and
tested at the annual conference in Heidelberg, where
it enabled delegates to view the talks, abstracts, sessions and speakers’ contact details on mobile devices and to organize and utilize the information.
The app is still in use and will be employed again at
the 2015 conference. The GSCN Central Office used
e-mail to send newsletters to its members and supporters and circulate details of calls for proposals,
conferences, grants and workshops. Development of
First meeting of the new workshop “Communication of Stem Cell Research” in Hannover
56 Photos: GSCN
2014 it therefore appointed journalist
Stefanie Mahler as Communication
Coordinator at the Central Office. Her
first task was to produce three films
about the researchers Magdalena
Götz (Munich), Andreas Trumpp (Heidelberg), and Antony D. Ho (Heidelberg)
and their different approaches to stem cell
research. These films opened the public outreach
event “Stem cells as opportunity – Reality and
prospects” that was sponsored by the DKFZ and the
Ernst Schering Foundation and concluded the 2nd
Annual Conference in Heidelberg (5 Nov. 2014). The
films and the accompanying panel discussion met
with a very positive response from the 120 visitors
who attended. Key issues raised in the discussion
were the translation of research findings into the
concrete development of therapies, and assessment
of the time scale involved. The GSCN films can be
watched online on the website and YouTube.
Long Night of Sciences, Berlin
Photo: GSCN
the GSCN website also continued with an updated
news column, PDF versions of the annual magazine
in English and German, and information on a variety
of aspects of stem cell research. The GSCN Central
Office and the GSCN website (www.gscn.org; 2014:
18,000 visits by 9,500 users) were a central port of
call for anyone interested in stem cell research. Enquires about the current state of research are regularly received from journalists, patients, teachers
and students and are answered by office staff with
the help of scientists. The website provides an overview of materials and information on stem cell research available on the Internet. The major printed
publication produced by the GSCN was a bilingual
annual magazine containing an extensive editorial
section on stem cell research in Germany and a section on the GSCN. The second of these annual magazines, this time focusing on stem cell technology, is
now before you. Also available on the GSCN website
are films that the association has produced for information and as visual aids.
On the international front, the GSCN was actively
involved in the European project EuroStemCell, in
which it acted both as an advisor and as a translator
of factsheets on stem cell research and human diseases. It also played an active part in EuroStemCell’s
renewed application for funding from the European Commission, which was approved in September
2014 for the coming three years. The kick-off event
for the new funding period with the 30 European
partners took place on 18 – 19 Feb. 2015 in Brussels. Here, Daniel Besser undertook coordination of
a work package aimed at developing active interaction with the public in European countries. This will
improve international coordination of the production and use of information materials on stem cell
research. There was likewise additional coordination with the International Society for Stem Cell
Research (ISSCR).
Annual GSCN Magazine 2014/15 On the European policy level, the GSCN supported the
Joint Institute for Innovation Policy (JIIP) by providing advice on stem cell research for a workshop
on future innovation projects with Daniel Besser as
speaker and advisor on major innovations (17 Nov.
2014 and 12 Feb. 2015). The GSCN was actively involved in the Welcome Trust’s declaration to European MPs and the European Commission in connection
with the citizens’ initiative “One-of-Us”. The initiative organized a petition opposing the further funding of research involving human embryonic stem
cells. The Welcome Trust’s declaration, which emphasizes the importance of this research, was widely
supported by the scientific community. The European Commission has now decided to continue funding
research under the same conditions as before.
In the wake of the Heidelberg conference, the GSCN
was particularly in the public spotlight, with various articles appearing in regional newspapers
(Rhein-Neckar-Zeitung, Stuttgarter Zeitung), the
national newspaper Die Welt, online biotechnology
journals, and other online media.
Finances
The GSCN is a non-profit organization funded by
membership subscriptions and a grant from the
BMBF. Under Section 4 of its statute, the level of subscriptions is set by subscription rules adopted at the
General Membership Meeting. Subscriptions are detailed on the GSCN’s membership form.
The business year is the calendar year. Subscriptions
are due at the start of the business year. The Executive Board is responsible for producing the annual
accounts and submitting them to the General Membership Meeting. Details of the association’s finances
are provided at the Membership Meetings.
57
Jahresmagazin des GSCN 2014/15 KAPITEL 1 | LEBENDER KOLUMNENTITEL
59

Stem Cell Technologies

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