www.cemm.

at Research Report 2007

Research Report 2007

Ce — M­—M­—
Research Report 2007
Ce — M­— M­— Research Report 2007 Ce — M­— M­— Research Report 2007
Ce — M­— M­— Research Report 2007 Ce — M­— M­— Research Report 2007
Director’s Intro — The Austrian Academy of
> p. 8—11

Sciences — The CeMM Building — History of CeMM —

> p. 11 > p. 12—13 > p. 14 —15

Concept of CeMM — Know Yourself — Defend

> p. 16—17 > p. 18—25

Yourself — Control Yourself — Treat Yourself —

> p. 28—35 > p. 38—45 > p. 48—55

Heal Yourself — Accelerator Projects — The First

> p. 58—63 > p. 66–69

Conference of CeMM (Synergy in action) — > p. 70–73

CeMM Karl Landsteiner Lectures — CeMM Retreat — > p. 74–75 > p. 76–79

CeMM Phd Program — CeMM Principal Investigators —

> p. 80–82 > p. 83–91

CeMM Directory — CeMM Publications 2007 —

> p. 92–95 > p. 96–97

Scientific Advisory Board — Acknowledgements — > p. 98 > p. 99

CeMM “Our light blue-
colored
Research
lab journal”
Report
This is the first printed CeMM Research Report
and as such brings many reasons to be cheerful.
2007
It summarizes the first chapter of all the activities
that have been connected with CeMM and con­
tributed to its development from the very begin­
ning of its virtual life in the year 2000. There are
Introduction by Giulio Superti-Furga reasonable chances that from a future perspective
many of the efforts of these first years will be
considered a period of heroic fanaticism as on
uncountable occasions the CeMM project seemed
very very close to hitting the wall. However, this
report is testament to the commitment of many
people connected with CeMM that it thankfully
didn’t. It is impossible to thank properly in this
short introduction all the people who deserve
to be mentioned. From the initiators, sponsors
and administrators in the Austrian Academy of
Sciences, to the first group of CeMM project lead­
ers, to the managers and colleagues at the Medical
University of Vienna and two Ministers of Science
and Research and their officers and managers.
There are very many other people in different
positions and functions, including our founding
“Beirat” board who helped in numerous ways,
including welcome advice, important criticism
or even just a cup of coffee. You all know who
you are, and we would like to express our sincere
gratitude.
There are a few people that nevertheless need
to be mentioned, especially as they may not
otherwise be given due credit. First, it is my
privilege to acknowledge the work of my pre­
decessor, CeMM’s founding Scientific Director
Dieter ­Maurer, Professor in the Dermatology
Department of the Medical University of Vienna.
His idea, his founding documents and his strive
for scientific excellence, are the basis for all the
work we have done since. I am honoured to con­
tinue being able to call on his advice and wish
to keep him a close CeMM friend for the years to
come. It is also critical to let readers know that
without the professional, persistent and precise
activity of my precious colleagues Dr. Gerhard
Schadler, Administrative Director at CeMM and
Anita Ender, all-rounder (who, would it not be
for CeMM would already be “magister” in busi­
ness and administration), CeMM and I would
not be here. Thank you very much. Last but not
CeMM Scientific Director least, the people to whom goes my unconditional
Giulio Superti-Furga admiration and thanks are the valiant group of
Ce — M­— M­— Research Report 2007
CeMM scientists and their families who without
losing faith kept working at CeMM’s only fun­
damental mission, to do innovative research
to assist medicine, throughout those years of
constant uncertainties and push-backs. You are
the explanation as to why we exist, why this
Research Report is possible and you will enable
us to make this center for molecular medicine
a success.
CeMM’s young faculty decided to divide this
report into five episodes that should accompany
you through fundamental aspects of what our
research approach is about: Know Yourself
(the strive to know our molecular makeup, the
“human system” in health and disease), Defend
Yourself (the ability to understand and boost
the body’s capability to defend itself against
hostile agents like pathogens), Control Your­
self (the understanding and exploitation of the
processes by which cells and tissues maintain
their properties and do not lose identity or over-
proliferate to form diseases such as cancer),
Treat Yourself (understanding the mechanism
of existing therapeutics and learning from them),
and Heal Yourself (the ultimate goal of prevent­
ing disease, by selectively modulating the body’s
own capability to maintain a healthy state).
We have just started. We will have our building
hopefully in the next couple of years. Please
understand that we are far from having achieved
much yet. Much of the content of this report
are thoughts and notions entirely projected in
a future of very hard work integrated with the
work of many others. We hope you agree that
it is all worthwhile.
The cover of this research report reproduces one
of our light blue-colored lab journals (note­
books), where we record our everyday findings.
The intention was to create a symbol illustrating
that what we present in this report is the syn­
thesis of what is found in our books. This makes ­
a direct link between the CeMM researchers and
the readers’ community of stakeholders and
­supporters.
We hope you enjoy the reading.
Giulio Superti-Furga
Ce — M­— M­— Research Report 2007
Why CeMM?
The view of the
Scientific Director
What is Molecular Medicine? Why do we need
a research center dedicated to it? Has it not been
done already? How does it relate to several exist­
ing research institutes? These are the type of
questions that we have been confronted with
since we started CeMM some three years ago.
And these are the answers:
Molecular Medicine is an area in medicine where
the mechanisms of disease as well as the thera­
peutic and diagnostic initiatives are all based on
a detailed understanding at the molecular level.
This means that at CeMM we hunt the molec­
ular basis of disease and fight it in ways that are
understood in the language of molecules.
CeMM as a center is needed to anticipate, respond
and contribute as much as possible to the revolu­
tion in medicine that has begun from the sequenc-
­ing of individual genomes, the large increase in
quantitative data from patients and the prolifera­
tion of therapeutic opportunities.
In a nutshell, the challenges we are facing in
translating the knowledge gained through the
years of successful “reductionist” approaches
in molecular biology into improved medical
practice are disease complexity and patient vari­
ability associated with the socio-economical
dilemmas of affordability and safety require­
ments of treatment. The solutions generated by
the entire biomedical research community will
lead to medicines that are integrative and have
physiology as their central discipline. More than
it has been so far, the medicine of the future
will be predictive, preventive and personalised.
CeMM is a postgenomic research centre. What
does that mean? Its foundation and principles
were generated after the elucidation of the
sequence of the human genome. Knowledge
of the “parts”, i.e. the gene products and the
molecules, of the human body has been revealed.
What we are facing is the revaluation of physiol­
ogy. The human body as a biological system is
more than just the sum of its parts. It is the result
of countless interactions between the molecules
of which we are composed, that form higher order
structures such as networks. These in turn are
dynamic and result from the momentary as well
as past interactions of our bodies with the
8 9
 environ­ment, including exposure to food, patho­
gens, pollutants and drugs. The time is not far
away, maybe a reality for the next generation,
in which all the knowledge of the parts and its
interactions will allow for computational models
of a “virtual human” that, fed with data from
molecular pathology, will predict disease out­
come and suggest cures. The human biological
system is thought to be very robust, i.e. able to
absorb perturbations easily. However, both dis­
eases and cures depend on understanding and
modulating the fragile aspects of these otherwise
robust systems.
CeMM is not inventing molecular medicine,
an approach and research perspective that
is already successfully employed in numerous
laboratories in Austria and around the world.
CeMM can only exist as part of a thriving and
interactive biomedical research environment,
from the numerous excellent laboratories in
the various departments of the medical univer­
sities, particularly the ones surrounding CeMM
in Vienna, some of which are world-famous for
therapeutic innovation, to the flagship research
institutes IMP/IMBA. CeMM just aspires to
coalesce existing efforts and provide an addi­-
tion­al, necessary boost. CeMM would hope to
become one of the tools by which the Austrian
medical research and teaching community
can reconnect to the glorious past of the Vienna
Medical School, with physiology (i.e. “systems
medicine”) at its core. The patronage of the Aus­
trian Academy of Sciences, with its long tradition
of scientific excellence, imposes extraordinary
quality standards and prestige to the operation.
Part of this vision is the training of a young
­generation of medical scientists at CeMM. Again,
CeMM wants to assist the medical research com­
munity by supporting the “physician scientist”
and “scientist with medical knowledge” career
paths, initially finding tailor-made solutions for
young individual researchers and possibly paving
the way for more institutionalized career options
in the future.
Ce — M­— M­— Research Report 2007
Already, our current molecular viewpoint is
different to the phenomenological description
of disease. For example, the same molecular
malfunction may be at the basis of quite dif­
ferent diseases and, conversely, diseases that
are currently believed to be the same may have
distinct molecular roots. Some inflamma­
tory processes and the respective underlying
molecular pathways and networks may be
common to diseases as varied as rheumatoidar­
thritis, type I diabetes, atherosclerosis, cancer,
and even some neurological diseases. Therefore
CeMM can and will do research that benefits
several disciplines and departments. In fact, it
is CeMM’s molecular perspective that makes it
interdepartmental and interdisciplinary, similar
to physiology having been the central discipline
in the Vienna Medical School of the 19th century.
Being a useful “research vehicle” is one of the
fundamental ways of accomplishing CeMM’s
mission to assist and cooperate with a variety
of clinical units and basic biomedical research
departments, by providing common links.
Genes are the foundation, the “blueprint”, but
everything else is “genome in action”. For
example, the one-gene one-disease relationship
holds true for only a fraction of “monogenic”
diseases and many important diseases such as
cancer, cardiovascular, metabolic and inflam­
matory diseases, are multi-factorial. In fact there
may well be more disease conditions than the
23,000 or so different genes. Moreover, individu­
als often respond differently to therapy. Long
before this booklet will turn yellow, we will
know the sequence of the genome of every one
of us and it will be possible to obtain detailed
molecular measurements for diagnosis.
How does CeMM bridge basic and applied
research? Many people consider the distinction
obsolete. It has been shown that it is difficult to
predict or force applied research. People speak
more about “good” and “bad” research. Only
good research is worthwhile. Nevertheless we
do not think that relying on serendipity is
enough to close the gap between science and
medical practice and meet the urgent challenges
that we face in terms of medical need. CeMM
rather adopts a non-linear approach and attempts
to foster medically-relevant research not only
by reversing the bench-to-bedside slogan but by
closing the circuit: from the clinic to the clinic.
To achieve this, the only recipe we are aware The Austrian
of is one of immediate physical proximity and
project contiguity between the medical doctors Academy
with the clinical insight and the biomedical
researchers with the research weapons. We
have these people on the same project team and
of Sciences
stimulate the two sides to meet, collide and
connive. At the “receiving” end is a management
knowledgeable on the importance of securing
and protecting intellectual property generated
by taxpayer’s money and encouraging the explo­
ration of therapeutic and diagnostic opportuni­
ties in a healthy and educated (not too close/not
too distant) relationship with industry.
There is no doubt about it; our knowledge of
biological and human-biological processes is
exploding. In parallel, the costs and the oppor­
tunities associated with medical treatments are
also growing at a very fast pace and present us
with moral dilemmas, such as how to identify
better medical treatments and make them avail­
able to everybody. This is a formidable task for
the entire human society and certainly beyond
the capability of a single small research center.
However, in essence, CeMM has been founded
to do justice to this acceleration in knowledge
and contribute to increase, even slightly, the
ability of the Austrian biomedical community
to play an active role in coping with the associ­
ated opportunities and risks. Our ambition
is that CeMM will be able to act synergistically
and sometimes even catalytically with the large
and powerful biomedical research already going The Austrian Academy of Sciences, founded
on in numerous university and non-university in 1847, is the most prestigious and important
research institutes. Ultimately, as we now real­ organisation in Austria for the promotion of
ize the importance of molecular networks that non-university-based academic research.
form the basis of our organism, we believe that
significant research projects can only be success­ The Academy is both a learned society, com­
ful by networking competences and activities. prising highly qualified researchers from Austria
We hope to provide many of the necessary links. and abroad as its members, and a scientific
organisation promoting innovative research.
It is currently promoting 65 research institutions,
which are located in several federal states of
Austria, with the headquarters located in the Old
University in the center of Vienna. At present,
the Academy employs about 1100 people.
The Austrian Academy of Sciences has developed
from a mere learned society to include the orga­
nisation and management of modern scientific
research institutions. By founding basic research
centers, such as IMBA - Institute of Molecular
Biotechnology, and GMI - Gregor Mendel Insti­
tute of Molecular Plant Biology, as limited liabili­
ty companies under Austrian law, the Austrian
Academy of Sciences embarked on a new approach
to institutional organisation. The connection
between basic research and clinical research is
being established by setting up CeMM.
Ce — M­— M­— Research Report 2007 10 11
 The CeMM
Building – At the
center of the
Vienna General
Hospital
Location, location, location
The new CeMM building is located at the very
heart of the Vienna General Hospital (AKH), one
of the biggest and most modern general hospitals
in Europe. This privileged location is designed
to integrate the scientists of CeMM with the out­
standing medical community and facilities of the
hospital and the Medical University of Vienna, to
fully maximize the capabilities of this molecular-
medical institute. The main entrance of CeMM
will be shared with the complementary laborato­
ry of the Medical University of Vienna, and there
are connecting corridors on each floor, ensuring
easy access to the main building of the AKH, and
encouraging communication and the free-flow
of ideas and resources throughout the campus.
Fig. 1 Location of the
CeMM building within the
Vienna General Hospital.
Ce — M­— M­— Research Report 2007
Modern laboratories for a modern institute
The architect Kopper designed a modern molec­ Fig. 2 Projected view
ular biology building to symbolize one of CeMMs of the CeMM building.
missions; to be a leading institute that works Fig. 3 Inside the open-
as a team by promoting interactions between plan laboratories with
some computer work­
individuals, rather than a collection of separate stations at the windows.
laboratories. The building consists of eight floors,
and two thirds of it is lab space. Overall, there
is 5,620 m² total floor space, with 3.409 m²of
usable area. That’s room for around 100 people,
including support staff and administration.
The laboratories are open-plan and south facing,
ensuring they are light and spacious. There are
some computer workstations for up to 15 people
situated along the windows. The necessary sup­
port rooms are located inside the building and
are conveniently close to the laboratories. On the
north side of the building are the offices for the
scientists and the administration, and small sem­
inar rooms for informal meetings and discussions.
The CeMM building also has its own lecture hall.
To promote social interactions between the sci­
entists, there is a large cafeteria and two terraces
on the top floor.
The beginning of construction is in May 2008,
and CeMM will move in by March 2010.
Ce — M­— M­— Research Report 2007 12 13
The History January 1, 2005 August 13, 2005

Cover-Story Publication
October 6, 2005
EMBO elects
November 10, 2005
Approval of GEN-AU

of CeMM in Molecular Cell

“Structural basis for the cytoskeletal
asssociation of Bcr-Abl/c-Abl” by
Giulio Superti-Furga and colleagues.
40 top researchers
to its membership
including CeMM Director,
Giulio Superti-Furga.
grant application
“DRug Action by GenOmic
Network(s): DRAGON”.
GEN-AU supports genome
research in Austria.

January 1, 2006 January 22, 2006 January 23, 2006 March 23, 2006 April 1, 2006 June 1, 2006
Nature article publication FWF Grant CeMM is presented
by Giulio Superti-Furga and researchers awarded to Giulio Sperti-Furga’s group in a Nature issue
of Cellzome AG and EMBL Heidelberg for the project “Physical and Functional that has a Highlight on Austria
on the first genome-wide screen Map of Bcr-Abl Signalling”. section.
for complexes in an organism, budding
yeast, using affinity purification and
mass spectrometry.

September 27, 2006 October 2, 2006 October 22, 2006 January, 2007 April 27, 2007 May 3, 2007

ÖAW Lectures Publicaton in
Minister Elisabeth Gehrer Nature Methods
gave the introduction speech “An efficient tandem affinity
to Giulio Superti-Furga’s talk
“Molecular machines, molecular
purificaton procedure for interaction
proteomics in mammalian cells” by
networks and the medicine Tilman Bürckstümmer, PostDoc in the
of the 3rd millenium”. Director’s Group, with “News and
Views” commentary in the same issue
CeMM joins the Phd
program, CCHD: Cell
Communication in Health
and Disease
supported by the Medical University of
Vienna and the Austrian Science Fund
(FWF), providing advanced education in
biomolecular medicine.
Giulio Superti-Furga has
been elected as a
Corresponding Member
of the Austrian Academy
of Sciences,
Section for Mathematics and
the Natural Sciences.

May 23, 2007
A documentary
film about CeMM
is presented at the “Feierliche
Sitzung” of the Austrian Academy
of Sciences and on the German
television channel, Bayern alpha.
June 25, 2007
FWF Grant
awarded to Principal Investigator
Robert Kralovics for the project
“Genetic basis of myeloproliferative
disorders”.
August 3, 2007
Publication in
Molecular Cell
“Active and Repressive Chromatin
Is Interspersed without Spreading
in an Imprinted Gene Cluster in the
Mammalian Genome” by Principal
Investigator Denise Barlow.
August 14, 2007
Publication in PNAS
“The Btk tyrosine kinase is a major
target of the Bcr-Abl inhibitor
dasatinib” by Giulio Superti-Furga
and colleagues at the Medical
University of Vienna.
August 24, 2007 August 23—26, 2007
Publicaton in Blood
“Chemical proteomic profiles of the
BCR-ABL inhibitors imatinib, nilotinib
and dasatinib reveal novel kinase
and non-kinase targets” by Giulio
Superi-Furga, Peter Valent (Medical
University of Vienna) and colleagues.

September 25, 2007
Visit by Dr. Johannes
Hahn, Minister of
Science and Research
The Director’s lab had the
pleasure and honor to welcome
Minister Hahn and to present
the research activities of CeMM.
September 27, 2007
Publicaton in
Nature Methods
“Mass spectrometry-based functional
proteomics: from molecular machines
to protein networks” by Giulio Superti-
Furga and Thomas Köcher.
October 1, 2007 October 31, 2007
CEN-Online
(Chemical & Engineering News)
published a science and technology
report about the first CeMM
Conference: “Chemistry, Biology,
Cross-Fertilization”.
November 22, 2007 January 1, 2008
Science Day Meeting Report of the
CeMM invited the Presidium, first CeMM Conference,
interested persons of the Academy published in Nature
and the Scientific Community
of Vienna to a first “Science Day”.
Chemical Biology
“Drugs in Action” by CeMM Director
Giulio Superti-Furga and co-organizer
Ulrike Eggert.
The Concept
of CeMM
“CeMM’s young faculty decided to divide
this report into five episodes that should Know The three ‘omics’
Knowing your
Genomics: SNP
mapping and
Proteomics:
Mass Spectrometry
Bioinformatics:
Making sense
accompany you through fundamental
aspects of what our research approach is Yourself molecular makeup
> p. 20—21
Gene Sequencing
> p. 22
> p. 23
of it all
> p. 24—25

about: Know Yourself (the strive to know

our molecular makeup, the “human
system” in health and disease), Defend
Yourself (the ability to understand and
boost the body’s capability to defend Defend The Fight
for Survival
Innate Immunity:
Molecular Mechanisms
Inflammation
Double-edged Sword
Bacterial Toxins

Yourself
> p. 35
itself against hostile agents like pathogens), > p. 30—31
of Disease Recognition > p. 34
Cell Detectives
Control Yourself (the understanding and
> p. 32—33
exploitation of the processes by which
cells and tissues maintain their properties
and do not lose identity or over-proliferate
to form diseases such as cancer), Treat
Yourself (understanding the mechanism Control Maintaining
Biological Order
Genetics and
Epigenetics of Cancer
Hematological
Malignancies

of existing therapeutics and learning from

them), and Heal Yourself (the ultimate
Yourself The Origin of Cancer
Gene Regulation
Getting Out of Control
Controlling the genome
Master Controllers
> p. 44 —45
> p. 40—41 > p. 42—43
goal of preventing disease, by selectively
modulating the body’s own capability
to maintain a healthy state).”
Giulio Superti-Furga
Treat Smart Drugs:
Hitting where it hurts
Understanding drugs Achilles heel of Cancer

Yourself
> p. 52—53 > p. 54 —55
What’s in a Drug?
Smart Drugs
Putting Knowledge
to work
> p. 50—51

Heal Learning from

the Experts
Natural Antibodies
and Atherosclerosis

Yourself Natural Antibodies

> p. 60—61
Natural Born Killer
Keeping the Blood
Vessels Clear
> p. 62—63
 Know
Know
Yourself

Met –
Val – His –
Leu – Thr – Pro – Glu –

Yourself
Glu – Lys – Ser – Ala – Val – Thr – Ala –
Leu – Trp – Gly – Lys – Val – Asn – Val – Asp – Glu – Val – Gly – Gly –
Glu – Ala – Leu – Gly – Arg – Leu – Leu – Val – Val – Tyr – Pro – Trp – Thr – Gln – Arg –
Phe – Phe – Glu – Ser – Phe – Gly – Asp – Leu – Ser – Thr – Pro – Asp – Ala – Val – Met – Gly –
Asn – Pro – Lys – Val – Lys – Ala – His – Gly – Lys – Lys – Val – Leu – Gly – Ala – Phe – Ser – Asp – Gly –
Leu –Ala –His –Leu –Asp –Asn –Leu –Lys –Gly –Thr –Phe – Ala – Thr – Leu – Ser – Glu – Leu – His – Cys – Asp –
Lys – Leu – His – Val – Asp – Pro – Glu – Asn – Phe – Arg – Leu – Leu – Gly – Asn – Val – Leu – Val – Cys – Val – Leu – Ala –
His – His – Phe – Gly – Lys – Glu – Phe –Thr –Pro –Pro –Val –Gln –Ala –Ala –Tyr –Gln –Lys –Val – Val – Ala – Gly – Val – Ala – Asn – Ala – Leu – Ala – His –
Lys – Tyr – His – +++ – Met – Val – Leu – Ser – Pro – Ala – Asp – Lys – Thr – Asn – Val – Lys – Ala – Ala – Trp – Gly – Lys – Val – Gly –Ala –His –Ala –Gly –Glu –Tyr –Gly –Ala –Glu –Ala –
Leu – Glu – Arg – Met – Phe – Leu – Ser – Phe – Pro – Thr – Thr – Lys – Thr –Tyr –Phe –Pro –His –Phe –Asp –Leu –Ser –His –Gly –Ser – Ala –Gln –Val –Lys –Gly –His – Gly – Lys – Lys – Val – Ala –
Asp –Ala –Leu –Thr –Asn –Ala –Val –Ala –His –Val –Asp –Asp –Met –Pro –Asn – Ala – Leu – Ser – Ala – Leu – Ser – Asp – Leu – His – Ala – His – Lys – Leu – Arg – Val – Asp – Pro – Val – Asn – Phe –
Lys –Leu –Leu –Ser –His –Cys –Leu –Leu –Val –Thr –Leu –Ala –Ala –His –Leu –Pro –Ala –Glu –Phe –Thr –Pro –Ala –Val –His –Ala –Ser –Leu –Asp –Lys –Phe –Leu –Ala – Ser – Val – Ser – Thr – Val –
Leu –Thr –Ser –Lys –Tyr –Arg –+++ –Met –Val –His –Leu –Thr –Pro –Glu –Glu –Lys –Ser –Ala –Val –Thr –Ala –Leu –Trp –Gly –Lys –Val –Asn –Val –Asp –Glu –Val – Gly – Gly – Glu – Ala – Leu –
Gly – Arg – Leu – Leu – Val – Val – Tyr – Pro – Trp – Thr – Gln – Arg – Phe – Phe – Glu – Ser – Phe – Gly – Asp – Leu – Ser – Thr – Pro – Asp – Ala – Val – Met – Gly – Asn – Pro – Lys –
Val – Lys – Ala – His – Gly – Lys –Lys –Val –Leu –Gly –Ala –Phe –Ser –Asp –Gly –Leu –Ala –His – Leu – Asp – Asn – Leu – Lys –
Gly – Thr – Phe – Ala – Thr – Leu – Ser – Glu – Leu – His – Cys – Asp – Lys – Leu – His – Val – Asp –Pro –Glu –Asn –Phe –
Arg – Leu – Leu – Gly – Asn – Val – Leu – Val – Cys – Val – Leu – Ala – His – His – Phe – Gly – Lys – Glu – Phe – Thr –
Pro – Pro – Val – Gln – Ala – Ala – Tyr – Gln – Lys – Val – Val – Ala – Gly – Val – Ala – Asn – Ala – Leu – Ala –
His – Lys – Tyr – His – +++ – Met – Val – Leu – Ser – Pro – Ala – Asp – Lys – Thr – Asn – Val – Lys – Ala –
Ala – Trp – Gly – Lys – Val – Gly – Ala – His – Ala – Gly – Glu – Tyr – Gly – Ala – Glu – Ala – Leu – Glu – Arg –
Met – Phe – Leu – Ser – Phe – Pro –Thr –Thr –Lys –Thr –Tyr –Phe –Pro – His – Phe – Asp – Leu – Ser –
His – Gly – Ser – Ala – Gln – Val – Lys – Gly – His – Gly – Lys – Lys – Val – Ala – Asp – Ala – Leu – Thr – + Genomics: SNP Mapping + Proteomics: + Bioinformatics:
Asn – Ala – Val – Ala – His – Val – Asp – Asp – Met – Pro – Asn – Ala – Leu – Ser – Ala – Leu – Ser –
Asp – Leu – His – Ala – His – Lys – Leu –Arg –Val –Asp –Pro –Val – Asn – Phe – Lys – Leu – Leu – and Gene Sequencing Mass Spectrometry Making sense of it all
Ser – His – Cys – Leu – Leu – Val – Thr – Leu – Ala – Ala – His – Leu – Pro – Ala – Glu – Phe – Thr – Pro –
Ala – Val – His – Ala – Ser – Leu – Asp – Lys – Phe – Leu – Ala – Ser – Val – Ser –Thr –Val –Leu –Thr –Ser –
Lys –Tyr –Arg –+++ –Met –Val –His –Leu – Thr – Pro – Glu – Glu – Lys – Ser – Ala – Val – Thr – Ala – Leu – Trp – Gly – Lys – Val –
Asn – Val – Asp – Glu – Val – Gly – Gly – Glu – Ala – Leu – Gly – Arg – Leu – Leu – Val – Val – Tyr – Pro – Trp – Thr – Gln – Arg – Phe –
Phe –Glu –Ser –Phe –Gly –Asp –Leu –Ser – Thr – Pro – Asp – Ala – Val – Met – Gly – Asn – Pro – Lys – Val – Lys – Ala – His – Gly – Lys –
Lys –Val –Leu –Gly –Ala –Phe –Ser –Asp –Gly –Leu –Ala –His –Leu –Asp –Asn –Leu –Lys –Gly –Thr –Phe –Ala –Thr –Leu –Ser –Glu –Leu –
His –Cys –Asp –Lys –Leu –His –Val –Asp –Pro –Glu –Asn –Phe –Arg –Leu –Leu –Gly –Asn –Val –Leu –Val –Cys –Val –Leu –Ala –His –
His –Phe –Gly –Lys –Glu –Phe –Thr –Pro –Pro –Val –Gln –Ala –Ala –Tyr –Gln –Lys –Val –Val –Ala –Gly –Val –Ala –Asn –Ala –Leu –
Ala –His –Lys –Tyr –His –+++ –Met –Val –Leu –Ser –Pro –Ala –Asp –Lys –Thr –Asn –Val –Lys –Ala –Ala –Trp –Gly –Lys –Val –
Gly –Ala –His –Ala –Gly –Glu –Tyr –Gly –Ala –Glu –Ala –Leu –Glu –Arg –Met –Phe –Leu –Ser –Phe –Pro –Thr –Thr –Lys –
Thr – Tyr – Phe – Pro – His – Phe – Asp – Leu – Ser – His – Gly – Ser – Ala – Gln – Val – Lys – Gly – His – Gly – Lys – Lys – Val –
Ala – Asp – Ala – Leu – Thr – Asn – Ala – Val – Ala – His – Val – Asp – Asp – Met – Pro – Asn – Ala – Leu – Ser – Ala – Leu –
Ser –Asp –Leu –His –Ala –His –Lys –Leu –Arg –Val –Asp –Pro –Val –Asn –Phe –Lys –Leu –Leu –Ser –His –Cys –
Leu –Leu –Val –Thr –Leu –Ala –Ala –His –Leu –Pro –Ala –Glu –Phe –Thr –Pro –Ala –Val –His –Ala –Ser –Leu –
Asp –Lys –Phe –Leu –Ala –Ser –Val –Ser –Thr –Val –Leu –Thr –Ser –Lys –Tyr –Arg –+++ –Met –Val –His –
Leu –Thr –Pro –Glu –Glu –Lys –Ser –Ala –Val –Thr –Ala –Leu –Trp –Gly –Lys –Val –Asn –Val –Asp –Glu –
Val – Gly – Gly – Glu – Ala – Leu – Gly – Arg – Leu – Leu – Val – Val – Tyr – Pro – Trp – Thr – Gln – Arg – Phe –
Phe –Glu –Ser –Phe –Gly –Asp –Leu –Ser –Thr –Pro –Asp –Ala –Val –Met –Gly –Asn –Pro –Lys –Val –
Lys –Ala –His –Gly –Lys –Lys –Val –Leu –Gly –Ala –Phe –Ser –Asp –Gly –Leu –Ala –His –Leu –Asp –
hemoglobin Asn – Leu – Lys – Gly – Thr – Phe – Ala – Thr – Leu – Ser – Glu – Leu – His – Cys – Asp – Lys – Leu – His –
For the Know Yourself Val –Asp –Pro –Glu –Asn –Phe –Arg –Leu –Leu –Gly –Asn –Val –Leu –Val –Cys –Val –Leu –Ala –
topic, we have chosen the His – His – Phe – Gly – Lys – Glu – Phe – Thr – Pro – Pro – Val – Gln – Ala – Ala – Tyr – Gln – Lys – Val –
sequence of the human Val –Ala –Gly –Val –Ala –Asn –Ala –Leu –Ala –His –Lys –Tyr –His –+++ –Met –Val –Leu –Ser –
beta-globin and alpha- Pro –Ala –Asp –Lys –Thr –Asn –Val –Lys –Ala –Ala –Trp –Gly –Lys –Val –Gly –Ala –His –Ala –
globin genes, the protein Gly – Glu – Tyr – Gly – Ala – Glu – Ala – Leu – Glu – Arg – Met – Phe – Leu – Ser – Phe – Pro – Thr –
components of human Thr – Lys – Thr – Tyr – Phe – Pro – His – Phe – Asp – Leu – Ser – His – Gly – Ser – Ala – Gln – Val –
hemoglobin, which is Lys – Gly – His – Gly – Lys – Lys – Val – Ala – Asp – Ala – Leu – Thr – Asn – Ala – Val – Ala – His –
responsible for carrying Val – Asp – Asp – Met – Pro – Asn – Ala – Leu – Ser – Ala – Leu – Ser – Asp – Leu – His – Ala –
oxygen in our blood. His – Lys – Leu – Arg – Val – Asp – Pro – Val – Asn – Phe – Lys – Leu – Leu – Ser – His – Cys –
The corresponding DNA Leu – Leu – Val – Thr – Leu – Ala – Ala – His – Leu – Pro – Ala – Glu – Phe – Thr – Pro – Ala –
­s equences were two of Val – His – Ala – Ser – Leu – Asp – Lys – Phe – Leu – Ala – Ser – Val – Ser – Thr – Val – Leu –
the first to be isolated and Thr –Ser –Lys –Tyr –Arg –+++ –Met –Val –His –Leu –Thr –Pro –Glu –Glu –Lys –Ser –
determined. The human Ala – Val – Thr – Ala – Leu – Trp – Gly – Lys – Val – Asn – Val – Asp – Glu – Val – Gly – Gly –
population carries many Glu – Ala – Leu – Gly – Arg – Leu – Leu – Val – Val – Tyr – Pro – Trp – Thr – Gln – Arg –
variants of these sequenc- Phe – Phe – Glu – Ser – Phe – Gly – Asp – Leu – Ser – Thr – Pro – Asp – Ala – Val – Met –
es, some of which are Gly –Asn –Pro –Lys –Val –Lys –Ala –His –Gly –Lys –Lys –Val –Leu –Gly –Ala –Phe –
associated with severe Ser – Asp – Gly – Leu – Ala – His – Leu – Asp – Asn – Leu – Lys – Gly – Thr – Phe – Ala – Defend
disease conditions. Knowl­ Thr – Leu – Ser – Glu – Leu – His – Cys – Asp – Lys – Leu – His – Val – Asp – Pro – Glu – Yourself
edge about them is critical Asn – Phe – Arg – Leu – Leu – Gly – Asn – Val – Leu – Val – Cys – Val – Leu – Ala – His – His –
for prevention and therapy. Phe – Gly – Lys – Glu – Phe – Thr – Pro – Pro – Val – Gln – Ala – Ala – Tyr – Gln – Lys – Val –
Val –Ala –Gly –Val –Ala –Asn –Ala –Leu –Ala –His –Lys –Tyr –His –+++ –Met –Val –Leu –
Ser – Pro – Ala – Asp – Lys – Thr – Asn – Val – Lys – Ala – Ala – Trp – Gly – Lys – Val – Gly – Ala – Control
HBB_HUMAN Uniprot Yourself
P68871 His –Ala –Gly –Glu –Tyr –Gly –Ala –Glu –Ala –Leu –Glu –Arg –Met –Phe –Leu –Ser –Phe –
Pro – Thr – Thr – Lys – Thr – Tyr – Phe – Pro – His – Phe – Asp – Leu – Ser – His – Gly – Ser – Ala –
HBA_HUMAN Uniprot Gln –Val –Lys –Gly –His –Gly –Lys –Lys –Val –Ala –Asp –Ala –Leu –Thr –Asn –Ala –Val –Ala –
P69905 His –Val –Asp –Asp –Met –Pro –Asn –Ala –Leu –Ser –Ala –Leu –Ser –Asp –Leu –His –Ala –His – Treat
Lys –Leu –Arg –Val –Asp –Pro –Val –Asn –Phe –Lys –Leu –Leu –Ser –His –Cys –Leu –Leu –Val – Yourself
Thr – Leu – Ala – Ala – His – Leu – Pro – Ala – Glu – Phe – Thr – Pro – Ala – Val – His – Ala – Ser – Leu –
Asp –Lys –Phe –Leu –Ala –Ser –Val –Ser –Thr –Val –Leu –Thr –Ser –Lys –Tyr –Arg –+++ –Met –Val –
His – Leu – Thr – Pro – Glu – Glu – Lys – Ser – Ala – Val – Thr – Ala – Leu – Trp – Gly – Lys – Val – Asn – Val –
Asp –Glu –Val –Gly –Gly –Glu –Ala –Leu –Gly –Arg –Leu –Leu –Val –Val –Tyr –Pro –Trp –Thr –Gln –Arg – Heal
Yourself
Phe – Phe – Glu – Ser – Phe – Gly – Asp – Leu – Ser – Thr – Pro – Asp – Ala – Val – Met – Gly – Asn – Pro – Lys –
Val – Lys – Ala – His – Gly – Lys – Lys – Val – Leu – Gly – Ala – Phe – Ser – Asp – Gly – Leu – Ala – His – Leu – Asp –
Asn –Leu –Lys –Gly –Thr –Phe –Ala –Thr –Leu –Ser –Glu –Leu –His –Cys –Asp –Lys –Leu –His –Val –Asp –Pro –
Glu –Asn –Phe –Arg –Leu –Leu –Gly –Asn –Val –Leu –Val –Cys –Val –Leu –Ala –His –His –Phe –Gly –Lys –Glu –
Phe –Thr –Pro –Pro –Val –Gln –Ala –Ala –Tyr –Gln –Lys –Val –Val –Ala –Gly –Val –Ala –Asn –Ala –Leu –Ala –His –
Lys –Tyr –His –+++ –Met –Val –Leu –Ser –Pro –Ala –Asp –Lys –Thr –Asn –Val –Lys –Ala –Ala –Trp –Gly –Lys –Val –
“There is no
“Knowledge of the self is the mother of all knowl­
edge. So it is incumbent on me to know myself,
to know it completely, to know its minutiae, its
shame in not
characteristics, its subtleties, and its very atoms.”
Kahlil Gibran, Lebanese-American Philosopher,
1883-1931. This is not a small thing to ask, but a
comprehensive knowledge of the molecular self
knowing, the
is critical when dealing with health and disease.
When a car breaks down, the best person to fix it
is a mechanic who understands exactly how an
engine works and how a car operates in its enti­
shame lies
rety. To treat disease, we first need to know and
understand the human body in its healthy state,
at homeostasis, so we can make an accurate dia­
gnosis of any diseased state and use this to deve­
in not finding
lop and select effective treatments to cure disease.
Science comes from the Latin scientia, meaning
knowledge. Scientists unite in their pursuit of
out.”
knowledge, and biologists pursue knowledge
about life. CeMMs ambition to ‘know yourself’,
means to strive to identify and understand our
(Russian Proverb)
molecular self, that is the molecules that make up
Studying the molecular repertoires and networks our bodies. It has become clear that the knowl­
to understand the human system in health and disease. edge of individual molecules goes no way towards
describing the workings of the cells and tissues
that form a functioning human being, as no
molecule works entirely alone. Scientists need
to study molecular interactions and networks
to really understand the human system in health
and disease.
Knowing your molecular makeup:
The three ‘omics’
Genomics
In the 21st Century, scientists entered the post-
genomic era. The first full draft of the human
genome hit the electronic shelves in June 2000.
It had taken almost ten years to generate the
sequence of 3.1 billion letters of DNA, and it
was hailed as one of the most influential scien-
­tific discoveries of all time. They weren’t wrong.
Knowing the sequence of DNA means that
scientists not only have the blueprint of the
human system, but can also identify all genes that
cause disease. At CeMM, Robert Kralovics uses
the data to find which genes can cause blood
disorders. Sebastian Nijman uses it to find genes
that can cause cancer. Once scientists know
which faulty genes cause disease, they can work
towards generating effective treatments.
Ce — M­— M­— Research Report 2007
While the human genome project tells scientists
the sequences and the variations of all the genes,
it doesn’t tell them their activity. This information
is useful when studying the effects of external
influences such as disease or therapeutics on the
body. Microarray technology can tell scientists
the activity of the entire genome at one moment
in time. It is used extensively at CeMM in colla­
boration with the Medical University of Vienna
to study gene activity under a variety of physio­
logical conditions.
Proteomics
Genes make proteins, which are the tools of the
cell. The protein components of a cell are its
trademark, so you can tell a lot about a cell from
the proteins it contains (its proteome). However,
while scientists already have the tools to start
sequencing the genome of every human being,
they are much further away from understanding
the proteome of even a single cell. The number
of proteins, unlike the number of genes, is
much more difficult to predict, and scientists
want to know not only the number, but also
the complex three-dimensional structure and
the function of each protein, and when and
where they are produced. Moreover, proteins
are modified, by various chemical changes, like
phosphorylation and acetylation or the addition
of small peptides, like in the process called ubi­
quitination. As a result, for each gene there may
be several corresponding protein species, each
with a slightly different function. Mass spec­
trometry has been set up at CeMM as a valuable
proteomics approach to study the molecular
effects of various conditions such as disease or
drugs, by identifying the protein components
and their modifications in a biological sample.
Ce — M­— M­— Research Report 2007
Metabolomics Know
Knowing the sequence and activity of the genes, Yourself
as well as the assortment of proteins, gives
scientists a lot of information about the state of
a cell and ultimately about health and disease
states. Genes and proteins provide circumstantial
evidence that a particular activity or event might
occur in a cell, and goes some way towards pre­
dicting cellular responses to certain factors. How­
ever, they do not reveal everything about a cell’s
activity. The repertoire of metabolites generated
by diverse chemical reactions that both break
down and build up molecules in our bodies and
transform energy, is known as the metabolome.
Metabolic profiling, or metabolomics, can give
scientists a unique indication of what biological
activity has actually occurred in the cell, and tech­
nology of this kind is being used at CeMM to
supplement and extend data obtained from the
other approaches.
Knowledge generated by each of the ‘omics’
individually and collectively provides valuable
information about the molecular self. Giulio
Superti-Furga is using a combination of all three
to provide a comprehensive molecular analy­
sis of specific body states. His group plans on
generating extensive knowledge of the effects
of therapeutics on the body. In collaboration
with Peter Valent at the Medical University of
Vienna, along with the sophisticated technology
platform provided by BIOCRATES Life Sciences,
a company in Innsbruck, Austria, they have
formed the consortium DRAGON (DRug Action
by GenOmic network(s)), which generates data
from a combination of functional genomics,
proteomics and metabolomics approaches. The
goal is to minimize the damage caused by the­
rapeutic side-effects on patients, by developing
detailed analysis of their molecular effects.
Managing the Knowledge
Scientists are no longer focusing on individual
genes and proteins. They are more interested
in studying groups and networks, and whole
body states. Scientists at CeMM are using com­
binations of genomics, proteomics and meta­
bolomics to study various conditions, such as
the effects of therapeutics on the body. These
approaches each generate substantial data that
somehow need to be integrated to generate Defend
meaningful biological conclusions. This is one Yourself
of the challenges now facing the systems bio­
logists and bioinformaticians, who develop
Control
analytical methods using computer programs to Yourself
integrate and analyze complex biological datasets.
Treat
Yourself
Heal
Yourself
20 21

“Significant
advances in
instrument design
and technology
have led to drama-
tic improve­ments
in ­sensitivity
and accuracy.”
Fig. 1 A microarray
­r evealing the activity of
genes in cells. RNA pro-
duced (transcribed) from
active genes is taken from
cells under two different
physiological conditions
and fluorescently labeled
either red or green. This
mixture is then incubated
with a special slide on
which DNA is attached in
spots. The spots that are
either red or green reveal
genes that are active in
only one condition, and
spots that are yellow are
active in both.
Ce — M­— M­— Research Report 2007
Genomics: SNP
mapping and
Gene Sequencing
The first published sequence of ‘the’ human
genome was in actual fact a mixture of the
sequence of a very small group of individuals,
because the genome sequence of every human
being is unique. Genetic variations are thought
to contribute to physical and even social char­
acteristics. The most frequent type of variation
is the single nucleotide polymorphism (SNP).
Scientists have now identified many of these
SNPs (currently more than 9 million) and this
information can be used to identify genetic
risk factors that are associated with disease. This
also gives scientists the opportunity to under­
stand further the molecular basis of specific
genetic diseases. Robert Kralovics is looking at
large numbers of SNPs in human samples to
discover which ones account for the tendencies
of patients with specific blood disorders known
as myeloproliferative disorders (MPDs) to develop
additional disease symptoms like throm­bosis.
Thrombosis, deregulated blood clotting brought
about by small cells in our blood called platelets,
is a particularly nasty complication of MPD that
significantly contributes to mortality associated
with the disease. Using genomics approaches
to generate knowledge and understanding of the
genetic basis of the disease, Robert hopes to
develop effective strategies to treat susceptible
patients and improve their quality of life.
Other genetic variations, like the loss of large
regions of DNA containing many genes, are also
linked to certain genetic diseases. Finding out
which gene and which mutation is a big challenge
for molecular-medical scientists. The develop­
ment of comprehensive high-throughput gene
sequencing technologies enables them to more
quickly pin-point genetic mutations responsible
for disease. Robert’s group has installed the first
of such modern sequencing machine: the Genetic
Analyzer instrument manufactured by Applied
Biosystems, and they already have experience
using it to hunt for disease-causing mutations.
Now they have set their sites on finding the gene
that is mutated within a region commonly deleted
in patients with MPD, which contains around
10 candidate genes. Identifying the disease-causing
genetic mutation will lead to a more precise diag­
nostic approach and hopefully the development
of novel therapeutics.
Fig. 1
Proteomics:
Mass Spectrometry
The protein content of the human cell (the
proteome) is largely uncharacterized. Under­
standing the proteome is vital in furthering
our knowledge, as it constitutes the necessary
equipment that enables a cell to function and
thus survive. Current estimates are that there
are around 20,000 protein-coding genes result­
ing in greater than 500,000 different proteins
in human cells. So, it is not difficult to see how
investigation of the proteome and determina­
tion of the function of every protein is a huge
challenge for modern-day scientists. While most
cells in a body have an almost identical genome,
they all have very different expressed proteomes.
The last ten years have seen great progress in
the development of sophisticated proteomic
technologies allowing us to begin working on
this problem. Mass spectrometry has emerged as
one of the leading approaches for protein charac­
terization and identification, and has become an
indispensable tool for many biological scientists.
Mass spectrometry is an analytical technique that
Keiryn Bennett and her small team have spent
considerable time and effort implementing and
developing in relation to the medical questions
at CeMM. It is a sensitive technique that actually
measures the physical properties of proteins.
Mass spectrometry can be used to identify the
individual protein components of complex
­biological samples. A mass spectrometer is a
Fig. 2
Ce — M­— M­— Research Report 2007
complex instrument that generates charged
ions ­(specific types of atoms or molecules)
Know
Yourself
from ­a sample, and separates these ions based
on a ­mass-to-charge ratio. Ions with a specific
mass-to-­charge ratio are detected and the infor­
mation ­collated to produce a mass spectrum.
Mass spectrometrists can then interpret the
spectrum and deduce the identity of the pro­
teins and therefore the content of the sample.
The capacity of mass spectrometry has increased
dramatically in the last few decades. Until the
1990’s, mass spectrometry was only able to
­characterize an individual protein from a fairly
pure sample. Significant advances in instrument
design and technology have led to dramatic
improvements in sensitivity and accuracy. With
the sequencing of the human genome, all pro­
teins and protein fragments can theoretically be
identified from a mass spectrum.
There still exists enormous potential for mass
spectrometry. The ultimate aim would of course
be to analyze entire human proteomes, including
modifications and in a quantitative manner,
with this technology. Such a goal is still far from
being realized. At CeMM, scientists have a par­
ticular interest in the molecular context that can
be identified using proteomics, the interactions
between proteins and the interactions between
drugs and their protein targets. In a scientific com­-
munity that is rapidly gaining knowledge and
understanding of cells and cellular function, the
aim of having a description of all proteins and
their interactions is not completely unattainable.
Technologies such as mass spectrometry are vital
in assisting in this quest.
Fig. 2 A mass spectrum
is a plot of mass-to-charge
(m/z) ratio versus fre-
quency. This plot shows
a tandem mass spectrum
of a ­doubly-charged ion at
m/z 560.31. The spectrum
was used to determine the
sequence of the peptide,
which reads from right to
left: D (I or L), A (I or L), A, T. Defend
Yourself
Control
Yourself
Treat
Yourself
Heal
Yourself
22 23
 Bioinformatics:
Making sense
of it all
“The process of Here the challenge at stake is formidable. Integra­
tion of knowledge can give scientists information
data analysis and on the makings of the body and its malfunctions,
interpretation to an extent never before dreamed possible.
has now become With the generation of new technologies, such
as mass spectrometry, comes the need to develop
as important as computer-based methods to analyze complex
the laboratory datasets. Many of the technologies used at CeMM
experiment itself.” generate large volumes of data. These data need
to be carefully examined to extract knowledge
of biological interest. Gone are the days when
biologists could get by with direct inspection
of each experimental result. The process of data
analysis and interpretation has now become
as important as the laboratory experiment itself.
“Sophisticated Bioinformatics is a relatively new field that
integrates informatics, computer science, and
data integration mathematics with biological sciences, such
can provide as genetics and cell biology. It can be applied
important new to data generated by many different ­methods,
and has been used to make valuable discoveries
insights into on diverse topics from the origin of species
­cellular functions to cell behavior and disease.
that will then
Jacques Colinge’s team manages data flow
drive new direc- and storage of data produced at CeMM through
tions for research.” distributed information systems that allow
automatic processing of batches of data com­
bined with quality control. For example, the data
generated by mass spectrometry is systematically
re-calibrated by an innovative algorithm before
being submitted to search sequence databases
in order to identify proteins present in biological
samples. In collaboration with the Swiss Insti­
tute of Bioinformatics (Swiss-Prot, PROSITE,
­Melanie, Phenyx, etc.), CeMM’s bioinformatics
team is developing a new database search algo­
rithm, which combined with the system in
place, will make it able to identify many more
proteins from a biological sample. There are
many other types of data that are managed by the
bioinformatics team, including sequencing and
microarray data.Microarrays are used to describe
the simultaneous activity of thousands of genes.
Ce — M­— M­— Research Report 2007
The bioinformatics platform and research are
focused towards the detection and analysis Fig. 1 Profiling of anti-
Know
Yourself
of molecular interactions. Once experimental cancer drugs. Proteomics
drug pulldown experi-
data has been generated, bioinformatics analysis ments reveal the targets
determines the statistical significance of the of three kinase inhibitors
(green) directed against
results and produces a verified dataset. For exam­ the oncogene fusion
ple, they have developed statistical models to protein Bcr-Abl (red) that
extract true molecular interactions from the mass is involved in chronic
myeloid leukemia, a cancer
spectrometry experiments at low and controlled of blood cells.
false discovery rates. Jacques team is interested
in translating the proteomics data generated by
multiple experiments into detailed molecular
networks describing physical interactions. They
use data generated at CeMM, particularly by
the group of Giulio Superti-Furga. There, strong
emphasis is put on identification of protein-
molecule interactions of several kinds: protein-
protein, drug-protein, and DNA/RNA-protein.
The platform makes it possible to integrate
­networks with existing similar public data
released by other laboratories with CeMM gene
expression data generated in collaboration with
the Medical University of Vienna. Using this
platform, it is possible for instance to relate the
effects of a drug treatment on gene expression
changes with the targets of the drug and newly
discovered protein networks to better under­
stand the treatment of leukemia (CML). The
team is currently working on the integration
of metabolomic, genomic and proteomic data
for specific CeMM projects.
Sophisticated data integration can provide
important new insights into cellular functions
that will then drive new directions for research.
The group plans to develop and extend the bio­
informatics platform at CeMM. The methods
set up by the bioinformatics team form a basis
forthe modeling and simulation of partial or
complete biological systems, which is an impor­
tant goal for the future.
Defend
Yourself
Control
Yourself
Treat
Yourself
Heal
Yourself
Ce — M­— M­— Research Report 2007 24 25
 Dr. Heinz Fischer
President of the Austrian Republic

Discovery is based on curiosity and execution of ideas. It is

satisfactory to see ideas turn into reality. The idea behind
the Center of Molecular Medicine was to bring science and
medicine close together and allow young scientists and medical
doctors to do innovative and interdisciplinary work together.
The realization of this idea through the location of a new
research institution on the grounds of the Vienna General
Hospital with its long and extraordinary tradition of medical
innovation is a wonderful opportunity to execute ideas into
medical practice. In the research process, cycles of frustrated
attempts and failures alternate with accomplishments and
successes. We wish the Center of Molecular Medicine of the
Austrian Academy of Sciences on the occasion of this inaugural
Research Report all possible successes and important discoveries.
We congratulate the Academy of Sciences as well as the
Scientific Director for establishing a new international research
institution that not only will tackle important medical prob­lems
but will also train young scientists for the important challenges
of the future.

Ce — M­— M­— Research Report 2007 Ce — M­— M­— Research Report 2007
 Defend
Know
Yourself

Defend
Yourself
Met –
Pro – His – Thr – Leu – Trp –
Met – Val – Trp – Val – Leu – Gly – Val – Ile – Ile – Ser – Leu –

Yourself
Ser – Lys – Glu – Glu – Ser – Ser –Asn –Gln –Ala –Ser –Leu –Ser –Cys –
Asp – Arg – Asn – Gly – Ile – Cys – Lys – Gly – Ser – Ser – Gly – Ser – Leu –Asn –Ser –
Ile –Pro –Ser –Gly –Leu –Thr –Glu – Ala – Val – Lys – Ser – Leu – Asp – Leu – Ser – Asn –
Asn – Arg – Ile – Thr – Tyr – Ile – Ser – Asn – Ser – Asp – Leu – Gln – Arg – Cys – Val – Asn – Leu –
Gln – Ala – Leu – Val – Leu – Thr – Ser – Asn –Gly –Ile –Asn –Thr –Ile –Glu –Glu –Asp –Ser –Phe –
Ser – Ser – Leu – Gly – Ser – Leu – Glu – His –Leu –Asp –Leu –Ser –Tyr –Asn –Tyr –Leu –Ser –Asn –
Leu –Ser –Ser –Ser –Trp –Phe –Lys – Pro –Leu –Ser –Ser –Leu –Thr –Phe –Leu –Asn –Leu –Leu –
Gly – Asn – Pro – Tyr – Lys – Thr – Leu – Gly – Glu – Thr – Ser – Leu – Phe – Ser – His – Leu – Thr –
Lys – Leu – Gln – Ile – Leu – Arg – Val – Gly – Asn – Met – Asp – Thr – Phe – Thr – Lys – Ile –
Gln – Arg – Lys – Asp – Phe – Ala –Gly –Leu –Thr –Phe –Leu –Glu –Glu –Leu –Glu –Ile –Asp –
Ala – Ser – Asp – Leu – Gln – Ser – Tyr – Glu – Pro – Lys – Ser – Leu – Lys – Ser – Ile – Gln – Asn – Val –
Ser – His – Leu – Ile – Leu – His – Met – Lys – Gln – His – Ile – Leu – Leu – Leu – Glu – Ile – Phe – Val – Asp –
Val – Thr – Ser – Ser – Val – Glu – Cys – Leu – Glu – Leu – Arg – Asp – Thr – Asp – Leu – Asp – Thr – Phe – His –
Phe – Ser – Glu – Leu – Ser – Thr – Gly – Glu – Thr – Asn – Ser – Leu – Ile – Lys – Lys – Phe – Thr – Phe – Arg – Asn –
Val – Lys – Ile – Thr – Asp – Glu – Ser – Leu – Phe – Gln – Val – Met – Lys – Leu – Leu – Asn – Gln – Ile – Ser – Gly –
Leu – Leu – Glu – Leu – Glu – Phe – Asp – Asp – Cys – Thr – Leu – Asn – Gly – Val – Gly – Asn – Phe – Arg – Ala – Ser –
Asp – Asn – Asp – Arg – Val – Ile – Asp – Pro – Gly – Lys – Val – Glu – Thr – Leu – Thr – Ile – Arg – Arg – Leu – His – Ile –
Pro – Arg – Phe – Tyr – Leu – Phe – Tyr – Asp – Leu –Ser –Thr –Leu –Tyr –Ser –Leu –Thr –Glu –Arg –Val –Lys –Arg –
Ile – Thr – Val – Glu – Asn – Ser – Lys – Val – Phe – Leu –Val –Pro –Cys –Leu –Leu –Ser –Gln –His –Leu –Lys –Ser –Leu –
Glu – Tyr – Leu – Asp – Leu – Ser – Glu – Asn – Leu – Met –Val –Glu –Glu –Tyr –Leu –Lys –Asn –Ser –Ala –Cys –Glu –Asp –
Ala –Trp –Pro –Ser –Leu –Gln –Thr –Leu –Ile –Leu –Arg –Gln –Asn –His –Leu –Ala –Ser –Leu –Glu –Lys –Thr –Gly –Glu –Thr –
Leu – Leu – Thr – Leu – Lys – Asn – Leu – Thr – Asn – Ile – Asp – Ile – Ser – Lys – Asn – Ser – Phe – His – Ser – Met – Pro – Glu –
For Defend Yourself we Thr –Cys –Gln –Trp –Pro –Glu –Lys –Met –Lys –Tyr –Leu –Asn –Leu –Ser –Ser –Thr –Arg –Ile –
His – Ser – Val – Thr – Gly – Cys – Ile – Pro – Lys – Thr – Leu – Glu – Ile – Leu – Asp – Val – Ser – + Innate Immunity: + Inflammation + Bacterial Toxins
chose the human Toll-like
receptor 2. It recognizes
Asn – Asn – Asn – Leu – Asn – Leu – Phe – Ser – Leu – Asn – Leu – Pro – Gln – Leu – Lys – Molecular Mechanisms
Glu – Leu – Tyr – Ile – Ser – Arg – Asn – Lys – Leu – Met – Thr – Leu – Pro – Asp – Ala – of Disease Recognition
bacteria at the cell surface
Ser – Leu – Leu – Pro – Met – Leu – Leu – Val – Leu – Lys – Ile – Ser – Arg – Asn –
and relays a signal that Ala – Ile – Thr – Thr – Phe – Ser – Lys – Glu – Gln – Leu – Asp – Ser – Phe – His –
elicits a set of cellular and Thr – Leu – Lys – Thr – Leu – Glu – Ala – Gly – Gly – Asn – Asn – Phe – Ile – Cys –
systemic responses to Ser – Cys – Glu – Phe – Leu – Ser – Phe – Thr – Gln – Glu – Gln – Gln – Ala – Leu –
fight a possible infection. Ala – Lys – Val – Leu – Ile – Asp – Trp – Pro – Ala – Asn – Tyr – Leu – Cys – Asp – Ser –
The Toll-like receptor Pro –Ser –His –Val –Arg –Gly –Gln –Gln –Val –Gln –Asp –Val –Arg –Leu –Ser –Val –
family are at the center Ser – Glu – Cys – His – Arg – Thr – Ala – Leu – Val – Ser – Gly – Met – Cys – Cys – Ala – Leu –
of CeMM’s research and Phe –Leu –Leu –Ile –Leu –Leu –Thr –Gly –Val –Leu –Cys –His –Arg –Phe –His –Gly –Leu – Trp – Tyr – Met –
are being studied in the Lys – Met – Met – Trp – Ala – Trp – Leu – Gln – Ala – Lys – Arg – Lys – Pro – Arg – Lys – Ala – Pro – Ser –Arg –Asn –Ile –Cys –
Knapp, Binder and Superti­- Tyr – Asp – Ala – Phe – Val – Ser – Tyr – Ser – Glu – Arg – Asp – Ala – Tyr – Trp – Val – Glu – Asn – Leu – Met – Val – Gln – Glu –
Furga laboratories. Leu –Glu –Asn –Phe –Asn –Pro –Pro –Phe –Lys –Leu –Cys –Leu –His –Lys –Arg –Asp –Phe –Ile – Pro – Gly – Lys – Trp – Ile – Ile –
Asp –Asn –Ile –Ile –Asp –Ser –Ile –Glu –Lys –Ser –His –Lys –Thr –Val –Phe –Val –Leu –Ser –Glu – Asn – Phe – Val – Lys – Ser –
Glu – Trp – Cys – Lys – Tyr – Glu – Leu – Asp – Phe – Ser – His – Phe – Arg – Leu – Phe – Asp – Glu – Asn – Asn – Asp – Ala – Ala – Ile –
TLR2_HUMAN Uniprot
Leu – Ile – Leu – Leu – Glu – Pro – Ile – Glu – Lys – Lys – Ala – Ile – Pro – Gln – Arg – Phe – Cys – Lys – Leu – Arg – Lys – Ile – Met – Asn –
O60603 Thr – Lys – Thr – Tyr – Leu – Glu – Trp – Pro – Met – Asp – Glu – Ala – Gln – Arg – Glu – Gly – Phe – Trp – Val – Asn – Leu – Arg –
Ala – Ala – Ile – Lys – Ser – +++ – Met – Pro – His – Thr – Leu – Trp – Met – Val – Trp – Val – Leu – Gly – Val – Ile – Ile – Ser – Leu –
Ser – Lys – Glu – Glu – Ser – Ser – Asn – Gln – Ala – Ser – Leu – Ser – Cys – Asp – Arg – Asn – Gly – Ile – Cys – Lys – Gly – Ser – Ser –
Gly – Ser – Leu – Asn – Ser – Ile – Pro – Ser – Gly – Leu – Thr – Glu – Ala – Val – Lys – Ser – Leu – Asp – Leu – Ser – Asn –Asn –Arg –
Ile –Thr –Tyr –Ile –Ser –Asn –Ser –Asp –Leu –Gln –Arg –Cys –Val –Asn –Leu –Gln –Ala –Leu –Val –Leu –Thr – Ser – Asn – Gly –
Ile – Asn – Thr – Ile – Glu – Glu – Asp – Ser – Phe – Ser – Ser – Leu – Gly – Ser – Leu – Glu – His – Leu – Asp – Leu – Ser – Tyr – Asn – Tyr –
Leu –Ser –Asn –Leu –Ser –Ser –Ser –Trp –Phe –Lys –Pro –Leu –Ser –Ser –Leu –Thr –Phe –Leu –Asn –Leu –Leu –Gly –Asn –Pro –Tyr –
Lys – Thr – Leu – Gly – Glu – Thr – Ser – Leu – Phe – Ser – His – Leu – Thr – Lys – Leu – Gln – Ile – Leu – Arg – Val – Gly – Asn – Met – Asp – Thr –
Phe – Thr – Lys – Ile – Gln – Arg – Lys – Asp – Phe – Ala – Gly – Leu – Thr – Phe – Leu – Glu – Glu – Leu – Glu – Ile – Asp – Ala – Ser – Asp – Leu –
Gln –Ser –Tyr –Glu –Pro –Lys –Ser –Leu –Lys –Ser –Ile –Gln –Asn –Val –Ser –His –Leu –Ile –Leu –His –Met –Lys –Gln –His –Ile –Leu –
Leu –Leu –Glu –Ile –Phe –Val –Asp –Val –Thr –Ser –Ser –Val –Glu –Cys –Leu –Glu –Leu –Arg –Asp –Thr –Asp –Leu –Asp –Thr –Phe –
His –Phe –Ser –Glu –Leu –Ser –Thr –Gly –Glu –Thr –Asn –Ser –Leu –Ile –Lys –Lys –Phe –Thr – Phe – Arg – Asn – Val – Lys – Ile –
Thr – Asp – Glu – Ser – Leu – Phe – Gln – Val – Met – Lys – Leu – Leu – Asn – Gln – Ile – Ser – Gly – Leu – Leu – Glu – Leu – Glu –
Phe –Asp –Asp –Cys –Thr –Leu –Asn –Gly –Val –Gly –Asn –Phe –Arg –Ala –Ser –Asp – Asn – Asp – Arg – Val –
Ile – Asp – Pro – Gly – Lys – Val – Glu – Thr – Leu – Thr – Ile – Arg – Arg – Leu – His – Ile – Pro – Arg – Phe –
Tyr – Leu – Phe – Tyr – Asp – Leu – Ser – Thr – Leu – Tyr – Ser – Leu – Thr – Glu – Arg – Val – Lys –
Arg –Ile –Thr –Val –Glu –Asn –Ser –Lys –Val –Phe –Leu –Val –Pro –Cys –Leu –Leu –
Ser – Gln – His – Leu – Lys – Ser – Leu – Glu – Tyr – Leu – Asp – Leu – Ser – Glu – Asn –
Leu –Met –Val –Glu –Glu –Tyr –Leu –Lys –Asn –Ser –Ala –Cys –Glu –Asp –Ala –Trp –
Pro – Ser – Leu – Gln – Thr – Leu – Ile – Leu – Arg – Gln – Asn – His – Leu – Ala – Ser –
Leu – Glu – Lys – Thr – Gly – Glu – Thr – Leu – Leu – Thr – Leu – Lys – Asn – Leu – Thr –
Asn –Ile –Asp –Ile –Ser –Lys –Asn –Ser –Phe –His –Ser –Met –Pro –Glu –Thr –Cys –
Gln –Trp –Pro –Glu –Lys –Met –Lys –Tyr –Leu –Asn –Leu –Ser –Ser –Thr –Arg –Ile –
His – Ser – Val – Thr – Gly – Cys – Ile – Pro – Lys – Thr – Leu – Glu – Ile – Leu – Asp – Val –
Ser – Asn – Asn – Asn – Leu – Asn – Leu – Phe – Ser – Leu – Asn – Leu – Pro – Gln – Leu –
Lys – Glu – Leu – Tyr – Ile – Ser – Arg – Asn – Lys – Leu – Met – Thr – Leu – Pro – Asp – Ala –
Ser –Leu –Leu –Pro –Met –Leu –Leu –Val –Leu –Lys –Ile –Ser –Arg –Asn –Ala –Ile –Thr –
Thr –Phe –Ser –Lys –Glu –Gln –Leu –Asp –Ser –Phe –His –Thr –Leu –Lys –Thr –Leu –Glu –
Ala – Gly – Gly – Asn – Asn – Phe – Ile – Cys – Ser – Cys – Glu – Phe – Leu – Ser – Phe – Thr – Gln –
Glu –Gln –Gln –Ala –Leu –Ala –Lys –Val –Leu –Ile –Asp –Trp –Pro –Ala –Asn –Tyr –Leu –Cys – Control
Asp – Ser – Pro – Ser – His – Val – Arg – Gly – Gln – Gln – Val – Gln – Asp – Val – Arg – Leu – Ser – Val – Yourself
Ser –Glu –Cys –His –Arg –Thr –Ala –Leu –Val –Ser –Gly –Met –Cys –Cys –Ala –Leu –Phe –Leu –
Leu –Ile –Leu –Leu –Thr –Gly –Val –Leu –Cys –His –Arg –Phe –His –Gly –Leu –Trp –Tyr –Met –
Lys –Met –Met –Trp –Ala –Trp –Leu –Gln –Ala –Lys –Arg –Lys –Pro –Arg –Lys –Ala –Pro –Ser –
Treat
Arg – Asn – Ile – Cys – Tyr – Asp – Ala – Phe – Val – Ser – Tyr – Ser – Glu – Arg – Asp – Ala – Tyr – Trp – Val – Yourself
Glu – Asn – Leu – Met – Val – Gln – Glu – Leu – Glu – Asn – Phe – Asn – Pro – Pro – Phe – Lys – Leu – Cys – Leu –
His –Lys –Arg –Asp –Phe –Ile –Pro –Gly –Lys –Trp –Ile –Ile –Asp –Asn –Ile –Ile –Asp –Ser –Ile –Glu –Lys –Ser –
His – Lys – Thr – Val – Phe – Val – Leu – Ser – Glu – Asn – Phe – Val – Lys – Ser – Glu – Trp – Cys – Lys – Tyr – Glu – Leu –
Asp – Phe – Ser – His – Phe – Arg – Leu – Phe – Asp – Glu – Asn – Asn – Asp – Ala – Ala – Ile – Leu – Ile – Leu – Leu – Glu – Heal
Pro –Ile –Glu –Lys –Lys –Ala –Ile –Pro –Gln –Arg –Phe –Cys –Lys –Leu –Arg –Lys –Ile –Met –Asn –Thr –Lys –Thr –Tyr –Leu – Yourself
Glu –Trp –Pro –Met –Asp –Glu –Ala –Gln –Arg –Glu –Gly –Phe –Trp –Val –Asn –Leu –Arg –Ala –Ala –Ile –Lys –Ser –+++ –Met –
Pro –His –Thr –Leu –Trp –Met –Val –Trp –Val –Leu –Gly –Val –Ile –Ile –Ser –Leu –Ser –Lys –Glu –Glu –Ser –Ser –Asn –Gln –Ala –Ser –
Leu –Ser –Cys –Asp –Arg –Asn –Gly –Ile –Cys –Lys –Gly –Ser –Ser –Gly –Ser –Leu –Asn –Ser –Ile –Pro –Ser –Gly –Leu –Thr –Glu –Ala –Val –
Lys – Ser – Leu – Asp – Leu – Ser – Asn – Asn – Arg – Ile – Thr – Tyr – Ile – Ser – Asn – Ser – Asp – Leu – Gln – Arg – Cys – Val – Asn – Leu – Gln – Ala – Leu –
Val –Leu –Thr –Ser –Asn –Gly –Ile –Asn –Thr –Ile –Glu –Glu –Asp –Ser –Phe –Ser –Ser –Leu –Gly –Ser –Leu –Glu –His –Leu –Asp –Leu –Ser –Tyr –Asn –
Tyr –Leu –Ser –Asn –Leu –Ser –Ser –Ser –Trp –Phe –Lys –Pro –Leu –Ser –Ser –Leu –Thr –Phe –Leu –Asn –Leu –Leu –Gly –Asn –Pro –Tyr –Lys –Thr –Leu –Gly –
The Fight
The remaining natural wildernesses of Africa
and Asia are home to many different populations
of wild animals. Nature documentaries allow
for Survival
us to witness the extraordinary interactions
between predator and prey, giving us a glimpse
of the unrelenting drive of evolution. It is a
world of survival of the fittest. Over millions
of years, the predators have developed distinc­
The goal is to understand the molecular mechanisms by which tive characteristics that make them efficient
pathogens invade our bodies and how our bodies react to them, hunters, including great power and strength,
to strengthen our fight against disease. and sharp teeth for attacking and devouring
their victims. To avoid being easy targets, the
other animals have evolved their own strategies
for survival by living in large groups and keep­
ing a careful watch for approaching danger.
Our bodies provide the setting for some of
nature’s fiercest battles, that between health
and disease. As the host, we have evolved a
sophisticated immune system with which to
defend our bodies from invasion by pathogens.
This immune system is made up of many dif­
ferent components: small molecules, proteins,
cells and organs, which provide a collective
group of defense mechanisms to protect us
against infection. They cover all aspects of
disease control, from identification to eventual
elimination. Unfortunately, new diseases are
continually evolving alternative strategies for
attacking our bodies. They devise ways to hide
from our immune system so that we are unable
to find and destroy them. Our bodies need to
constantly adapt to keep them from taking over.
When a pathogenic microorganism enters the
body, our front-line of defense is the innate
immune system. It is activated within hours after
an infection and works by inducing an inflamma­
tory response to stop microorganisms from freely
growing inside our bodies. In most cases, this
response is sufficient to clear the infection. Some­
times, however, a more specialized response,
known as the adaptive immune response, may
be required for complete removal of the patho­
gen. The innate immune system relies on many
different types of cells, which are found in the
blood. Phagocytes are cells that detect and engulf
pathogens, and help to coordinate other defense
responses of the body, such as inflammation.
Ce — M­— M­— Research Report 2007
To mount a successful defense, the innate
immune system must first recognize that the
body has been invaded. This isn’t quite as
straight­forward as one might think. There are an
enormous variety of different pathogens, with
high replication and mutation rates that enable
them to constantly change and adapt quickly
to our defenses. Discovering a relatively small
number of pathogens, which have evolved many
crafty ways of surviving unnoticed in the body,
requires a sophisticated detection system. It’s
essentially a microscopic game of hide-and-seek.
Our bodies are patrolled by cells of the immune
system, which randomly come into contact
with hundreds of different types of cells. Most
of these cells are part of the host i.e. self, but
when they encounter an invading microbe that
they have probably never seen before, they
need to be able to immediately recognize it as
a non-self cell so that it can be destroyed.
Recognition of non-self cells by the innate
immune system involves identifying molecules
that are unique to pathogens and are not found
in the host. Using surface receptors, cells of the
innate immune system recognize features that are
found on many pathogens, so called pathogen-
associated molecular patterns (PAMPs). Although
there are different types of PAMPs, importantly
they retain enough similarity within a specific
class of pathogen, to be used as a reliable method
for detection. Receptors of the innate immune
system, known as Pattern Recognition Receptors
(PRRs), recognize these PAMPs and raise the alarm
by activating the immune response.
Ce — M­— M­— Research Report 2007
Identifying and understanding this recognition Know
Yourself
mechanism is a relatively new topic for research­
ers and there is still much to be learnt. The groups
of Giulio Superti-Furga and Sylvia Knapp at Defend
CeMM are investigating the molecular compo­ Yourself
nents of the recognition machinery. Of course,
realizing that there is an invasion is only the
beginning. “A cascade of biochemical events is
triggered on recognition of an invading pathogen
by a host cell”, says Giulio. They are using a vari­
ety of techniques to discover what this is and
how it signals to the rest of the immune system.
Some pathogens, particularly viruses, actually
enter our cells, which means that we also need
intracellular defense mechanisms toeliminate
them. Viruses tend to hijack a cell and take over
control, using host functions to propagate and
continue infecting other cells and organisms.
Once a virus has taken over a cell, it is virtually
impossible to regain control, the preferred option
being to eliminate the infected cell, along with
the intruder. “When viruses and viral compo­
nents enter a cell, we want to know what they
bind to and what molecules and proteins they
need in order to take over control”, says Giulio,
whose group is focusing on figuring out how this
works.
Understanding the molecular mechanisms of
­disease and immune responses can help strength­
en our body’s own ability to defend itself, and
gives us the opportunity to develop therapeutics
to act as reinforcements for maintaining health.
After all, knowledge is half the battle. “Although
our general objectives are in furthering the
understanding of clinically relevant pathogens,
our primary aim is to improve current diagnostic
procedures and ultimately influence therapies
and survival …”, says Sylvia. It is unlikely that
our immune system will ever be completely
victorious over all the pathogens that can cause
human diseases. However, we’re putting up a
good fight, and of course it’s not really about win­
ning. It’s far more important to stay in the game.
Control
Yourself
Treat
Yourself
Heal
Yourself
30 31
 Innate Immunity:
Molecular
Mechanisms
of Disease
Recognition
Cell Detectives
The first challenge facing our bodies is to recog­
nize when we have been invaded. We need
an early warning system so we can assemble our
defenses and fight. Unfortunately, pathogens
don’t infect our bodies in broad daylight by
“The aim is to marching up to the front gates and knocking
­create a protein- loudly. They slip in, unnoticed through the back
binding map of door. It’s up to our body to find them and raise
the alarm. Scientists now understand at least one
the cell, containing of the main principles behind the recognition
­all the proteins of pathogens by the innate immune system, and
involved in reco- that is the interaction between PAMPs (patterns
from the microorganism) and PRRs (receptors
gnizing a specific on our defense cells). However, for many patho­
pathogen and gens that pose a significant threat to human
generating the health, we still don’t understand what the pat­
terns are and which receptors bind to them. Sylvia
subsequent cellular Knapp and Giulio Superti-Furga are working on
response.” filling in those missing details at CeMM.
Toll-like receptors (TLRs) are a large family
of PRRs (pattern recognition receptor) that
detect invading material in the body. They are
essential components of our innate immune
system, and are thought to be part of the reason
why some individuals are more vulnerable
to disease. Christoph Baumann and Tilmann
Buerckstummer, both Post-docs in Giulio’s lab,
are trying to understand how these, and other
surface receptors, work. These proteins are part
of a large intracellular signaling network, which
is very complex. To get a handle on how this is
organized, Giulio’s group is taking a physical
approach. Using a starting protein, such as a TLR,
they try to determine which other proteins or
molecules it physically associates with. “Essen­
tially, we go fishing in the cell”, explains Tilmann.
“Proteins that bind to each other are often part of
the same signaling network, and therefore have
similar functions”. The aim is to create a protein-
binding map of the cell, containing all the pro­
teins involved in recognizing a specific pathogen
and generating the subsequent cellular response.
Ce — M­— M­— Research Report 2007
Sylvia’s group is also interested in the intracel­
lular signaling cascades that are activated in cells
Sylvia has already studied CD14, LBP and Toll-
like receptors (e.g. TLR2), which are known PRRs
Her group is also studying another PRR, known
as Trem-1. They are interested in how it works
Know
Yourself
during infection. PI3K is a protein kinase, which
is a type of protein that can radically alter the
that recognize pneumococci, in mouse models
of pneumonia. Her group is now interested in
during bacterial infections in vivo. “There seems
to be a connection between Trem-1 activation Defend
function of other proteins by adding a chemical,
phosphorylation group to them. PI3K is an
co-receptors for TLR2. TLR2 is known to bind the
ligand LTA, which is found on the cell wall of a
and inflammation, which we still don’t fully
understand”, explains Sylvia. They have pre­
Yourself
important component of many signal transduc­
tion pathways that are used to translate cellular
large group of bacteria known as Gram-positive
bacteria. However, it seems that the LTA ligand
viously shown that TLR2 contributes to the
inflammatory response during pneumococcal
signals into specific cellular responses. Infection
is one such signal that is thought to trigger PI3K
activation, although its precise function during
on S. pneumoniae is quite unique. It contains a
chemical modification that they believe is impor­
tant for this distinctive function, which they are
pneumonia. Inflammation is an early and critical
response by the body to infection. It is caused
by increased blood flow to the infected tissue,
bacterial infection, especially within the lungs, currently investigating. which is triggered by chemical factors that are
is quite controversial. “We don’t know how criti­ released by the injured cells. Inflammation acts
cal it is for the cellular response to infection …”, as a signal to recruit cells that can fight infection
says Sylvia, who is developing specific mouse and heal damaged tissues (see also below).
models of disease to answer this question.
Other cellular receptors recognize pathogens that
actually invade our cells. Viruses and bacteria, Fig. 1 The immunofluores­
like human cells, are programmed by genes that cence analysis shows a
newly discovered modula-
are encoded by nucleic acids, in the form of either tor of IFN-beta production,
NLS
DNA or RNA. These nucleic acids need to be
copied many times in order to make new patho­
a protein activated in
response to pathogenic
NLS
gens, and this can be achieved by using cellular
infections. The modulator
shuttles between two
proteins that are normally used to copy our own separate compartments
in the cell, the nucleus
DNA. Internal receptors are used to recognize
NES
and the cytosol. Nuclear
these types of molecular invaders and researchers entry is mediated by a
in Giulio’s lab are using the same physical NES
nuclear localization signal
(NLS) and nuclear export
approach­es to identify what they are and how is medi­ated by a nuclear
they work. ­e xport signal (NES).
Where­a s the wild-type
Sylvia has been working for some time on the
(wt) protein is predomi-
nantly cytosolic (top left
molecular basis of pneumonia. Community-
wt
image), mutation of the
NES (L12A and L21A)
acquired pneumonia is primarily caused by the NES leads to its accumulation
bacteria Streptococcus pneumoniae. There are in the nucleus (bottom
left images).
an estimated 570,000 cases of pneumococcal
pneumonia every year in the USA alone, and of
these around 175,000 require hospital treatment.
It is a major cause of morbidity and mortality in
L12A
humans. The regular treatment for pneumococcal
pneumonia is antibiotics. However, as so often NES
happens, the bacteria are responding by develop­
ing resistance to these drugs. “The situation is
looking pretty dire …”, says Sylvia, “and this has
prompted renewed urgency in understanding the
molecular mechanisms of this dangerous disease.” L21A
NES
Control
Yourself
Treat
Yourself
Heal
Yourself
Ce — M­— M­— Research Report 2007 32 33
 Inflammation Sylvia also thinks we may be able to utilize OxPL
to work for us and fight diseases caused by intra­
cellular pathogens. “We want to understand
Bacterial Toxins Fig. 3—4 Two light micro-
scope images of mouse
Know
Yourself

lungs. Each cell (blue)

Double-edged Sword
The inflammatory response is a very powerful
defense mechanism against disease. It is the pri­
mary reason we feel pain upon injury and infec­
tion, and it also causes other symptoms including
“Once the molecular redness and swelling. Work at CeMM is focused
effects of toxins on understanding the molecular mediators of
inflammation. Uncontrolled inflammation can
are known, the also cause serious disease, and so the body tightly
goal will be to regulates it. Christoph Binder, an independent
design drugs to researcher at CeMM, is studying the molecular
mechanisms of atherosclerosis, which is a chronic
stop them causing inflammatory disease of the vasculature, and
harm.” the underling cause for heart attacks and stroke.
During the inflammatory response, cells of the
innate immune system, known as phagocytes,
attack bacteria by generating reactive oxygen
species. These free radicals can also damage cells,
subsequently generating oxidized phospholipids
(OxPL). OxPL are considered to be endogenous
mediators of inflammation, however the biologi­
cal functions of this highly diverse class of lipids
are not well understood. Recently, Sylvia has
shown that a specific type of OxPL, such as those
produced during inflammation, actually impair
the immune response by inhibiting the function
of phagocytes. This work was published in the
Journal of Immunology in 2007, and is being used
as the foundation for future studies on OxPL in
the Knapp lab.
more about the role of OxPL specifically during
bacterial infections, which at the moment is
entirely unknown”, says Sylvia. OxPL are also
important mediators of atherosclerosis. Athero­
sclerosis is characterized by the accumulation of
oxidized LDL (OxLDL) in the walls of the arteries.
Inflammation is a known contributor to the prog­
ress of the disease, and there is increasing evidence
that certain other immune responses can also
affect atherogenesis. Christoph Binder has been
involved in developing this line of research in
the last five years, and is now investigating it in
his own lab at CeMM (see Heal Yourself).
Ventilator-associated pneumonia (VAP) is
the most serious and most frequent hospital-
acquired infection, affecting 20% of patients in
intensive care units (ICU). It is a treatable disease,
however mortality rates of up to 60% have been
reported, and we are losing the battle predomi­
nantly due to an inability to detect it early enough.
“Non-specific clinical signs as well as the lack
of appropriate biomarkers often delay diagnosis
and treatment”, explains Sylvia. “We intend to
examine local inflammation in ventilated ICU
patients to search for specific biomarkers which
will enable us to detect the presence of the disease
early enough for treatment to be effective”.
has a darker stained Defend
nucleus. The lungs on the Yourself
bottom are infected with
Many pathogens produce poisonous toxins that ­Streptococcus pneumoniae
can cause serious harm to the host. In some cases, bacteria. IRAK-M, which
these toxins are so powerful that they can even is induced upon bacterial
infection, was detected
cause the death of a human being. Pore-forming by labeling with antibodies
toxins are a group of potent toxins associated (brown).
with virulent bacteria such as Clostridium
perfringens and Staphylococcus aureus. These
bacteria cause many serious human diseases.
S. aureus is actually the second most common
pathogen isolated from people and causes a wide
range of symptoms, from relatively minor skin
infections to deadly pneumonia. However, for
many pore-forming toxins, we know next to
nothing about how they work.
“We want to know exactly what it is about these
toxins that cause such a dramatic effect on the
human body …”, says Sylvia. Her group plans
to break down toxins into smaller components
to help understand how they work. “We want
to know which cells they target in the body, how
they interact with those cells, and what effects Fig. 5 Fluoresence
they have on cellular function.” To really under­ ­microscope image show-
ing phagocytosis (“cell
stand how a toxin works when it infects a bio­ eating”) of Streptococcus
logical organism, they are also developing animal pneumoniae (yellow) by
two alveolar macrophages
models of disease. Then they can study toxins (lysosomes are stained
in their natural environment. Once the molecular red, the nucleus in blue),
effects of toxins are known, the goal will be to which are defense cells
of the innate immune
design drugs to stop them causing harm. system.

Fig. 1 and 2 Streptococcus Fig. 1 Fig. 2 Fig. 6 Fluoresence

­pneumoniae bacterial ­microscope image of a
colonies growing on blood macrophage (actin fibers
agar plates. in the cell are stained
green), that has been
incubated with oxidized
lipids which causes
damage to the cell.

Control
Yourself

Treat
Yourself

Heal
Yourself

Ce — M­— M­— Research Report 2007 Ce — M­— M­— Research Report 2007 34 35
 Dr. Johannes Hahn
Federal Minister for Science and Research

It is a pleasure for me to accompany the first Research Report

of the Center of Molecular Medicine (CeMM) of the Austrian
Academy of Science with my best wishes and some introducing
words.
For our Government Science and Research are of high impor-
tance regarding preparing a “knowledge and information
society” to reach the Lisbon research quota goals as quick as
possible. Science at the interface to medicine is my personal
priority and of particular importance for our society.
CeMM seems to me like a long wanted and very special child.
It has been a rather delicate gestation, but the extraordinary
collaborative will of the City of Vienna, the Austrian Academy
of Science, the Medical University of Vienna and the Ministry
of Science and Research has successfully brought up a unique
institution that promises to change the way basic biomedical
research and clinical requirements are integrated. I know the
young team of international investigators already assembled
at CeMM personally and trust their energy and vision.
We will accompany and support CeMM and expect that it
will become a model for biomedical translational research in
our country. We wish Giulio Superti-Furga, all the Principal
Investigators and all CeMM Scientists success in their research
endeavors.

Ce — M­— M­— Research Report 2007 Ce — M­— M­— Research Report 2007 36 37
 Control
For Control Yourself we Know
chose the human p53 pro­ Yourself
Met – Glu –
tein, a tumor suppressor
Glu –Pro –Gln –Ser –Asp –Pro –
that has been designated
Ser – Val – Glu – Pro – Pro – Leu – Ser – Gln –
the “guardian of the Defend
Glu – Thr – Phe – Ser – Asp – Leu – Trp – Lys – Leu –
genome” as it coordinates Yourself
Leu –Pro –Glu –Asn –Asn –Val –Leu –Ser –Pro –Leu –Pro –
the control of the cell-cycle
Ser – Gln – Ala – Met – Asp – Asp – Leu – Met – Leu – Ser – Pro –
and genome repair. It is
Asp – Asp – Ile – Glu – Gln – Trp – Phe – Thr – Glu – Asp – Pro – Gly –
one of the proteins more
Pro –Asp –Glu –Ala –Pro –Arg –Met –Pro –Glu –Ala –Ala –Pro –Pro –

Yourself
often mutated in cancer Control
Val – Ala – Pro – Ala – Pro – Ala – Ala – Pro – Thr – Pro – Ala – Ala – Pro – Yourself
and relates to the research
Ala – Pro – Ala – Pro – Ser – Trp – Pro – Leu – Ser – Ser – Ser – Val – Pro –
of Sebastian Nijman and
Ser – Gln – Lys – Thr – Tyr – Gln – Gly – Ser – Tyr – Gly – Phe – Arg – Leu –
Robert Kralovics. The
Gly – Phe – Leu – His – Ser – Gly – Thr – Ala – Lys – Ser – Val – Thr – Cys –
second sequence is the
Thr –Tyr –Ser –Pro –Ala –Leu –Asn –Lys –Met –Phe –Cys –Gln –Leu –
p53 related protein p73.
Ala – Lys – Thr – Cys – Pro – Val – Gln – Leu – Trp – Val – Asp – Ser – Thr –
Pro – Pro – Pro – Gly – Thr – Arg – Val – Arg – Ala – Met – Ala – Ile – Tyr –
P53_HUMAN Uniprot Lys – Gln – Ser – Gln – His – Met – Thr – Glu – Val – Val – Arg – Arg – Cys –
P04637 Pro –His –His –Glu –Arg –Cys –Ser –Asp –Ser –Asp –Gly –Leu –Ala –
Pro – Pro – Gln – His – Leu – Ile – Arg – Val – Glu – Gly – Asn – Leu –
P73_HUMAN Uniprot Arg – Val – Glu – Tyr – Leu – Asp – Asp – Arg – Asn – Thr – Phe –
O15350 Arg – His – Ser – Val – Val – Val – Pro – Tyr – Glu – Pro – Pro –
Glu –Val –Gly –Ser –Asp –Cys –Thr –Thr –Ile –His –Tyr –
Asn – Tyr – Met – Cys – Asn – Ser – Ser – Cys – Met –
Gly – Gly – Met – Asn – Arg – Arg – Pro – Ile – Leu –
Thr – Ile – Ile – Thr – Leu – Glu – Asp – Ser – Ser –
Gly – Asn – Leu – Leu – Gly – Arg – Asn – Ser –
Phe –Glu –Val –Arg –Val –Cys –Ala –Cys –Pro –
Gly – Arg – Asp – Arg – Arg – Thr – Glu – Glu – Glu –
Asn – Leu – Arg – Lys – Lys – Gly – Glu – Pro – His – His – Glu –
Leu – Pro – Pro – Gly – Ser – Thr – Lys – Arg – Ala – Leu – Pro – Asn –
Asn – Thr – Ser – Ser – Ser – Pro – Gln – Pro – Lys – Lys – Lys – Pro – Leu – + Genetics and + Hematological
Asp – Gly – Glu – Tyr – Phe – Thr – Leu – Gln – Ile – Arg – Gly – Arg – Glu – Arg –
Phe – Glu – Met – Phe – Arg – Glu – Leu – Asn – Glu – Ala – Leu – Glu – Leu – Lys –
Epigenetics of Cancer Malignancies
Asp –Ala –Gln –Ala –Gly –Lys –Glu –Pro –Gly –Gly –Ser –Arg –Ala –His –Ser –Ser –
His –Leu –Lys –Ser –Lys –Lys –Gly –Gln –Ser –Thr –Ser –Arg –His –Lys –Lys –Leu –Met –
Phe – Lys – Thr – Glu – Gly – Pro – Asp – Ser – Asp – +++ – Met – Ala – Gln – Ser – Thr – Ala – Thr –
Ser –Pro –Asp –Gly –Gly –Thr –Thr –Phe –Glu –His –Leu –Trp –Ser –Ser –Leu –Glu –Pro –Asp –Ser –
Thr –Tyr –Phe –Asp –Leu –Pro –Gln –Ser –Ser –Arg –Gly –Asn –Asn –Glu –Val –Val –Gly –Gly –Thr –Asp –
Ser – Ser – Met – Asp – Val – Phe – His – Leu – Glu – Gly – Met – Thr – Thr – Ser – Val – Met – Ala – Gln – Phe – Asn – Leu –
Leu – Ser – Ser – Thr – Met – Asp – Gln – Met – Ser – Ser – Arg – Ala – Ala – Ser – Ala – Ser – Pro – Tyr – Thr – Pro – Glu – His – Ala –
Ala –Ser –Val –Pro –Thr –His –Ser –Pro –Tyr –Ala –Gln –Pro –Ser –Ser –Thr –Phe –Asp –Thr –Met –Ser –Pro –Ala –Pro –Val –Ile –
Pro – Ser – Asn – Thr – Asp – Tyr – Pro – Gly – Pro – His – His – Phe – Glu – Val – Thr – Phe – Gln – Gln – Ser – Ser – Thr – Ala – Lys – Ser – Ala – Thr –
Trp – Thr – Tyr – Ser – Pro – Leu – Leu – Lys – Lys – Leu – Tyr – Cys – Gln – Ile – Ala – Lys – Thr – Cys – Pro – Ile – Gln – Ile – Lys – Val – Ser – Thr – Pro – Pro –
Pro –Pro –Gly –Thr –Ala –Ile –Arg –Ala –Met –Pro –Val –Tyr –Lys –Lys –Ala –Glu –His –Val –Thr –Asp –Val –Val –Lys –Arg –Cys –Pro –Asn –His –Glu –
Leu –Gly –Arg –Asp –Phe –Asn –Glu –Gly –Gln –Ser –Ala –Pro –Ala –Ser –His –Leu –Ile –Arg –Val –Glu –Gly –Asn –Asn –Leu –Ser –Gln –Tyr –Val –Asp –
Asp –Pro –Val –Thr –Gly –Arg –Gln –Ser –Val –Val –Val –Pro –Tyr –Glu –Pro –Pro –Gln –Val –Gly –Thr –Glu –Phe –Thr –Thr –Ile –Leu –Tyr –Asn –Phe –Met –
Cys –Asn –Ser –Ser –Cys –Val –Gly –Gly –Met –Asn –Arg –Arg –Pro –Ile –Leu –Ile –Ile –Ile –Thr –Leu –Glu –Met –Arg –Asp –Gly –Gln –Val –Leu –Gly –Arg –Arg –
Ser –Phe –Glu –Gly –Arg –Ile –Cys –Ala –Cys –Pro –Gly –Arg –Asp –Arg –Lys –Ala –Asp –Glu –Asp –His –Tyr –Arg –Glu –Gln –Gln –Ala –Leu –Asn –Glu –Ser –Ser –
Ala –Lys –Asn –Gly –Ala –Ala –Ser –Lys –Arg –Ala –Phe –Lys –Gln –Ser –Pro –Pro –Ala –Val –Pro –Ala –Leu –Gly –Ala –Gly –Val –Lys –Lys –Arg –Arg –His –Gly –Asp –
Glu – Asp – Thr – Tyr – Tyr – Leu – Gln – Val – Arg – Gly – Arg – Glu – Asn – Phe – Glu – Ile – Leu – Met – Lys – Leu – Lys – Glu – Ser – Leu – Glu – Leu – Met – Glu – Leu – Val – Pro –
Gln –Pro –Leu –Val –Asp –Ser –Tyr –Arg –Gln – Gln – Gln – Gln – Leu – Leu – Gln – Arg – Pro – Ser – His – Leu – Gln – Pro – Pro – Ser – Tyr – Gly – Pro – Val – Leu – Ser – Pro –
Met – Asn – Lys – Val – His – Gly – Gly – Met – Asn – Lys – Leu – Pro – Ser – Val – Asn – Gln – Leu – Val – Gly – Gln – Pro – Pro – Pro – His – Ser – Ser – Ala – Ala – Thr – Pro –
Asn – Leu – Gly – Pro – Val – Gly – Pro – Gly – Met – Leu – Asn – Asn – His – Gly – His – Ala – Val – Pro – Ala – Asn – Gly – Glu – Met – Ser – Ser – Ser – His – Ser – Ala – Gln –
Ser – Met – Val – Ser – Gly – Ser – His – Cys – Thr – Pro – Pro – Pro – Pro – Tyr – His – Ala – Asp – Pro – Ser – Leu – Val – Ser – Phe – Leu – Thr – Gly – Leu – Gly – Cys – Pro –
Asn – Cys – Ile – Glu – Tyr – Phe – Thr – Ser – Gln –Gly –Leu –Gln –Ser –Ile –Tyr –His –Leu –Gln –Asn –Leu –Thr –Ile –Glu –Asp –Leu –Gly –Ala –Leu –Lys –Ile –Pro –
Glu –Gln –Tyr –Arg –Met –Thr –Ile –Trp – Arg –Gly –Leu –Gln –Asp –Leu –Lys –Gln –Gly –His –Asp –Tyr –Ser –Thr –Ala –Gln –Gln –Leu –Leu –Arg –Ser –Ser –
Asn –Ala –Ala –Thr –Ile –Ser –Ile –Gly – Gly – Ser – Gly – Glu – Leu – Gln – Arg – Gln – Arg – Val – Met – Glu – Ala – Val – His – Phe – Arg – Val – Arg – His – Thr – Ile –
Thr – Ile – Pro – Asn – Arg – Gly – Gly – Pro –Gly –Gly –Gly –Pro –Asp –Glu –Trp –Ala –Asp –Phe –Gly –Phe –Asp –Leu –Pro –Asp –Cys –Lys –Ala –Arg –Lys –
Gln – Pro – Ile – Lys – Glu – Glu – Phe – Thr –Glu –Ala –Glu –Ile –His –+++ –Met –Glu –Glu –Pro –Gln –Ser –Asp –Pro –Ser –Val –Glu –Pro –Pro –Leu –Ser –
Gln – Glu – Thr – Phe – Ser – Asp – Leu – Trp – Lys – Leu – Leu – Pro – Glu – Asn – Asn – Val – Leu – Ser – Pro – Leu – Pro – Ser – Gln – Ala – Met – Asp – Asp – Leu –
Met –Leu –Ser –Pro –Asp –Asp –Ile –Glu – Gln – Trp – Phe – Thr – Glu – Asp – Pro – Gly – Pro – Asp – Glu – Ala – Pro – Arg – Met – Pro – Glu – Ala – Ala – Pro – Pro –
Val – Ala – Pro – Ala – Pro – Ala – Ala – Pro – Thr –Pro –Ala –Ala –Pro –Ala –Pro –Ala –Pro –Ser –Trp –Pro –Leu –Ser –Ser –Ser –Val –Pro – Ser –Gln –Lys –Thr –
Tyr – Gln – Gly – Ser – Tyr – Gly – Phe – Arg – Leu –Gly –Phe –Leu –His –Ser –Gly –Thr –Ala –Lys –Ser –Val –Thr –Cys –Thr –Tyr –Ser – Pro – Ala – Leu –
Asn – Lys – Met – Phe – Cys – Gln – Leu – Ala – Lys – Thr – Cys – Pro – Val – Gln – Leu – Trp – Val – Asp – Ser – Thr – Pro – Pro – Pro – Gly –Thr –Arg –Val –
Arg – Ala – Met – Ala – Ile – Tyr – Lys – Gln – Ser – Gln – His – Met – Thr – Glu – Val – Val – Arg – Arg – Cys – Pro – His – His – Glu – Arg – Cys –Ser –Asp –Ser –
Asp – Gly – Leu – Ala – Pro – Pro – Gln – His – Leu –Ile –Arg –Val –Glu –Gly –Asn –Leu –Arg –Val –Glu –Tyr –Leu –Asp –Asp –Arg – Asn – Thr – Phe –
Arg – His – Ser – Val – Val – Val – Pro – Tyr – Glu –Pro –Pro –Glu –Val –Gly –Ser –Asp –Cys –Thr –Thr –Ile –His –Tyr –Asn –Tyr –Met –Cys –Asn –Ser –Ser –
Cys – Met – Gly – Gly – Met – Asn – Arg – Arg –Pro –Ile –Leu –Thr –Ile –Ile –Thr –Leu –Glu –Asp –Ser –Ser –Gly –Asn –Leu –Leu –Gly –Arg –Asn –Ser –
Phe –Glu –Val –Arg –Val –Cys –Ala –Cys –Pro –Gly –Arg –Asp –Arg –Arg –Thr –Glu –Glu –Glu –Asn –Leu –Arg –Lys –Lys –Gly –Glu –Pro –His –His –
Glu –Leu –Pro –Pro –Gly –Ser –Thr –Lys –Arg –Ala –Leu –Pro –Asn –Asn –Thr –Ser –Ser –Ser –Pro –Gln –Pro –Lys –Lys –Lys –Pro –Leu –Asp –
Gly –Glu –Tyr –Phe –Thr –Leu –Gln –Ile –Arg –Gly –Arg –Glu –Arg –Phe –Glu –Met –Phe –Arg –Glu –Leu –Asn –Glu –Ala –Leu –Glu –
Leu –Lys –Asp –Ala –Gln –Ala –Gly –Lys –Glu –Pro –Gly –Gly –Ser –Arg –Ala –His –Ser –Ser –His –Leu –Lys –Ser –Lys –Lys –
Gly – Gln – Ser – Thr – Ser – Arg – His – Lys – Lys – Leu – Met – Phe – Lys – Thr – Glu – Gly – Pro – Asp – Ser – Asp – +++ –
Met –Ala –Gln –Ser –Thr –Ala –Thr –Ser –Pro –Asp –Gly –Gly –Thr –Thr –Phe –Glu –His –Leu –Trp –Ser –
Ser – Leu – Glu – Pro – Asp – Ser – Thr – Tyr – Phe – Asp – Leu – Pro – Gln – Ser – Ser – Arg – Gly –
Asn – Asn – Glu – Val – Val – Gly – Gly – Thr – Asp – Ser – Ser – Met – Asp – Val – Phe – His –
Leu – Glu – Gly – Met – Thr – Thr – Ser – Val – Met – Ala – Gln – Phe – Asn – Leu – Leu – Ser –
Ser –Thr –Met –Asp –Gln –Met –Ser –Ser –Arg –Ala –Ala –Ser –Ala –Ser –Pro –Tyr –Thr –
Pro –Glu –His –Ala –Ala –Ser –Val –Pro –Thr –His –Ser –Pro –Tyr –Ala –Gln –Pro –Ser –Ser – Treat
Thr – Phe – Asp – Thr – Met – Ser – Pro – Ala – Pro – Val – Ile – Pro – Ser – Asn – Thr – Asp – Tyr – Yourself
Pro –Gly –Pro –His –His –Phe –Glu –Val –Thr –Phe –Gln –Gln –Ser –Ser –Thr –Ala –Lys –Ser –
Ala – Thr – Trp – Thr – Tyr – Ser – Pro – Leu – Leu – Lys – Lys – Leu – Tyr – Cys – Gln – Ile – Ala – Lys –
Thr –Cys –Pro –Ile –Gln –Ile –Lys –Val –Ser –Thr –Pro –Pro –Pro –Pro –Gly –Thr –Ala –Ile –Arg –
Ala –Met –Pro –Val –Tyr –Lys –Lys –Ala –Glu –His –Val –Thr –Asp –Val –Val –Lys –Arg –Cys –Pro – Heal
Yourself
Asn – His – Glu – Leu – Gly – Arg – Asp – Phe – Asn – Glu – Gly – Gln – Ser – Ala – Pro – Ala – Ser – His –
Leu – Ile – Arg – Val – Glu – Gly – Asn – Asn – Leu – Ser – Gln – Tyr – Val – Asp – Asp – Pro – Val – Thr –
Gly –Arg –Gln –Ser –Val –Val –Val –Pro –Tyr –Glu –Pro –Pro –Gln –Val –Gly –Thr –Glu –Phe –Thr –
Thr – Ile – Leu – Tyr – Asn – Phe – Met – Cys – Asn – Ser – Ser – Cys – Val – Gly – Gly – Met – Asn – Arg –
Arg – Pro – Ile – Leu – Ile – Ile – Ile – Thr – Leu – Glu – Met – Arg – Asp – Gly – Gln – Val – Leu – Gly – Arg –
Arg –Ser –Phe –Glu –Gly –Arg –Ile –Cys –Ala –Cys –Pro –Gly –Arg –Asp –Arg –Lys –Ala –Asp –Glu –
Maintaining The public transport system in Vienna is incred­
ibly well organized. With five underground lines,
and 80 bus and 31 tram lines covering 24 hours
Biological
of the day, it enables the people of Vienna to get
almost anywhere in the city easily and quickly.
This transport network requires a high level of
control to manage the individual parts of the
Order
system and ensure it works efficiently as a whole.
Any disturbances, such as a technical malfunction
or an obstacle on the line, can be easily dealt with,
and the system quickly returned to full capacity.
Understanding and exploiting the processes by which cells
All systems and organizations are under some
and tissues maintain their properties and don’t lose identity
degree of control. This control is in place to direct
or over-proliferate to form diseases such as cancer.
and regulate the behavior of the system and
ensure it works as well as possible. However,
the control of a city’s transport system is nothing
compared to the level of control that goes into
the production and maintenance of life. “Our
internal checkpoints and controls are vital to
maintain a healthy body”, explains Giulio ­Superti-
Furga. “If we can learn to understand what they
are and how they work, we can find ways to
correct them when they break down and cause
disease”.
Control of the human body begins as soon as life
does, following the fusion between two cells,
a sperm and an egg. This fusion generates a chain
reaction of cell growth and differentiation, begin­
ning the journey through embryonic develop­
ment. A cell’s main control center is its nucleus,
which contains the DNA. Cells are directed
by external signals that are transported from the
surface of the cell into the nucleus. Depending
on which signals are received, the cell reads out
certain combinations of genes from its DNA,
and uses them to make specific proteins, which
are the building blocks of the cell. Proteins are
likethe tools of a trade and with them a cell can
perform a specialized function. Skin cells, for
example, form a barrier to protect us from absorb­
ing harmful material from our surroundings,
and cardiac muscle cells rhythmically contract
to pump blood and oxygen around our bodies.
Ce — M­— M­— Research Report 2007
The Origin of Cancer
A fully developed human being contains many
millions of cells, of many different types. All the
cells of a specific type originate from one com­
mon ancestral cell, or stem cell, and the mecha­
nism of cell growth and differentiation is under
careful control. “Mistakes in the DNA that occur
early on in development, or those that come
from our parents, are inherited by many cells,
which can cause them to function incorrectly
later on and cause disease”, says Robert Kralovics.
His group is interested not only in what the
defects are, but also when and where they happen
during the development of blood cells.
Cells are spatially restricted within our bodies,
and although we stop growing in our late teenage
years, many of our cells, including our blood
cells and skin cells, will continue to divide until
we die. To ensure that our bodies maintain equi­
librium, some cells are also programmed to die,
to make way for new cells. This process also
requires a highly orchestrated and sophisticated
mechanism of control. Normal, healthy cells are
instructed when to grow or die by specific signals
acting through the DNA. Cancer cells have altered,
or mutated DNA, which enables them to escape
this tight control on their function.
Cancer cells can eventually spread to other parts
of our bodies, wreaking havoc on our balanced
system. Cancer can be thought of as an out of
control vehicle. Using the analogy with a trans­
port system, cancer is the runaway bus that
travels randomly throughout a city, without
schedule or destination. It would disrupt the
normal running of the other buses and trams,
and eventually the transport network would
complete­ly break down. “Cancer is essentially
caused by a deregulation of growth control”, says
Sebastian Nijman, whose group is using genetic
screens to study deregulated cellular functions
that can cause cancer.
Ce — M­— M­— Research Report 2007
Gene Regulation Know
Yourself
Understanding how individual genes are regulat­
ed is one of the finest levels of control within the
body. Turning genes on and off at specific times Defend
and in response to the correct signals is vital Yourself
for all cells to function. These patterns of gene
expression are regulated at many different levels,
Control
by molecules that can bind to the DNA. Epige­ Yourself
netic regulation works on the DNA by modifying
its structure and so altering its ability to respond
to external signals. It has been known for some
time to play a vital role during development and
certain diseases. Now, researchers are finding
that it plays an equally important role in cancer.
Epigenetic regulation of gene expression is a
process studied at CeMM by Denise Barlow. In
2005, scientists discovered that over 70% of the
DNA that is copied or transcribed into RNA, does
not go on to make protein. However, only a few
have a known function. “We are very interested
in finding out what these non-coding RNAs do,
and how they do it”, says Denise. The group is
working on characterizing a class of macro ncR­
NAs, which they have shown work back on the
DNA from which they were copied, to directly
control gene expression. This is a relatively new
approach for understanding cancer epigenetics,
and scientists have only recently documented
a connection between macro ncRNAs and
epigenetic silencing of genes that lead to cancer.
Our body plans are prearranged even before
we come into existence. Complex mechanisms
of control are in place to ensure life is ordered
and functional. Identifying and studying them
all is a tough challenge for researchers, but it’s
essential if they are to understand the cause of
many diseases. When control breaks down, it
has dramatic consequences, both at the cellular
and organismal level. Not all mutations are
bad of course, even ones that bypass control.
They have also allowed DNA to change and
evolve over millions of years to eventually cre­
ate Homo sapiens, with large brains amongst
other characteristics necessary to navigate the
complicated transport systems in our various
­cities and live a fairly successful life on this earth.
Treat
Yourself
Heal
Yourself
40 41

Fig. 1 The human genome
contains approximately
90 deubiquitinating
enzymes (DUBs) that can
remove the polypeptide
ubiquitin from protein
substrates. DUBs are
involved in all aspects of
biology, including inflam-
mation and cancer. This
unrooted dendrogram
shows the degree of
sequence relatedness of
the 90 DUB genes, which
divide into five separate
sub-classes. The Nijman
lab is using RNAi and
genetic screens to study
the biological function
of DUBs in disease.
Fig. 2 A high-throughput
bar-coding experiment
using 24,000 RNAi vectors.
Each dot (black, green or
red) represents one RNAi
vector and the position
indicates its abundance
in the population. The
red and green dots are
significantly more or less
abundant than average,
and represent genes that
are potentially important
for growth control.
Ce — M­— M­— Research Report 2007
Genetics and
Epigenetics
of Cancer
Getting Out of Control
Cancer is caused by a dramatic loss of cellular
control. This loss of control occurs by numerous
mechanisms that alter the activity of genes. At
present, if we group cancers according to their
tissue of origin, there are around 100 different
types. However, if we look at their gene expres­
sion patterns, that is which genes are switched
on and which are off, no two cancers are the
same. Each cancer develops in a unique way,
although they use many general approaches
to escape cellular control. Identifying the exact
alterations and perturbations of the DNA that
cause each cancer seems an insurmountable
task. However, with the recent sequencing of
the human genome came the opportunity to
discover new principles of cancer develop­
ment and make major contributions to the field.
“Scientists are no longer taking a gene by gene
approach”, says Sebastian Nijman. “We can
now take on the entire genome.” The 21st Cen­
tury marks the beginning of an era of ­discovery
in cancer biology. Suddenly, Mount Everest
doesn’t look like such a big mountain to climb.
Cancer biology is one of the largest fields in cell
biology. It began over thirty years ago with the
discovery of the first proto-oncogene by Harold
Varmus and Michael Bishop at the University
of California, San Francisco, in the USA. The
pair went on to receive the Nobel Prize for their
discovery in 1989. Proto-oncogenes and Tumor
suppressor genes are types of genes that have
the capacity to significantly increase the chance
that a cell will become cancerous when they are
mutated. Cancer can be thought of as an out of
control car. Proto-oncogenes act as accelerators,
and if they can be jammed on, they can force
a cell to continually divide even when there are
no signals to tell it to do so. In the opposite
way, tumor suppressor genes act as the brakes.
If they fail, cells are able to grow unrestricted.
M =²log (Cy5/Cy3)
One major challenge taken on by researchers at
CeMM is to identify new cancer-associated genes
and understand their functions and how they
are regulated. Cataloguing cancer in this way
means scientists can develop more sophisticated
therapeutics to target individual cancers, rather
than the relatively non-specific chemotherapies
that are commonly used to treat the disease today.
Sebastian’s lab is using a technique known as
RNAi, to search through the genome and find
cancer-causing genes. Technology exists so
that scientists can switch off individual genes
in a cell, and see if that gives the cell a growth
advantage over other cells. RNAi has emerged
as a powerful mechanism to study gene function.
Sebastian’s work at the NKI in the Netherlands
and the Broad institute at MIT has given him
valuable experience designing and performing
successful genetic screens, as well as access to
libraries containing short hairpin RNAs, which
target all of the 20,000 or so genes in the human
genome. “By introducing these shRNAs into
cells, we can ask the cells to show us which
genes are important for certain functions”, says
Sebastian. It is possible to discover new tumor
suppressor genes using this approach, and iden­
tify new targets for the development of drugs.
Sebastian has been developing new technologies
to help improve the efficiency of the screens,
which he is now testing on signaling pathways
that are deregulated in cancer. The aim is to
identify new components of these pathways,
to help understand how they are regulated,
and what can go wrong to cause disease.
Fig. 2
SMAD4
5 genetic mutations causes
0 one copy of the gene
–5
0 5 10
A = log (√Cy5/Cy3)
²
Controlling the genome
Although, to date, over 80 genomes have been
sequenced, understanding how the genetic code
translates into cellular function is only beginning
to be understood. There are over 20,000 genes in
the human genome, and a complex mechanism
of control exists for the expression of each one.
Epigenetic regulation is one of these mechanisms,
and it works by altering the structure or the
modification of the DNA, and the chromatin
proteins bound to it, and so regulating its ability
to respond to certain signals. For example, the
addition of small chemical groups such as methy­
lation to the DNA can silence the activity of
specific genes. These epigenetic marks are mostly
stable, and each time the cell divides, the marks
are retained in both resulting (daughter) cells.
Many different proteins are known to mediate
the epigenetic regulation of genes. However,
more recently it has been shown that some non-
coding RNA (ncRNA) molecules are also respon­
sible for controlling gene expression. Although
ncRNAs are abundantly produced in every cell,
it is not clear what they are doing. “We believe
that epigenetic regulation of gene expression may
be quite a general function for ncRNAs”, says
Denise Barlow.
The Barlow lab has worked for many years on the
mechanisms of imprinting, since their discovery
in 1991 of the first imprinted gene. Mammals
are diploid organisms, meaning they carry two
copies of every gene in each cell. One copy
is inherited from the mother and one from the
father. Occasionally, one of the two genes is
switched off while the other is left on, a process
known as imprinting. This differential control
of the two copies of the same gene is regulated
epigenetically. Work done in Denise’s lab five
years ago identified the first ncRNA that was
required to silence a small cluster of imprinted
Fig. 3
Tumor suppressor gene 1st allele silenced
2 active alleles
15 Epigenetic silencing
Ce — M­— M­— Research Report 2007
genes. Since then, several more ncRNAs func­
tioning in this way have been identified in both
Know
Yourself
imprinted and non-imprinted regions of the
genome. Defend
Yourself
The lab went on to study the Air ncRNA, find­
ing functional and structural characteristics that
Control
gave insight into how these molecules might Yourself
work and how they can be regulated. However,
it is still not clear how these ncRNAs actually
silence genes, and the lab is devoted to figuring
this out. “Many fundamental questions still
remain”, says Denise. “For example, we don’t
know if it is the ncRNA molecules themselves
that are important, or whether it is the act of
their production that blocks gene activity”.
Denise’s lab is currently committed to a large-
scale analysis of a group of ncRNAs, known
as macro ncRNAs, in the human and mouse
genomes. Like Sebastian’s group, they are also
fully exploiting the recent sequencing of the
human and mouse genomes. They are using
post-genomic technology, like SOLEXA that
sequences millions of fragments of DNA in
one go, and specialized microarrays, that can
in a single experiment tell you the activity
of all the genes within an entire genome.
The past five years has seen a rising interest in the
epigenetics of cancer in terms of looking at DNA
modifications and chromatin changes in cancer
tissues. “Now we can show that in imprinted
clusters the prime target of DNA methylation
is to regulate macro ncRNAs that can regulate
neighboring genes”, says Denise. “Now we want
to know if the large subset of human tumors
that show DNA methylation changes will have
specific macro ncRNAs that are able to upregu­
late or downregulate flanking tumor associated
genes.” This could essentially be thought of as
a new principle for the molecular cause of cancer.
Fig. 3 In 1971, the
American geneticist Alfred
Knudson proposed that
gradual accumulation of
LOH
cancer. Tumor suppres-
sor genes are frequently
inactivated by silencing
Clonal expansion 2 silenced alleles
of heterozygous cells clonal eypansion
(allele), and then losing
(dosage sensitive gene) of homozygous cells
the other active allele,
pre-cancer state cancer state
known as loss of heterozy-
gosity (LOH). Tumor
suppressors can also be
Treat
silenced epigenetically, Yourself
however the extent to
Epigenetic silencing which this occurs in cancer
is currently unclear.
Heal
Yourself
42 43
 Hematological
Malignancies
Master Controllers
Cells become cancerous by acquiring a series
of mutations that each confers a function on
the cell giving it an advantage over other cells.
“Most cancers are These mutations are highly diverse. Some may
directly activate an oncogene or inactivate
thought to origi- a tumor suppressor gene, to give the cell the
nate from a key opportunity to divide more times than it should.
mutation in one Others mean that the cell acquires more muta­
tions than normal, giving it a bigger chance of
individual cell.” mutating a key gene that would make it more
likely to become cancerous. Most cancers are
thought to originate from a key mutation in
one individual cell. This cell then acquires sub­
sequent, critical mutations and eventually is
“This mutation able to become cancerous. The danger increases
when the cell with the founding mutation
causes only a very is a stem cell that will eventually give rise to
small change in a large number of cells within a certain organ or
the sequence of lineage, all of which will then carry that crucial
mutation. Myeloproliferative disorders (MPD)
the gene, but it is are considered to be one such stem cell disease.
so powerful that
if you introduce Robert Kralovics is interested in the genetic
mutations that cause MPD. MPDs are a hetero­
the mutant protein geneous group of diseases characterized by an
into mice, you can excessive production of certain types of blood
essentially cause cells and their precursors. Symptoms of this
disease can also include bleeding or thrombosis.
them to develop The biggest danger of MPDs is that they can
cancer.” progress to secondary myelofibrosis or eventu­
ally develop a therapy resistant form of Acute
Myeloid Leukemia, which is the most common
acute leukemia in adults. It accounts for around
1.2% of cancer deaths in the USA, and its inci­
dence increases with age, so rates are expected
to rise as the population continues to age.
Classical MPD and MPD-like syndromes are
familial diseases, meaning that multiple family
members can be affected. Diseases with an
inheritable component also give researchers
a unique opportunity to discover more about
their molecular basis. Humans contain two cop­
ies of each gene, and children inherit one copy
from their mother and one from their father.
By looking at which family members have the
disease, it is possible to follow the inheritance
of a causative mutation through the generations,
and eventually identify exactly which gene
contains the critical, founding mutation.
Ce — M­— M­— Research Report 2007
A major step towards understanding the molec­
ular basis of MPDs was the identification of a Fig. 1 Crystal structure of
Know
Yourself
specific mutation in the JAK2 gene in 50% of the active conformation of
the JAK2 protein tyrosine
patients. The invariant nature of this mutation kinase domain in complex Defend
makes it an attractive candidate for targeted drug with a high-affinity pan- Yourself
JAK inhibitor (PDB entry
therapy. Robert Kralovics made this discovery 2B7A)
when he was a Post-doc in the lab of Radek
Control
Skoda, in Switzerland in 2005. “This mutation Yourself
causes only a very small change in the sequence
of the gene, but it is so powerful that if you
introduce the mutant protein into mice, you
can essentially cause them to develop cancer”,
explains Robert. They know that the mutation
allows cells to evade important growth control
mechanisms by constitutively activating the
JAK/STAT molecular pathway. Although this
is an important mutation for MPD, it seems
it is not the critical first mutation that sets the
disease in motion. In his own lab, Robert is using
patient samples to try to discover these elusive
disease-initiating mutations and other muta­
tions that are important for MPD development.
They hope to identify new targets for therapy,
which may also be applicable to other myeloid
diseases, since some of the mutations are also
found in other leukemia-related conditions.
Thrombosis, the formation of a clot that obstructs
the flow of blood, is a clinical complication of
MPD, and is a leading cause of morbidity and
mortality. Its occurrence strongly correlates with
the presence of the activating JAK2 mutation,
however, why this happens, and how it might
work at the molecular level is completely
unknown. Using genome–wide techniques,
Robert’s group has been trying to understand
the molecular consequences of having a consti­
tutively activated JAK-STAT pathway, to try to
link this to the increased incidence of thrombosis
in MPD patients. “We suspect that the JAK muta­
tion somehow affects the function of platelets
or neutrophils, which are specific types of blood
cells important for coagulation of the blood”,
says Robert. To study this, his group is develop­
ing mouse models, which allow them to intro­
duce the JAK mutation into one specific type of
blood cell at a time. They have already shown
that MPD-associated thrombosis has a complex
cause, and that JAK2 mutations are only one of
several important risk factors. Now, in close col­
laboration with the Medical University in Vienna,
they have identified additional genes and path­
ways that influence this disease process. The aim
of these studies is to gain insight into the molec­
ular processes of MPD thrombosis and develop a
therapeutic strategy that can profoundly improve
the quality of life of MPD patients.
Treat
Yourself
Heal
Yourself
Ce — M­— M­— Research Report 2007 44 45
 Dr. Michael Häupl
Mayor of the City of Vienna

As mayor of the City of Vienna I am very proud of the Center

of Molecular Medicine because it is one outstanding research
institution out of a large number of top scientific institutes
based in our city. I personally congratulate Professor Superti-
Furga as one of the world’s leading scientists in the field of
molecular biology on the excellent work done by him and all
scientists at CeMM. Being able to attract such a great number
of brilliant researchers underlines the enormous popularity
of Vienna as a business location also because of its ideal geo-
political position in the very heart of Europe being the hub
between East and West. And it emphasizes the high quality
of life we enjoy to share. But, to be able to achieve excel-
lence, scientists also need relevant financial support as well
as proper infrastructure. Therefore the City of Vienna and
the federal state of Austria jointly enabled the construction
of a new research facility for CeMM right on the site of
Vienna´s General Hospital for mutual transfer of knowledge
for the benefit of science and patients. Hence the stage for
further success of the “hot spot” Vienna is set.

Ce — M­— M­— Research Report 2007 Ce — M­— M­— Research Report 2007 46 47
 Treat
Know
Yourself

Met –
Ala – Leu – Trp – Met –
Defend
Arg – Leu – Leu – Pro – Leu – Leu –
Yourself
Ala – Leu – Leu – Ala – Leu – Trp – Gly – Pro –
Asp – Pro – Ala – Ala – Ala – Phe – Val – Asn – Gln –
His –Leu –Cys –Gly –Ser –His –Leu –Val –Glu –Ala –Leu –
Control

Yourself
Tyr – Leu – Val – Cys – Gly – Glu – Arg – Gly – Phe – Phe – Tyr –
Thr –Pro –Lys –Thr –Arg –Arg –Glu –Ala –Glu –Asp –Leu –Gln – Yourself
Val – Gly – Gln – Val – Glu – Leu – Gly – Gly – Gly – Pro – Gly – Ala – Gly –
Ser – Leu – Gln – Pro – Leu – Ala – Leu – Glu – Gly – Ser – Leu – Gln – Lys – Arg –
Gly –Ile –Val –Glu –Gln –Cys –Cys –Thr –Ser –Ile –Cys –Ser –Leu –Tyr –Gln –
Leu –Glu –Asn –Tyr –Cys –Asn –+++ –Met –Gly –Thr –Gly –Gly –Arg –Arg – Treat
Yourself
Gly – Ala – Ala – Ala – Ala – Pro – Leu – Leu – Val – Ala – Val – Ala – Ala – Leu –
Leu – Leu – Gly – Ala – Ala – Gly – His – Leu – Tyr – Pro – Gly – Glu – Val – Cys –
Pro –Gly –Met –Asp –Ile –Arg –Asn –Asn –Leu –Thr –Arg –Leu –His –Glu –
Leu – Glu – Asn – Cys – Ser – Val – Ile – Glu – Gly – His – Leu – Gln – Ile – Leu –
Leu –Met –Phe –Lys –Thr –Arg –Pro –Glu –Asp –Phe –Arg –Asp –Leu –Ser –
P h e – Pro – Lys – Leu – Ile – Met – Ile – Thr – Asp – Tyr – Leu – Leu – Leu –
Phe – Arg – Val – Tyr – Gly – Leu – Glu – Ser – Leu – Lys –
Asp – Leu – Phe – Pro – Asn – Leu – Thr – Val – Ile – Arg –
Gly – Ser – Arg – Leu – Phe – Phe – Asn – Tyr – Ala – Leu –
Val –Ile –Phe –Glu – Met – Val – His – Leu – Lys – Glu –
Leu – Gly – Leu – Tyr – Asn – Leu – Met – Asn – Ile – Thr – Arg –
Gly – Ser – Val – Arg – Ile – Glu – Lys – Asn – Asn – Glu – Leu –
Cys – Tyr – Leu – Ala – Thr – Ile – Asp – Trp – Ser – Arg – Ile –
Leu – Asp – Ser – Val – Glu – Asp – Asn – Tyr – Ile – Val – Leu –
Asn – Lys – Asp – Asp – Asn –Glu –Glu –Cys –Gly –Asp –Ile –Cys –Pro –
Gly – Thr – Ala – Lys – Gly – Lys – Thr – Asn – Cys – Pro – Ala – Thr – Val – Ile – Asn –
Gly – Gln – Phe – Val – Glu – Arg – Cys – Trp – Thr – His – Ser – His – Cys – Gln – Lys – Val – + Understanding + Achilles Heel
Cys – Pro – Thr – Ile – Cys – Lys – Ser – His – Gly – Cys – Thr – Ala – Glu – Gly – Leu – Cys – Cys – Drugs of Cancer
His – Ser – Glu – Cys – Leu – Gly – Asn – Cys – Ser – Gln – Pro – Asp – Asp – Pro – Thr – Lys – Cys –
Val –Ala –Cys –Arg –Asn –Phe –Tyr –Leu –Asp –Gly –Arg –Cys –Val –Glu –Thr –Cys –Pro –Pro –
Pro – Tyr – Tyr – His – Phe – Gln – Asp – Trp – Arg – Cys – Val – Asn – Phe – Ser – Phe – Cys – Gln – Asp –
Leu – His – His – Lys – Cys – Lys – Asn – Ser – Arg – Arg – Gln – Gly – Cys – His – Gln – Tyr – Val – Ile – His – Asn –
Asn – Lys – Cys – Ile – Pro – Glu – Cys – Pro – Ser – Gly – Tyr – Thr – Met – Asn – Ser – Ser – Asn – Leu – Leu – Cys –
Thr – Pro – Cys – Leu – Gly – Pro – Cys – Pro – Lys – Val – Cys – His – Leu – Leu – Glu – Gly – Glu – Lys – Thr – Ile – Asp –
Ser – Val – Thr – Ser – Ala – Gln – Glu – Leu – Arg – Gly – Cys – Thr – Val – Ile – Asn – Gly – Ser – Leu – Ile – Ile – Asn – Ile –
Arg –Gly –Gly –Asn –Asn –Leu –Ala –Ala –Glu –Leu –Glu –Ala –Asn –Leu –Gly –Leu –Ile –Glu –Glu –Ile –Ser –Gly –
Tyr – Leu – Lys – Ile – Arg – Arg – Ser – Tyr – Ala – Leu – Val – Ser – Leu – Ser – Phe – Phe – Arg – Lys – Leu – Arg – Leu – Ile –
Arg –Gly –Glu –Thr –Leu –Glu –Ile –Gly –Asn –Tyr –Ser –Phe –Tyr –Ala –Leu –Asp –Asn –Gln –Asn –Leu –Arg –Gln –Leu –
Trp – Asp – Trp – Ser – Lys – His – Asn – Leu – Thr – Thr – Thr – Gln – Gly – Lys – Leu – Phe – Phe – His – Tyr – Asn – Pro – Lys – Leu – Cys –
Leu –Ser –Glu –Ile –His –Lys –Met –Glu –Glu –Val –Ser –Gly –Thr –Lys –Gly –Arg –Gln –Glu –Arg –Asn –Asp –Ile –Ala –Leu –Lys –Thr –Asn –
Gly –Asp –Lys –Ala –Ser –Cys –Glu –Asn –Glu –Leu –Leu –Lys –Phe –Ser –Tyr –Ile –Arg –Thr –Ser –Phe –Asp –Lys –Ile –Leu –Leu –Arg –Trp –Glu –Pro –
Tyr –Trp –Pro –Pro –Asp –Phe –Arg –Asp –Leu –Leu –Gly –Phe –Met –Leu –Phe –Tyr –Lys –Glu –Ala –Pro –Tyr –Gln –Asn –Val –Thr –Glu –Phe –Asp –Gly –
Gln –Asp –Ala –Cys –Gly –Ser –Asn –Ser –Trp –Thr –Val –Val –Asp –Ile –Asp –Pro –Pro –Leu –Arg –Ser –Asn –Asp –Pro –Lys –Ser –Gln –Asn –His –Pro –Gly –
Trp –Leu –Met –Arg –Gly –Leu –Lys –Pro –Trp –Thr –Gln –Tyr –Ala –Ile –Phe –Val –Lys –Thr –Leu –Val –Thr –Phe –Ser –Asp –Glu –Arg –Arg –Thr –Tyr –Gly –Ala –
Lys –Ser –Asp –Ile –Ile –Tyr –Val –Gln –Thr –Asp –Ala –Thr –Asn –Pro –Ser –Val – Pro –Leu –Asp –Pro –Ile –Ser –Val –Ser –Asn –Ser –Ser –Ser –Gln –Ile –Ile –Leu –
Lys –Trp –Lys –Pro –Pro –Ser –Asp –Pro –Asn –Gly –Asn –Ile –Thr –His –Tyr –Leu – Val – Phe – Trp – Glu – Arg – Gln – Ala – Glu – Asp – Ser – Glu – Leu – Phe – Glu – Leu – Asp –
Tyr – Cys – Leu – Lys – Gly – Leu – Lys – Leu – Pro – Ser – Arg – Thr – Trp – Ser – Pro – Pro – Phe – Glu – Ser – Glu – Asp – Ser – Gln – Lys – His – Asn – Gln – Ser – Glu – Tyr – Glu – Asp – Ser –
Ala –Gly –Glu –Cys –Cys –Ser –Cys –Pro –Lys –Thr –Asp –Ser –Gln –Ile –Leu –Lys – Glu –Leu –Glu –Glu –Ser –Ser –Phe –Arg –Lys –Thr –Phe –Glu –Asp –Tyr –Leu –His –Asn –Val –Val –Phe –
Val – Pro – Arg – Lys – Thr – Ser – Ser – Gly – Thr – Gly – Ala – Glu – Asp – Pro – Arg – Pro – Ser – Arg – Lys – Arg – Arg – Ser – Leu – Gly – Asp – Val – Gly – Asn – Val – Thr – Val – Ala – Val – Pro – Thr – Val –
Ala – Ala – Phe – Pro – Asn – Thr – Ser – Ser – Thr – Ser – Val – Pro – Thr – Ser – Pro – Glu – Glu – His – Arg – Pro – Phe – Glu – Lys – Val – Val – Asn – Lys – Glu – Ser – Leu – Val – Ile – Ser – Gly – Leu – Arg – His –
Phe –Thr –Gly –Tyr –Arg –Ile –Glu –Leu –Gln –Ala –Cys –Asn –Gln –Asp –Thr – Pro –Glu –Glu –Arg –Cys –Ser –Val –Ala –Ala –Tyr –Val –Ser –Ala –Arg –Thr –Met –Pro –Glu –Ala –Lys –Ala –Asp –Asp –
Ile – Val – Gly – Pro – Val – Thr – His – Glu – Ile – Phe – Glu – Asn – Asn – Val – Val – His – Leu – Met – Trp – Gln – Glu – Pro – Lys – Glu – Pro – Asn – Gly – Leu – Ile – Val – Leu – Tyr – Glu – Val – Ser – Tyr – Arg – Arg –
Insulin Tyr –Gly –Asp –Glu –Glu –Leu –His –Leu –Cys –Val –Ser –Arg –Lys –His –Phe –Ala –Leu –Glu –Arg –Gly –Cys –Arg –Leu –Arg –Gly –Leu –Ser –Pro –Gly –Asn –Tyr –Ser –Val –Arg –Ile –Arg –Ala –Thr –
For Treat Yourself we Ser –Leu –Ala –Gly –Asn –Gly –Ser –Trp –Thr –Glu –Pro –Thr –Tyr –Phe –Tyr –Val –Thr –Asp –Tyr –Leu –Asp –Val –Pro –Ser –Asn –Ile –Ala –Lys –Ile –Ile –Ile –Gly –Pro –Leu –Ile –Phe –Val –Phe –Leu –
chose the sequence of Phe –Ser –Val –Val –Ile –Gly –Ser –Ile –Tyr –Leu –Phe –Leu –Arg –Lys –Arg –Gln –Pro –Asp –Gly –Pro –Leu –Gly –Pro –Leu –Tyr –Ala – Ser – Ser – Asn – Pro – Glu – Tyr – Leu – Ser – Ala – Ser – Asp –
human insulin precursor Val –Phe –Pro –Cys –Ser –Val –Tyr –Val –Pro –Asp –Glu –Trp –Glu –Val –Ser –Arg –Glu –Lys –Ile –Thr –Leu –Leu –Arg –Glu –Leu –Gly – Gln –Gly –Ser –Phe –Gly –Met –Val –Tyr –Glu –Gly –Asn –
(A and B chains) and the Ala –Arg –Asp –Ile –Ile –Lys –Gly –Glu –Ala –Glu –Thr –Arg –Val –Ala –Val –Lys –Thr –Val –Asn –Glu –Ser –Ala –Ser –Leu –Arg –Glu – Arg – Ile – Glu – Phe – Leu – Asn – Glu – Ala – Ser – Val –
cognate human insulin 1 Met – Lys – Gly – Phe – Thr – Cys – His – His – Val – Val – Arg – Leu – Leu – Gly – Val – Val – Ser – Lys – Gly – Gln – Pro – Thr – Leu – Val – Val – Met –Glu –Leu –Met –Ala –His –Gly –Asp –Leu –Lys –
receptor. Not only does it Ser – Tyr – Leu – Arg – Ser – Leu – Arg – Pro – Glu – Ala – Glu – Asn – Asn – Pro – Gly – Arg – Pro – Pro – Pro – Thr – Leu – Gln – Glu – Met – Ile – Gln – Met – Ala – Ala – Glu – Ile – Ala – Asp – Gly –
represent one of the first Met –Ala –Tyr –Leu –Asn –Ala –Lys –Lys –Phe –Val –His –Arg –Asp –Leu –Ala –Ala –Arg –Asn –Cys –Met –Val –Ala –His –Asp – Phe – Thr – Val – Lys – Ile – Gly – Asp – Phe – Gly –
and most potent examples Met –Thr –Arg –Asp –Ile –Tyr –Glu –Thr –Asp –Tyr –Tyr –Arg –Lys –Gly –Gly –Lys –Gly –Leu –Leu –Pro –Val –Arg –Trp –Met – Ala – Pro – Glu – Ser – Leu – Lys – Asp – Gly – Val –
of molecular medicine, Phe –Thr –Thr –Ser –Ser –Asp –Met –Trp –Ser –Phe –Gly –Val –Val –Leu –Trp –Glu –Ile –Thr –Ser –Leu –Ala –Glu –Gln –Pro – Tyr –Gln –Gly –Leu –Ser –Asn –Glu –Gln –Val –
it also honours the work Leu –Lys –Phe –Val –Met –Asp –Gly –Gly –Tyr –Leu –Asp –Gln –Pro –Asp –Asn –Cys –Pro –Glu –Arg –Val –Thr –Asp –Leu – Met – Arg – Met – Cys – Trp – Gln – Phe – Asn –
of Prof. Hans Tuppy, who, Pro –Lys –Met –Arg –Pro –Thr –Phe –Leu –Glu –Ile –Val –Asn –Leu –Leu –Lys –Asp –Asp –Leu –His –Pro –Ser –Phe –Pro – Glu –Val –Ser –Phe –Phe –His –Ser –Glu –
along with Fred Sanger, Glu – Asn – Lys – Ala – Pro – Glu – Ser – Glu – Glu – Leu – Glu – Met – Glu – Phe – Glu – Asp – Met – Glu – Asn – Val – Pro – Leu – Asp – Arg – Ser – Ser – His – Cys – Gln –
first determined the amino Arg – Glu – Glu – Ala – Gly – Gly – Arg – Asp – Gly – Gly – Ser – Ser – Leu – Gly – Phe – Lys – Arg – Ser – Tyr – Glu – Glu – His – Ile – Pro – Tyr – Thr – His – Met – Asn –
acid sequence of insulin in Gly –Gly –Lys –Lys –Asn –Gly –Arg –Ile –Leu –Thr –Leu –Pro –Arg –Ser –Asn –Pro –Ser –+++ –Met –Ala –Leu –Trp – Met – Arg – Leu – Leu – Pro – Leu –
the 1950s. Prof. Tuppy has Leu – Ala – Leu – Leu – Ala – Leu – Trp – Gly – Pro – Asp – Pro – Ala – Ala – Ala – Phe – Val – Asn – Gln – His – Leu – Cys – Gly –Ser –His –Leu –Val –Glu –Ala –
been a guiding light for Leu –Tyr –Leu –Val –Cys –Gly –Glu –Arg –Gly –Phe –Phe –Tyr –Thr –Pro –Lys –Thr –Arg –Arg –Glu –Ala –Glu – Asp – Leu – Gln – Val – Gly – Gln –
the Austrian life sciences Val – Glu – Leu – Gly – Gly – Gly – Pro – Gly – Ala – Gly – Ser – Leu – Gln – Pro – Leu – Ala – Leu – Glu – Gly – Ser – Leu – Gln – Lys – Arg – Gly – Ile –
community ever since. Val – Glu – Gln – Cys – Cys – Thr – Ser – Ile – Cys – Ser – Leu – Tyr – Gln – Leu – Glu – Asn – Tyr – Cys – Asn – +++ – Met – Gly – Thr – Gly – Gly – Arg –
Arg –Gly –Ala –Ala –Ala –Ala –Pro –Leu –Leu –Val –Ala –Val –Ala –Ala –Leu –Leu –Leu –Gly –Ala –Ala – Gly – His – Leu – Tyr – Pro – Gly –
Glu –Val –Cys –Pro –Gly –Met –Asp –Ile –Arg –Asn –Asn –Leu –Thr –Arg –Leu –His –Glu –Leu –Glu – Asn – Cys – Ser – Val – Ile – Glu –
INS_HUMAN Uniprot Gly – His – Leu – Gln – Ile – Leu – Leu – Met – Phe – Lys – Thr – Arg – Pro – Glu – Asp – Phe – Arg – Asp – Leu – Ser – Phe – Pro – Lys –
P01308 Leu – Ile – Met – Ile – Thr – Asp – Tyr – Leu – Leu – Leu – Phe – Arg – Val – Tyr – Gly – Leu – Glu – Ser – Leu –Lys –Asp –Leu –Phe –Pro –
Asn – Leu – Thr – Val – Ile – Arg – Gly – Ser – Arg – Leu – Phe – Phe – Asn – Tyr – Ala – Leu – Val – Ile – Phe – Glu – Met – Val – His – Leu –
INSR_HUMAN Uniprot Lys – Glu – Leu – Gly – Leu – Tyr – Asn – Leu – Met – Asn – Ile – Thr – Arg – Gly – Ser – Val – Arg – Ile – Glu – Lys – Asn – Asn – Glu –
P06213 Leu –Cys –Tyr –Leu –Ala –Thr –Ile –Asp –Trp –Ser –Arg –Ile –Leu –Asp –Ser –Val – Glu – Asp – Asn – Tyr – Ile – Val – Leu – Asn –
Lys – Asp – Asp – Asn – Glu – Glu – Cys – Gly – Asp – Ile – Cys – Pro – Gly – Thr – Ala –Lys –Gly –Lys –Thr –Asn –Cys –Pro –Ala –Thr – Heal
Val –Ile –Asn –Gly –Gln –Phe –Val –Glu –Arg –Cys –Trp –Thr –His –Ser – His –Cys –Gln –Lys –Val –Cys –Pro –Thr –Ile –Cys –Lys –Ser – Yourself
His – Gly – Cys – Thr – Ala – Glu – Gly – Leu – Cys – Cys – His – Ser – Glu – Cys – Leu – Gly – Asn – Cys – Ser – Gln – Pro – Asp – Asp – Pro – Thr –
Lys – Cys – Val – Ala – Cys – Arg – Asn – Phe – Tyr – Leu – Asp – Gly – Arg – Cys – Val – Glu – Thr – Cys – Pro – Pro – Pro – Tyr – Tyr – His – Phe –
Gln –Asp –Trp –Arg –Cys –Val –Asn –Phe – Ser –Phe –Cys – Gln – Asp – Leu – His –
Smart Drugs:
Human populations were at the mercy of infec­
tious diseases until the late 19th Century. One
third of the population in Europe was wiped
Hitting where
out by the Bubonic plague in 1347, which is the
largest epidemic ever recorded. Modern medicine
has had an enormous impact on society and
brought most infectious diseases under control.
it hurts
HIV, for example, has gone from being fatal to
treatable in only a few decades. How­ever, some
diseases are developing resistance to our drugs
and making a comeback, and others, like SARS,
are only just emerging. The need to find effective
Understanding the mechanism of existing therapeutics and using
drugs is as urgent as ever.
existing knowledge to develop targeted drugs to treat disease
The first drugs were discovered in the natural
world. These early medicines were plants
that were used to treat a variety of symptoms.
A Chinese herbalist would prescribe fresh ginger
to treat such diverse conditions as toothache,
malaria and baldness, albeit not always with the
desired effect. The arrival of the modern practice
of medicine brought a more sophisticated
approach to drug discovery, and pharmaceutical
companies invested in identifying compounds
that were effective in treating symptoms and
diseases. They screened millions of chemical
compounds and discovered drugs that were suc­
cessful against many harmful human diseases.
Although this type of approach is certainly
productive, drug discovery and development is
a relatively slow and cost-intensive process.
Further­more, with persisting problems such as
drug resistance, side-effects and the emergence of
new untreatable diseases, it is clear that scientists
have to change tactics.
What’s in a Drug?
There are three main problems with the traditio­
nal methods of drug discovery. Firstly, there is
an immense gap in knowledge of how and why
the successful ones actually work. “We don’t
even know how Paracetamol really works”,
says Giulio Superti-Furga, whose group is
analyzing the mechanism of drug action using
chemical proteomics approaches. Importantly,
40% of the medicines that are on the market
today were not originally designed to treat
that specific disease. Viagra, for example, was
intended to treat high blood pressure and
cardio­vascular disease. However, it proved to
be ineffective for these conditions during clini­
cal trials, and now is most commonly used to
treat erectile dysfunction. This highlights the
serendipitous way in which it was developed.
Ce — M­— M­— Research Report 2007
Another major problem of many drugs on the
market today is that they have quite severe
side effects. In fact, side effects from drugs are
responsible for a staggering 3-5% of all hospital
admissions, making them a serious threat to
public health. Finally, many drugs treat symp­
toms rather than the underlying cause. For
instance, steroids and anti-inflammatory drugs
are invaluable tools used by doctors to treat many
common diseases such as arthritis and asthma.
But their use is limited as they only treat the
symptoms and therefore do not ‘cure’ the disease.
Smart Drugs
Today, many scientists believe that understan­
ding the molecular basis of the disease is funda­
mental to successfully treating it. This knowledge
can be used to generate smart medicine: drugs
designed to target the specific molecular defect
causing the disease. The goal is to hit them where
it hurts. Therapies generated in this way are
expected to be far more effective and carry fewer
side effects, making them much more desirable.
The first targeted therapies have already entered
the market, heralding the start of a new genera­
tion of medicine. A classic example is imatinib,
which was launched in 2001 by the pharma­
ceutical company Novartis, and touted as the
magic bullet to cure cancer. Imatinib is a small
molecule kinase inhibitor that specifically targets
the molecular defect found in Chronic Myeloid
Leukemia (CML), and inhibits its activity. This
defect is caused when the DNA on chromosomes
is rearranged, causing a translocation in which
two genes are incorrectly joined together. These
two genes generate a unique protein known as
Bcr-Abl, that is absent in normal cells and which
becomes inappropriately active, allowing blood
cells to grow uncontrollably causing leukemia.
Ce — M­— M­— Research Report 2007
Giulio has spent many years studying the struc­ Know
Yourself
ture and regulation of Bcr-Abl and its cellular
counterpart c-Abl. The identification of imatinib
was a major breakthrough, and although it is a Defend
relatively weak inhibitor, it is particularly specific Yourself
in targeting and inhibiting the Bcr-Abl protein
and little else in the cell. However, patients are Control
developing resistance to imatinib leading to Yourself
relapse, prompting the development of new
drugs. Having a range of drugs that target the
same molecular defect gives scientists a unique Treat
Yourself
tool to study how they actually work, and
why some drugs are more effective than others.
These are ongoing projects in Giulio’s lab.
Putting knowledge to work
The Post-genomic era, so called as it followed
the recent sequencing of the human genome,
has provided massive resources to help scientists
understand disease. “The only limit now seems
to be our imagination”, says Sebastian Nijman,
who was recruited to CeMM last year from the
Broad institute, the major contributor to the
sequence of the human genome. However, the
challenge to translate knowledge into suitable
treatments is proving more difficult than origi­
nally anticipated. “For certain diseases, we already
have quite a detailed understanding of the mole­
cular cause …”, says Sebastian. “However, there
seems to be a bottleneck somewhere, as for most
we have yet to see the development of effective
drugs”. Sebastian’s group is in the process of
designing genetic screens that will use knowledge
on the molecular basis of cancer to find potentially
useful therapeutics.
The total eradication of smallpox in 1979 is
arguably one of the greatest public health achieve­
ments to date. However, we are unlikely to see
this happen for any other diseases in the foresee­
able future. The gaps at the moment seem to be
mostly in our understanding of drug action, and
our ability to use information about the causes of
genetic disease, and resources from the human
genome projects, to develop smart drugs to target
disease. These are two areas currently being
addressed at CeMM.
Heal
Yourself
50 51
 Understanding
Drugs
“We concentrated Chemicals work on the body in extremely
complex ways that have proven rather difficult
on making sure to characterize. Many drugs have an unknown
that what binds mechanism of action. Understanding how and
to the drug in why certain drugs work, and what their intra­
cellular targets are, is a challenge taken on by
the assay, would the lab of Giulio Superti-Furga. They initially
­probably bind focused on characterizing three drugs that are
to the drug in the currently used to target the Bcr-Abl translocation
found in patients with Chronic Myelogenous
cell.” Leukemia (CML); imatinib, nilotinib and dasat­
inib. Although imatinib was certainly a wonder
drug when it hit the market, its efficacy generally
declines after long-term use as the cancer cells
evolve resistance. The genetic changes that
occur in these cells to make them insensitive
to imatinib, are quite similar in all patients
thatdevelop resistance. Now, other drugs have
been developed that can somehow target these
resistant cells, but the full scope of their target
profiles and thus of their efficacy and potential
for side-effects were unknown. Giulio’s group
has applied a chemical proteomics approach
to this problem. Analogous to the method
they use to understand the workings of the
immune system by looking for protein-protein
interactions, now they analyze protein-drug
interactions, revealing the intracellular targets.
Their approach is an advance on previous
methods used to study drug targets. This
is mainly because they use cellular protein
extracts to preserve the native structure and
chemical modifications of the proteins, which
are important for their function. “We con­
centrated on making sure that what binds to
the drug in the assay, would probably bind to
the drug in the cell”, says Giulio. And the first
results published in 2007 show that it works.
Ce — M­— M­— Research Report 2007
Dasatinib is an approved drug that is effective
against most imatinib-resistant CML. In collab­ Fig. 1 A Bcr-Abl inhibitor
Know
Yourself
oration with Peter Valent, and the Institute of kinome footprint to show
how similar drugs bind
Immunology and the Division of Hematology different groups of func- Defend
and Hemostaseology of the Medical University tionally and structurally Yourself
related proteins, which is
of Vienna, Giulio’s group identified three unex­ illustrated by their relative
pected protein targets of this drug. Their results position in the figure. Pro-
Control
were published in PNAS and Blood last year. tein kinases in purple are
targeted by three drugs,
Yourself
Not only does this help them to understand
how the drug works in the context of CML,
in orange by two, and in
red by only one. Kinases
it also potentially gives them new therapeutics in grey are only targeted
by drugs specifically in
Treat
Yourself
for other diseases caused by deregulation of patients with Chronic
Myelogenous Leukemia
the other targeted proteins. It appears that dasat­
inib is less specific for CML than imatinib, and
(CML).
indeed it seems to produce greater side-effects in
patients. However, Giulio suspects that its lower
specificity could actually turn out to be a valuable
aspect of dasatinib for treating CML, as it may
be less likely to cause the cells to become resistant
in the long term. Time will tell if this is the case.
The knowledge generated by this work not
only goes directly to the clinic, but it also
feeds back into basic biology. Chemical inhibi­
tors are powerful tools used by scientists to
study different biological processes. Drugs
that inhibit specific proteins or pathways in a
cell are used to discover more about how cells
work. Knowing the precise protein targets of
each drug is important for interpreting these
results. Now, the group is planning to use
their new tool to assist clinical departments
in evaluating therapies. They are focusing
mainly on cancer and immunology, which fits
in well with the work going on at CeMM.
Heal
Yourself
Ce — M­— M­— Research Report 2007 52 53
 Achilles heel Lex Luther discovered that kryptonite could kill
Superman rather by accident. For ­Samson, it was Fig. 2 Images of cells
Know
Yourself

of cancer
Mythical heroes are often blessed with super­
natural strength. However, with this strength
comes an inevitable weakness, which is always
exploited by the bad guys. Take Superman for
example; arguably one of the toughest super­
heroes. Armed with inhuman strength and X-ray
“We believe that vision, the ability to fly, and turn back time, is
every cancer there anything Superman cannot do? Well,
actually yes. He is unable to come within 10 feet
has an Achilles of a little piece of rock from another world:
heel, that we kryptonite. His apparent invincibility hides
hope to identify a rather distressing weakness. The same goes
for the Greek hero Achilles, who was invulner­
and develop able all over his body, except for his heel, and
drugs to exploit.” Samson, who had tremendous strength that
could only be overcome by cutting off his hair.
At first glance, cancer also seems to have great
strength and be apparently invincible. However,
scientists now think that their ability to grow
unrestricted causes the development of weak­
nesses. The challenge now is to find out what
those weaknesses are. “Escaping growth control
comes with a price”, says Sebastian. “We believe
the slyness of his wife Delilah that revealed grown under different
conditions, showing that
his secret and led to his capture by the Palestinians. treating cells that have Defend
Sebastian Nijman is developing a rather more certain cancer-associated Yourself
mutations (CYLD K.D.)
systematic way of uncovering the weaknesses with drugs such as aspirin
of cancer. “We take cells and genetically inhibit ­(bottom row) can stop
Control
a known tumor suppressor gene, or activate a CYLD K.D. them growing under Yourself
specific physiological
specific oncogene …”, explains Sebastian. Each conditions (+ TNF , right
genetic variation mimics in a different way, column).
what goes on inside cancer cells. So they are using Treat
Yourself
knowledge about the molecular causes of cancer
to design their genetic screens. Then, using
a collection of over 1000 chemical compounds,
they treat the cells and find out whether any of
the ‘cancer’ alterations make the cells specifically
sensitive to any given compound. Chemical
compounds can affect many different biological CYLD K.D.
processes in a cell, and it is this principle that + aspirin
Sebastian uses to tease out the areas in a cancer
cell that are significantly weakened compared
to a normal cell.
The pharmacologist and Nobel laureate James
Black once said, “The most fruitful basis for
the discovery of a new drug is to start with an
old drug”. Importantly, the compounds that
Sebastian uses in his screens are already clinically Fig. 3 Four Western
approved drugs. This means they have already blots, one for each of four
cancer-related proteins
been shown to be safe for human use. “Once (PTEN, SMAD4, pRB and

2
A–

A–
l

l
A
ro

ro

ro
that every cancer has an Achilles heel, that we we find compounds that target cancer cells by TSC2), showing how these

RN

RN

RN
nt

nt

nt
proteins (black bands)

sh
co

sh

sh
co

co
hope to identify and develop drugs to exploit”. exploiting their weaknesses, we essentially can be removed from cells
already have a usable drug”, says Sebastian. It using RNAi technology.
also gives them a unique biological insight into Each blot contains control
lanes (vertical), where one
the molecular mechanisms that drive cancer. PTEN SMAD4 protein band is clearly vis-
ible, and adjacent shRNA
lanes that have been
subjected to RNAi causing
the proteins to become
significantly reduced.

l
A

A
ro

ro

ro

ro
RN

RN
nt

nt

nt

nt
sh

sh
co

co

co

co
Fig. 1 Protein samples are pRB TSC2
run vertically through a
gel, causing them to sepa-
rate according to their
molecular weight into dis-
tinct bands, stained blue.
Some of these proteins
bound to a specific drug.
These bands can be cut
out of the gel and subject-
ed to mass spectrometry,
to identify the proteins.

Heal
Yourself

Ce — M­— M­— Research Report 2007 Ce — M­— M­— Research Report 2007 54 55
 Prof. Dr. Peter Schuster
President of the Austrian Academy of Sciences

The goal of CeMM is to perform cutting-edge research and

to break a path towards a new kind of medicine that takes
advantage of the large body of knowledge from present day
life sciences for diagnostic, preventive, and therapeutic
purposes. Modern genomics, proteomics, and systems biology
are indeed continuously collecting a wealth of highly relevant
data, which have not yet been exploited for human health.
Close cooperation between CeMM and medical sciences at
the General Hospital of Vienna (AKH) housing the clinics of
Medical University of Vienna was and is considered to be
indispensable for the success of the new institute. Thanks to
strong support from the local government of the Community
of Vienna, the Federal Government of Austria, and the Medi-
cal University of Vienna the construction of the building for
CeMM can now begin. In 2004, the academy succeeded in
appointing Giulio Superti-Furga as director of CeMM, who has
since done a marvelous job. He succeeded in recruiting an
excellent crew of enthusiastically motivated young scientists.
In a recent “Science Day” the CeMM groups presented their
excellent scientific achievements to the public and discussed
future plans for the work at the institute. The present volume
is the first CeMM official report and testifies that research
of high scientific standards is performed already under the
suboptimal conditions of the interim accommodation in small
rented laboratories. In the name of the Austrian Academy
of Sciences and on my own behalf I would like to use this
opportunity to congratulate the director for the work he has
done in the past and to wish him and the entire crew of
CeMM all the best for a brilliant future in the current rather
modest home as well as in the forthcoming new building
at the AKH. Science needs researchers that are willing and
enjoy taking the risk to explore new scientific territory, and
molecular medicine has plenty of opportunities to proceed
into the unknown.

Ce — M­— M­— Research Report 2007 Ce — M­— M­— Research Report 2007 56 57
 Heal
Know
Yourself

Defend
Yourself
Met –
Arg – Met – Leu – Leu –
His – Leu – Ser – Leu – Leu – Ala – Leu –
Control

Yourself
Gly – Ala – Ala – Tyr – Val – Tyr – Ala – Ile – Pro –
Yourself
Thr – Glu – Ile – Pro – Thr – Ser – Ala – Leu – Val – Lys –
Glu –Thr –Leu –Ala –Leu –Leu –Ser –Thr –His –Arg –Thr –
Leu – Leu – Ile – Ala – Asn – Glu – Thr – Leu – Arg – Ile – Pro – Val –
Pro –Val –His –Lys –Asn –His –Gln –Leu –Cys –Thr –Glu –Glu –Ile – Treat
Phe – Gln – Gly – Ile – Gly –Thr –Leu –Glu –Ser –Gln –Thr –Val –Gln –Gly – Yourself
Gly – Thr – Val – Glu – Arg – Leu – Phe – Lys – Asn – Leu – Ser – Leu – Ile – Lys – Lys –Tyr –Ile –Asp –Gly –Gln –Lys –Lys –
Lys – Cys – Gly – Glu – Glu – Arg – Arg – Arg – Val – Asn – Gln – Phe – Leu – Asp – Tyr – Leu – Gln – Glu – Phe – Leu – Gly – Val – Met –
Asn – Thr – Glu – Trp – Ile – Ile – Glu – Ser – +++ – Met – Ile – Ile – Val – Ala – His – Val – Leu – Leu – Ile – Leu – Leu – Gly – Ala – Thr – Glu – Ile – Leu –
Gln –Ala –Asp –Leu –Leu –Pro –Asp –Glu –Lys –Ile –Ser –Leu –Leu –Pro –Pro –Val –Asn –Phe –Thr –Ile –Lys –Val –Thr –Gly –Leu –Ala –Gln –Val –Leu – Heal
Yourself
Leu – Gln – Trp – Lys – Pro – Asn – Pro – Asp – Gln – Glu – Gln – Arg – Asn – Val – Asn – Leu – Glu – Tyr – Gln – Val – Lys – Ile – Asn – Ala – Pro – Lys – Glu – Asp – Asp –
Tyr – Glu – Thr – Arg – Ile – Thr – Glu – Ser – Lys – Cys – Val – Thr – Ile – Leu – His – Lys – Gly – Phe – Ser – Ala – Ser – Val – Arg – Thr – Ile – Leu – Gln – Asn – Asp – His –
Ser –Leu –Leu –Ala –Ser –Ser –Trp –Ala –Ser –Ala –Glu –Leu –His –Ala –Pro –Pro –Gly –Ser –Pro –Gly –Thr –Ser –Ile –Val –Asn –Leu –Thr –Cys –Thr –Thr –
Asn –Thr –Thr –Glu –Asp –Asn –Tyr –Ser –Arg –Leu –Arg –Ser –Tyr –Gln –Val –Ser –Leu –His –Cys –Thr –Trp –Leu –Val –Gly –Thr –Asp –Ala –Pro –
Glu –Asp –Thr –Gln –Tyr –Phe –Leu –Tyr –Tyr –Arg –Tyr –Gly –Ser –Trp –Thr –Glu –Glu –Cys –Gln –Glu –Tyr –Ser –Lys –Asp –Thr –Leu –Gly –Arg –
Asn –Ile –Ala –Cys –Trp –Phe –Pro –Arg –Thr –Phe –Ile –Leu –Ser –Lys –Gly –Arg –Asp –Trp –Leu –Ala –Val –Leu –Val –Asn –Gly –Ser –Ser –
Lys – His – Ser – Ala – Ile – Arg – Pro – Phe – Asp – Gln – Leu – Phe – Ala – Leu – His – Ala – Ile – Asp – Gln – Ile – Asn – Pro – Pro – Leu –
Asn – Val – Thr – Ala – Glu – Ile – Glu – Gly – Thr – Arg – Leu – Ser – Ile – Gln – Trp – Glu – Lys – Pro – Val – Ser – Ala – Phe – Pro – Ile –
His –Cys –Phe –Asp –Tyr –Glu –Val –Lys –Ile –His –Asn –Thr –Arg –Asn –Gly –Tyr –Leu –Gln –Ile – Glu – Lys – Leu – Met – Thr –
Asn –Ala –Phe –Ile –Ser –Ile –Ile –Asp –Asp –Leu –Ser –Lys –Tyr –Asp –Val –Gln –Val –Arg –Ala –Ala – Val –Ser –Ser –Met –Cys –
Arg –Glu –Ala –Gly –Leu –Trp –Ser –Glu –Trp –Ser –Gln –Pro –Ile –Tyr –Val –Gly –Asn –Asp –Glu –His – Lys – Pro – Leu – Arg –
For Heal Yourself we Glu –Trp –Phe –Val –Ile –Val –Ile –Met –Ala –Thr –Ile –Cys –Phe –Ile –Leu –Leu –Ile –Leu –Ser –Leu –Ile – Cys – Lys – Ile – Cys – His –
Leu – Trp – Ile – Lys – Leu – Phe – Pro – Pro – Ile – Pro – Ala – Pro – Lys – Ser – Asn – Ile – Lys – Asp – Leu – Phe – Val – Thr – Thr – Asn – Tyr – + Natural Antibodies
have chosen the signal-
ling cytokine IL-5 and its Glu – Lys – Ala – Gly – Ser – Ser – Glu – Thr – Glu – Ile – Glu – Val – Ile – Cys – Tyr – Ile – Glu – Lys – Pro – Gly – Val – Glu – Thr – Leu – Glu – Asp – and Atherosclerosis
cognate receptor. CeMM Ser – Val – Phe – +++ – Met – Arg – Met – Leu – Leu – His – Leu – Ser – Leu – Leu – Ala – Leu – Gly – Ala – Ala – Tyr – Val – Tyr – Ala – Ile – Pro – Thr –
Principal Investigator Glu – Ile – Pro – Thr – Ser – Ala – Leu – Val – Lys – Glu – Thr – Leu – Ala – Leu – Leu – Ser – Thr – His – Arg – Thr – Leu – Leu –Ile –Ala –Asn –Glu –Thr –
Christoph Binder works Leu – Arg – Ile – Pro – Val – Pro – Val – His – Lys – Asn – His – Gln – Leu – Cys – Thr – Glu – Glu – Ile – Phe – Gln – Gly – Ile – Gly – Thr – Leu – Glu – Ser –
on the ability of IL-5 to Gln – Thr – Val – Gln – Gly – Gly – Thr – Val – Glu – Arg – Leu – Phe – Lys – Asn – Leu – Ser – Leu – Ile – Lys – Lys – Tyr – Ile – Asp –Gly –Gln –Lys –Lys –Lys –
stimulate B-cells secreting Cys –Gly –Glu –Glu –Arg –Arg –Arg –Val –Asn –Gln –Phe –Leu –Asp –Tyr –Leu –Gln –Glu –Phe –Leu –Gly –Val –Met – Asn – Thr – Glu – Trp – Ile – Ile –
particular natural antibod- Glu – Ser – +++ – Met – Ile – Ile – Val – Ala – His – Val – Leu – Leu – Ile – Leu – Leu – Gly – Ala – Thr – Glu – Ile – Leu – Gln – Ala – Asp – Leu – Leu – Pro – Asp –
ies. In turn, these antibod- Glu – Lys – Ile – Ser – Leu – Leu – Pro – Pro – Val – Asn – Phe – Thr – Ile – Lys – Val – Thr – Gly – Leu – Ala – Gln – Val – Leu – Leu – Gln – Trp – Lys – Pro – Asn –
ies are thought to perform Pro –Asp –Gln –Glu –Gln –Arg –Asn –Val –Asn –Leu –Glu –Tyr –Gln –Val –Lys –Ile –Asn –Ala –Pro –Lys –Glu –Asp –Asp – Tyr – Glu – Thr – Arg – Ile –
housekeeping functions by Thr –Glu –Ser –Lys –Cys –Val –Thr –Ile –Leu –His –Lys –Gly –Phe –Ser –Ala –Ser –Val –Arg –Thr –Ile –Leu –Gln –Asn –Asp – His – Ser – Leu – Leu –
clearing the blood vessels Ala –Ser –Ser –Trp –Ala –Ser –Ala –Glu –Leu –His –Ala –Pro –Pro –Gly –Ser –Pro –Gly –Thr –Ser –Ile –Val –Asn –Leu –Thr –Cys – Thr – Thr – Asn – Thr –
of atherosclerotic lesions. Thr – Glu – Asp – Asn – Tyr – Ser –Arg –Leu –Arg –Ser –Tyr –Gln –Val –Ser –Leu –His –Cys –Thr –Trp –Leu –Val –Gly –Thr – Asp –Ala –Pro –Glu –Asp –Thr –Gln –Tyr –Phe –Leu –Tyr –Tyr –
At CeMM, we investigate if Arg – Tyr – Gly – Ser – Trp – Thr – Glu – Glu – Cys – Gln – Glu – Tyr – Ser – Lys – Asp – Thr – Leu – Gly – Arg – Asn – Ile – Ala – Cys – Trp – Phe –Pro –Arg –Thr –Phe –Ile –Leu –Ser –Lys –Gly –Arg –Asp –Trp –
it is possible to persuade Leu –Ala –Val –Leu –Val – Asn – Gly – Ser – Ser – Lys – His – Ser – Ala – Ile – Arg – Pro – Phe – Asp – Gln – Leu – Phe – Ala – Leu – His – Ala –Ile –Asp –Gln –Ile –Asn –Pro –Pro –Leu –Asn –Val –Thr –Ala –Glu –Ile –Glu –Gly –
the body to produce more Thr – Arg – Leu – Ser – Ile –Gln –Trp –Glu –Lys –Pro –Val –Ser –Ala –Phe –Pro –Ile –His –Cys –Phe –Asp –Tyr –Glu –Val –Lys –Ile –His –Asn –Thr –Arg –Asn –Gly –Tyr –Leu –Gln –Ile –Glu –Lys –Leu –Met –Thr –Asn –Ala –Phe –Ile –Ser –
of these “good”, natural Ile – Ile – Asp – Asp – Leu –Ser –Lys –Tyr –Asp –Val –Gln –Val –Arg –Ala –Ala –Val –Ser –Ser –Met –Cys –Arg –Glu –Ala –Gly –Leu –Trp –Ser –Glu –Trp –Ser –Gln –Pro –Ile –Tyr –Val –Gly –Asn –Asp –Glu –His –Lys –Pro –Leu –Arg –
antibodies. Glu – Trp – Phe – Val – Ile –Val –Ile –Met –Ala –Thr –Ile –Cys –Phe –Ile –Leu –Leu –Ile –Leu –Ser –Leu –Ile –Cys –Lys –Ile –Cys –His –Leu –Trp –Ile –Lys –Leu –Phe –Pro –Pro –Ile –Pro –Ala –Pro –Lys –Ser –Asn –Ile –Lys –Asp –Leu –Phe –
Val – Thr – Thr – Asn – Tyr –Glu –Lys –Ala –Gly –Ser –Ser –Glu –Thr –Glu –Ile –Glu –Val –Ile –Cys –Tyr –Ile –Glu –Lys –Pro –Gly –Val –Glu –Thr –Leu –Glu –Asp –Ser –Val –Phe –+++ –Met –Arg –Met –Leu –Leu –His –Leu –Ser –Leu –
Leu –Ala –Leu –Gly – Ala – Ala – Tyr – Val – Tyr – Ala – Ile – Pro – Thr – Glu – Ile – Pro – Thr – Ser – Ala – Leu – Val – Lys – Glu – Thr – Leu – Ala – Leu – Leu – Ser – Thr – His – Arg – Thr – Leu – Leu – Ile – Ala – Asn – Glu – Thr – Leu – Arg – Ile – Pro –
IL5_HUMAN Uniprot Val – Pro – Val – His – Lys –Asn –His –Gln –Leu –Cys –Thr –Glu –Glu –Ile –Phe –Gln –Gly –Ile –Gly –Thr –Leu –Glu –Ser –Gln –Thr –Val –Gln –Gly –Gly –Thr –Val –Glu –Arg –Leu –Phe –Lys –Asn –Leu –Ser –Leu –Ile –Lys –Lys –Tyr –
P05113 Ile – Asp – Gly – Gln – Lys –Lys –Lys –Cys –Gly –Glu –Glu –Arg –Arg –Arg –Val –Asn –Gln –Phe –Leu –Asp –Tyr –Leu –Gln –Glu –Phe –Leu –Gly –Val –Met –Asn –Thr –Glu –Trp –Ile –Ile –Glu –Ser –+++ –Met –Ile –Ile –Val –Ala –
His – Val – Leu – Leu – Ile – Leu – Leu – Gly – Ala – Thr – Glu – Ile – Leu – Gln – Ala – Asp – Leu – Leu – Pro – Asp – Glu – Lys – Ile – Ser – Leu – Leu – Pro – Pro – Val – Asn – Phe – Thr – Ile – Lys – Val – Thr – Gly – Leu – Ala – Gln – Val – Leu – Leu –
IL5RA_HUMAN Uniprot Gln – Trp – Lys – Pro – Asn – Pro – Asp – Gln – Glu – Gln – Arg – Asn – Val – Asn – Leu – Glu – Tyr – Gln – Val – Lys – Ile – Asn – Ala – Pro – Lys – Glu – Asp – Asp – Tyr – Glu – Thr – Arg – Ile – Thr – Glu – Ser – Lys – Cys – Val – Thr – Ile – Leu – His –
Q01344 Lys –Gly –Phe –Ser – Ala – Ser – Val – Arg – Thr – Ile – Leu – Gln – Asn – Asp – His – Ser – Leu – Leu – Ala – Ser – Ser – Trp – Ala – Ser – Ala – Glu – Leu – His – Ala – Pro – Pro – Gly – Ser – Pro – Gly – Thr – Ser – Ile – Val – Asn – Leu – Thr – Cys –
Thr – Thr – Asn – Thr –Thr –Glu –Asp –Asn –Tyr –Ser –Arg –Leu –Arg –Ser –Tyr –Gln –Val –Ser –Leu –His –Cys –Thr –Trp –Leu –Val –Gly –Thr –Asp –Ala –Pro –Glu –Asp – Thr – Gln – Tyr – Phe – Leu – Tyr – Tyr – Arg – Tyr –
Gly – Ser – Trp – Thr – Glu –Glu –Cys –Gln –Glu –Tyr –Ser –Lys –Asp –Thr –Leu –Gly –Arg –Asn –Ile –Ala –Cys –Trp –Phe –Pro –Arg –Thr –Phe –Ile –Leu –Ser –Lys – Gly – Arg – Asp – Trp – Leu – Ala – Val – Leu –
Val –Asn –Gly –Ser – Ser – Lys – His – Ser – Ala – Ile – Arg – Pro – Phe – Asp – Gln – Leu – Phe – Ala – Leu – His – Ala – Ile – Asp – Gln – Ile – Asn – Pro – Pro – Leu – Asn –Val –Thr –Ala –Glu –Ile –Glu –Gly –Thr –
Arg – Leu – Ser – Ile – Gln –Trp –Glu –Lys –Pro –Val –Ser –Ala –Phe –Pro –Ile –His –Cys –Phe –Asp –Tyr –Glu –Val –Lys –Ile –His –Asn –Thr –Arg –Asn – Gly –Tyr –Leu –Gln –Ile –Glu –Lys –Leu –Met –
Thr – Asn – Ala – Phe – Ile – Ser – Ile – Ile – Asp – Asp – Leu – Ser – Lys – Tyr – Asp – Val – Gln – Val – Arg – Ala – Ala – Val – Ser – Ser – Met – Cys – Arg – Glu – Ala – Gly – Leu – Trp – Ser – Glu – Trp – Ser – Gln – Pro –
Ile –Tyr –Val –Gly –Asn – Asp –Glu –His –Lys –Pro –Leu –Arg –Glu –Trp –Phe –Val –Ile –Val –Ile –Met –Ala –Thr –Ile –Cys –Phe –Ile –Leu –Leu –Ile –Leu –Ser – Leu – Ile – Cys – Lys – Ile – Cys – His – Leu – Trp –
Ile –Lys –Leu –Phe –Pro – Pro –Ile –Pro –Ala –Pro –Lys –Ser –Asn –Ile –Lys –Asp –Leu –Phe –Val –Thr –Thr –Asn –Tyr –Glu –Lys –Ala –Gly –Ser –Ser –Glu –Thr – Glu –Ile –Glu –Val –Ile –Cys –Tyr –Ile –Glu –Lys –
Pro –Gly –Val –Glu –Thr – Leu –Glu –Asp –Ser –Val –Phe –+++ –Met –Arg –Met –Leu –Leu –His –Leu –Ser –Leu –Leu –Ala –Leu –Gly –Ala –Ala –Tyr –Val –Tyr –Ala – Ile – Pro – Thr – Glu – Ile – Pro – Thr – Ser – Ala –
Leu – Val – Lys – Glu – Thr – Leu – Ala – Leu – Leu – Ser – Thr – His – Arg – Thr – Leu – Leu – Ile – Ala – Asn – Glu – Thr – Leu – Arg – Ile – Pro – Val – Pro – Val – His – Lys – Asn – His – Gln – Leu – Cys – Thr – Glu – Glu – Ile –
Phe – Gln – Gly – Ile – Gly –Thr –Leu –Glu –Ser –Gln –Thr –Val –Gln –Gly –Gly –Thr –Val –Glu –Arg –Leu –Phe –Lys –Asn –Leu –Ser –Leu –Ile –Lys –Lys –Tyr – Ile – Asp – Gly – Gln – Lys – Lys – Lys – Cys – Gly –
Glu – Glu – Arg – Arg – Arg –Val –Asn –Gln –Phe –Leu –Asp –Tyr –Leu –Gln –Glu –Phe –Leu –Gly –Val –Met –Asn –Thr –Glu –Trp –Ile –Ile –Glu – Ser – +++ – Met – Ile – Ile – Val – Ala – His – Val –
Leu – Leu – Ile – Leu – Leu –Gly –Ala –Thr –Glu –Ile –Leu –Gln –Ala –Asp –Leu –Leu –Pro –Asp –Glu –Lys –Ile –Ser –Leu –Leu –Pro –Pro – Val –Asn –Phe –Thr –Ile –Lys –Val –Thr –Gly –
Leu – Ala – Gln – Val – Leu –Leu –Gln –Trp –Lys –Pro –Asn –Pro –Asp –Gln –Glu –Gln –Arg –Asn –Val –Asn –Leu –Glu –Tyr –Gln – Val –Lys –Ile –Asn –Ala –Pro –Lys –Glu –Asp –
Asp – Tyr – Glu – Thr – Arg – Ile – Thr – Glu – Ser – Lys – Cys – Val – Thr – Ile – Leu – His – Lys – Gly – Phe – Ser – Ala – Ser – Val – Arg – Thr – Ile – Leu – Gln – Asn – Asp – His –
Ser –Leu –Leu –Ala – Ser –Ser –Trp –Ala –Ser –Ala –Glu –Leu –His –Ala –Pro –Pro –Gly –Ser –Pro –Gly – Thr – Ser – Ile – Val – Asn – Leu – Thr – Cys –
Thr – Thr – Asn – Thr – Thr – Glu – Asp – Asn – Tyr – Ser – Arg – Leu – Arg – Ser – Tyr – Gln – Val – Ser – Leu – His – Cys – Thr – Trp – Leu – Val – Gly –
Thr – Asp – Ala – Pro – Glu – Asp – Thr – Gln – Tyr – Phe – Leu – Tyr – Tyr – Arg – Tyr – Gly – Ser – Trp – Thr – Glu – Glu – Cys – Gln – Glu – Tyr – Ser –
Lys – Asp – Thr – Leu –Gly –Arg –Asn –Ile –Ala –Cys –Trp –Phe –Pro –Arg –Thr –Phe –Ile –Leu – Ser – Lys – Gly – Arg – Asp – Trp – Leu – Ala –
Val – Leu – Val – Asn – Gly – Ser – Ser – Lys – His – Ser – Ala – Ile – Arg – Pro – Phe – Asp – Gln – Leu – Phe – Ala – Leu – His – Ala – Ile –
Asp – Gln – Ile – Asn –Pro –Pro –Leu –Asn –Val –Thr –Ala –Glu –Ile –Glu –Gly –Thr – Arg – Leu – Ser – Ile – Gln –
Trp – Glu – Lys – Pro –Val –Ser –Ala –Phe –Pro –Ile –His –Cys –Phe –Asp –Tyr – Glu – Val – Lys – Ile – His –
Asn –Thr –Arg – Asn –Gly –Tyr –Leu –Gln –Ile –Glu –Lys –Leu –Met –Thr – Asn – Ala – Phe – Ile – Ser – Ile –
Ile – Asp – Asp – Leu – Ser – Lys – Tyr – Asp – Val – Gln – Val – Arg – Ala – Ala – Val – Ser – Ser – Met – Cys –
Arg –Glu –Ala – Gly – Leu – Trp – Ser – Glu – Trp – Ser – Gln – Pro – Ile – Tyr – Val – Gly – Asn – Asp – Glu –
His – Lys – Pro – Leu – Arg – Glu – Trp – Phe – Val – Ile – Val – Ile – Met – Ala – Thr – Ile – Cys – Phe – Ile –
Leu – Leu – Ile – Leu – Ser – Leu – Ile – Cys – Lys – Ile – Cys – His – Leu – Trp – Ile – Lys – Leu – Phe – Pro – Pro –
Ile – Pro – Ala – Pro – Lys – Ser – Asn – Ile – Lys – Asp – Leu – Phe – Val –
Thr – Thr – Asn – Tyr – Glu – Lys – Ala – Gly – Ser – Ser –
Glu –Thr –Glu –Ile – Glu – Val – Ile – Cys – Tyr – Ile –
Glu – Lys – Pro – Gly – Val – Glu – Thr – Leu –
Glu – Asp – Ser – Val – Phe – +++ – Met – Arg – Met –
Leu – Leu – His – Leu –
Learning from
“The art of healing comes from
nature, not from the physician.
Therefore the physician must start
the Experts
from nature, with an open mind.”
Paracelsus, Swiss physician and
alchemist, 1493–1541.
The ultimate goal of preventing disease is to selectively
modulate the body’s own capacity to maintain a healthy state.
Healing is the mechanism of repair. In times
of illness, we turn to medicine or sometimes
spiritual sources to stimulate the healing process.
However the body has its own natural ways
of healing itself. Antibodies are proteins found
in the blood that fight disease and return the
body to a healthy state. They are an essential
component of our immune response, and are
produced by special white blood cells known as
B cells. Each antibody is customized to an antigen,
usually a foreign protein or molecule found on
the surface of a pathogen. An antibody binds very
tightly to its specific antigen, and this serves
to tag its partner for destruction and clearance by
other immune cells, or to disable it so it can no
longer cause any harm.
Most antibodies are produced in response to
infection and they constitute part of the branch
of the immune system known as adaptive
immunity, aptly named to illustrate its speci­
ficity for an infection. Once a B cell comes into
contact with a pathogen, it binds an antigen and
becomes activated. Eventually this B cell will
be responsible for generating large quantities of
antibodies produced in the body that all bind
to this one specific antigen. Due to this speci­
ficity, adaptive immunity is the second line of
defense against disease, as it takes at least several
days after infection to become operational.
Ce — M­— M­— Research Report 2007 Ce — M­— M­— Research Report 2007
Natural Antibodies
There are other types of antibodies, known as
Know
Yourself
natural antibodies that work quite differently.
We all have these antibodies circulating in our Defend
blood, and they are unique because they are Yourself
present before any infection has taken place.
Originally dismissed as mere background, natural Control
antibodies have only recently been shown to Yourself
play a crucial role in combating disease. They
have a dual specificity, because they not only
Treat
recognize infectious antigens, but also antigens Yourself
on our own cells, produced in response to stress
or tissue damage. It is this unique aspect of
natural antibodies that suggests they promote Heal
Yourself
homeostasis and healing, by maintaining the
normal balance in the body. Christoph Binder
has been working on natural antibodies for
many years. He is now studying them with his
own group at CeMM, with a view to harnes­
sing their power to help the body heal itself.
Christoph studies natural antibodies in the con­
text of atherosclerosis, a chronic inflammatory
disease and the underlying cause of heart attack
and stroke. Atherosclerosis is a slow developing
disease, and one of the principle risk factors is
high cholesterol. This causes an accumulation of
specific lipids, known as oxidized LDL (OxLDL),
in the walls of blood vessels, which triggers
an inflammatory response. There is increasing
evidence that natural antibodies are also playing
some role in the progression of atherosclerosis,
although the details are entirely unclear.
60 61
 Natural
Antibodies and
Atherosclerosis
“Scientist have Natural Born Killer
Atherosclerosis is a deadly disease. It begins
shown that the almost as soon as our blood vessels develop
development during fetal life, but progression is slow, occur­
of atherosclerotic ring over decades with the gradual thickening
of blood vessel walls. High levels of LDL in the
lesions is closely bloodstream are required for disease progres­-
linked with sion. Oxidized LDL builds up and the ensuing
inflammation.” inflammatory response mediates the localized
recruitment of large numbers of immune
cells to blood vessel walls. Many of these cells
will eventually die, and their remains need to
be cleared away, otherwise these sites turn into
graveyards that, along with lipids and proteins,
“The hypothesis form lesions in the blood vessel walls. These
lesions aggregate and eventually form plaques
is that natural anti­ that are characteristic of advanced stages of
bodies are acting the disease. The plaques can eventually rupture,
like housekeepers, restricting the blood supply and potentially
causing death.
ensuring the
blood vessel walls There are many logical factors that cause an
are kept clear increased risk of atherosclerosis, including diet,
smoking and age. However, recent evidence
from obstruction.” has shown a rather unexpected collaboration
between this disease and the immune response,
a mechanism that is normally thought to be pro­
tective. Scientists have shown that the accumula­
tion of atherosclerotic lesions is closely linked
with inflammation. Many different types of
immune cells that are normally recruited to clear
an infection are found associated with these
lesions, and they are clearly important for their
formation and growth.
Ce — M­— M­— Research Report 2007
Keeping the Blood Vessels Clear
There is obviously a complex interplay between Fig. 1 Natural IgM
Know
Yourself
quite diverse components of the immune system ­antibodies are ­present in
atherosclerotic ­lesions.
and atherosclerosis. Both the adaptive and innate Section through an Defend
branches of immunity are involved. OxLDL is ­atherosclerotic aorta Yourself
(blood vessel) from mice
the primary candidate for triggering the immune fed with high levels of
response although the mechanisms of this are cholesterol, showing IgM
Control
poorly understood. Christoph is currently trying antibodies stained in red. Yourself
to work out some of the details. His group has Fig. 2 Oxidation-specific
epitopes are present in
recently discovered that an unexpectedly large
atherosclerotic lesions. Treat
number of natural antibodies have been primed
to target oxidized epitopes, including OxLDL.
Sections from cholesterol-
fed mice were stained to
Yourself
“Natural antibodies have also been found asso­
detect the presence of
malondialdehyde (MDA)
ciated with the atherosclerotic lesions”, says epitopes. MDA is a lipid-
peroxidation breakdown
Heal
Yourself
Christoph. In fact, they have already shown that
a specific type of natural antibody can provide
product. Positive staining
is indicated by red color.
protection against the disease. It is clear that
natural antibodies are important, but what they
are actually doing still needs to be investigated.
“We want to know the function of these natural
antibodies in atherosclerosis, and how they are
regulated”, says Christoph.
To do this, the group uses a combination of
approaches. Mouse models are an ideal system
as they provide a physiological setting in which
to study the disease. Christoph’s group has
been generating mice that are deficient in specific
types of natural antibodies to see if they provide
protection against the development of athero­
sclerosis. They are also trying to identify and
isolate more types of natural antibodies that are
primed to target these oxidized epitopes and
see if they can understand how they work. The
hypothesis is that natural antibodies are acting
like housekeepers, ensuring the blood vessel
walls are kept clear from obstruction. “We think
natural antibodies bind to the oxidized lipids
and thereby neutralize them and initiate their
clearance from the blood”, says Christoph. This
would effectively stop plaque formation and
disease progression.
“We also want to know how natural antibodies
themselves are regulated”, says Christoph. They
have found certain mouse strains that contain
higher amounts of natural antibodies than others
and now they are investigating what causes this.
If they can work out how natural antibodies are
generated, it may be possible to artificially stimu­
late their production, thereby targeting OxLDL in
individuals at risk of developing the disease. This
would essentially provide protection against the
disease, and potentially stimulate the body’s own
healing process.
Ce — M­— M­— Research Report 2007 62 63
 Prof. Dr. Wolfgang Schütz
Rector, Medical University of Vienna

It is a pleasure to congratulate the Center of Molecular

Medicine CeMM for its first research report. The Medical Uni-
versity of Vienna supports and fosters CeMM as an important
project together with the Austrian Academy of Sciences.
We look at CeMM as a strategic component of the strive of
the Medical University of Vienna to maintain and further
develop a leading role in biomedical research. CeMM aims
at bridging the gap between clinical and basic research and as
such is hoped to ease the translation of many projects towards
therapy and diagnostics. For this, CeMM’s location within the
hospital campus and physically linked to the newest of the
MUV research buildings is of paramount importance. Finally,
we are particularly happy about the training mission of CeMM.
Besides many common projects CeMM is linked to the MUV
with several common PhD programs, conferences, as well as
young investigators with double appointments. Nothing is as
valuable as the investment in students and young faculty and
CeMM represents an important addition for the interdisciplinary
training in molecular medicine.
On behalf of the entire faculty and MUV personnel we welcome
CeMM as a special partner to our research community and
wish it, for our own sake, a great future.

Ce — M­— M­— Research Report 2007 Ce — M­— M­— Research Report 2007 64 65
Accelerator
In 2005, CeMM created a fund to support
three Accelerator Projects, which were
to begin in January 2006 and run for two
Projects
years. These ­projects were designed to
extend the fruitful ­collaboration between
CeMM and some of its previously associated
members. The projects were specifically
required to be ‘application-orientated’ and
were carefully selected for their originality
and for their potential impact on therapy.
The three successful projects were:
+ Modulation of inflammatory
responses by manipulating the nuclear
export of nuclear receptors.
Project Leader: Bernd R Binder
+ Immunotherapy of Rheumatoid Arthritis.
Project Leader: Günter Steiner
+ Lymphatic endothelium as
gatekeeper for leukocyte trafficking”.
Project Leader: Dieter Maurer
Modulation
of inflammatory
responses
by manipulating
the nuclear
export of nuclear
receptors
ISG-12, a novel target for the modulation of
inflammatory responses: Development of
screening systems for drugs that interfere with
the ISG-12 mediated nuclear export of nuclear
receptors and generation of lead strategies
The aim of this project is based on our original
finding that the transcriptional activity of nuclear
receptors is down-regulated under inflammatory
conditions. Such down-regulation that inhibits
the anti-inflammatory, beneficial effects of nuclear
receptors, such as those of the NR 4A and the
PPAR family or RXR, FXR as well as LXR,
is mediated preferentially by type I interferons
and due to a small interferon inducible molecule,
the ISG-12.
Ce — M­— M­— Research Report 2007
Results Project Leader
Within the project we could confirm that ISG-12 Bernd R Binder
is located at the nuclear envelope and increases Department of Vascular
the nuclear export of a set of nuclear receptors Biology and Thrombosis
that are capable of heterodimerizing with RXR.
Using ISG-12 deficient mice generated by us and
Research, Medical University
of Vienna
mice double deficient for ISG-12 and NR4A1 or
ApoE or the LDLR, we could demonstrate that
ISG-12 deficiency is protective in a mainly NR4A1
dependent manner in animal models of chronic
vascular inflammation (restenosis) or acute
inflammatory models (endotoxin or sepsis mod­
els) and significantly reduces the extent of athero­
sclerotic lesions in atherosclerosis prone mice
transplanted with bone marrow from ISG-12
deficient mice.
In order to generate suitable peptides that can
interfere with ISG-12 activity, we successfully
determined the interaction site between ISG-12
and nuclear receptors, defining an ISG box that
interacts with an I-Box in the nuclear receptors.
This sequence information is currently used
to generate respective interfering peptides to be
used in animal models and eventually at a later
stage also in man. This information can also be
used to generate lead compounds for drug devel­
opment.
Coworkers
Nikolina Papac- Milicevic, PhD, PostDoc
Gabriel Wagner, Diploma student
Sabine Fenzl, Diploma student
Paul Dremsek, Diploma student
Judit Mihaly, MD thesis student
Relevant Publications
1. Papac-Milicevic, N.et al. The interferon induc­
ible gene 12 (ISG12), a novel factor modulating
the vascular response to injury, submitted.
2. Verwendung des Interferon induzierten Gens
12 (ISG-12, IFI27) zur Modulation transkription­
eller Aktivitäten von nucleären Faktoren PCT/
AT 06/000448; A1790/2005
66 67
Project Leader
Dieter Maurer Identification
Department of Dermatology,
Medical University of Vienna of novel receptor-
­ligand systems
regulating leuko­
cyte trafficking
into lymphatic
vessels.
Chemotactic factors are essential for the traffick­
ing of dendritic antigen-presenting cells (DCs)
into peripheral organs and lymph nodes via lym­
phatic vessels. This is required to mount specific
T cell responses against foreign pathogens found
in peripheral organs. There also exists a constant
flux of DCs into lymph nodes even in the absence
of foreign antigens/pathogens, which may be
essential to maintain T cell tolerance to self.
In this project, we focused on identifying mol­
ecules involved in the migration of DCs into
lymphatic vessels. Firstly, we investigated the
presence of such factors in lymphatic endothelial
cells (ECs) and have aimed to identify the specific
receptors on DCs. This would allow a mechanistic
understanding of DC trafficking in vivo and lead
to the development of rational therapeutic strate­
gies to regulate immunity and tolerance.
Results:
1. Lymphatic endothelial cells secrete factors
that regulate DC migration
We produced culture supernatants from human
skin blood and lymphatic ECs using our previ­
ously established methodology. Migration exper­
iments with purified human skin DCs (i.e. skin
Langerhans cells; LCs) showed that lymphatic
ECs secrete migration-inducing factors for DCs.
We enriched the biological activity and subjected
enriched fractions to MS analysis (together with
the group of Dr. Superti-Furga).
Ce — M­— M­— Research Report 2007
2. Global analysis of in vivo EC gene expression
as a tool to identify DC function-modulating
molecules
Bioinformatic analyses allowed us to define the
sets of genes that are specifically expressed in
lymphatic and blood ECs in vivo and to unravel
a pathway of self antigen presentation in MHC
class II that occurs on blood ECs and DCs and is
essential for the tuning of T cell activation
thresholds.
3. Lymphatic EC-derived neurotensin (NTS)
is a selective negative regulator of DC trafficking
Expression of neurotensin (NTS) was found
specifically in LECs and one out of the 4 human
NTS receptors was expressed on human LCs.
NTS effectively and dose-dependently inhib­
ited the migration of LCs to the “classical” LEC
chemotractant SLC/CCL21, correlating with
impairment of SLC/CCL21-induced, Rho-driven
activation of the focal adhesion-associated kinase,
Pyk2. These findings indicate that lymphatic
ECs are dedicated regulators of DC trafficking,
which can tune the rate of DC exit to lymph
nodes according to the demands of the tissues.
Co-workers
Ernst Kriehuber, MD, PostDoc
Paul Meraner, MD, PostDoc
Stefan Amatschek, MSc., Student
Bärbel Reininger, TA
Relevant Publications
1. Amatschek, S., E. Kriehuber, W. Bauer,
B. Reininger, P. Meraner, A. Wolpl, N. Schweifer,
C. Haslinger, G. Stingl, and D. Maurer. Blood and
lymphatic endothelial cell-specific differentia­
tion programs are stringently controlled by the
tissue environment. Blood 109:4777. (2007)
2. Meraner, P., V. Horejsi, A. Wolpl, G.F. Fischer,
G. Stingl, and D. Maurer. Dendritic cells sensitize
TCRs through self-MHC-mediated Src family
kinase activation. J. Immunol. 178:2262. (2007)
3. Winter, D., J. Moser, E. Kriehuber, C. Wiesner,
R. Knobler, F. Trautinger, P. Bombosi, G. Stingl,
P. Petzelbauer, A. Rot, and D. Maurer. Down-
modulation of CXCR3 surface expression and
function in CD8+ T cells from cutaneous T cell
lymphoma patients. J. Immunol. 179:4272. (2007)
Immunotherapy
of Rheumatoid
Arthritis
Rheumatoid arthritis (RA) is the most common
of the systemic autoimmune diseases and also the
most severe inflammatory joint disease, however
the role of autoimmune processes assumed to
initiate and drive the disease is unclear. Therapies
targeting antigen-specific autoimmune reactions
might be more effective, because they would
lead to specific elimination or down regulation
of pathogenic T and/or B cells. It has therefore
been the primary goal of this project to develop
a novel therapy for RA based on antigen specific
immune intervention to the well characterized
autoantigen hnRNP-A2 (RA33) that is targeted by
autoantibodies and T cells from patients with RA.
Results
1. Studies in patients. A major T cell epitope was
identified that was recognized by approximately
20% of RA patients but not by any of the (HLA
matched) controls.
2. Studies in rats with pristane-induced arthritis
(PIA). To identify potential autoantigens, we ana­
lyzed sera from rats with PIA and control animals
for the presence of autoantibodies using a panel
of 20 candidate antigens. An antibody response
against hnRNP-A2 was seen in the majority of
sera. Cellular studies revealed pronounced T cell
reactivity against hnRNP-A2 in pristane-primed
rats which showed a Th1 phenotype and was
present one week before disease onset. Further­
more, the antigen was massively overexpressed
in the joints of pristane-primed animals, sup­
porting earlier observations made in patients
with RA and TNFα transgenic mice. Remarkably,
hnRNP-A2 stimulated release of proinflamma­
tory cytokines such as TNFα and IL-6 in a toll-
like receptor (TLR) dependent manner, most
likely via interaction with TLR7. Taken together,
these data strongly suggest a role for hnRNP-A2
in the pathogenesis of PIA and human RA.
3. Therapeutic studies. To study the therapeutic
potency of hnRNP-A2 we used two different
arthritis animal models. Importantly, disease
onset and severity were significantly delayed
or almost completely abrogated by prior nasal
vaccination with hnRNP-A2 (unpublished,
preliminary observations).
Ce — M­— M­— Research Report 2007
4. Additional studies. We also identified hnRNP-D
(AUF1) as a target of autoantibodies of patients
Project Leader
Günter Steiner
with RA. AUF1 is involved in regulation of
stability of mRNAs encoding inflammatory
Division of Rheumatology,
Department of Internal
cytokines such as IL-1 or TNFα, prompting us
to investigate two other proteins involved in
Medicine III, Medical
University of Vienna
posttranscriptional regulation of TNFα expres­
sion, T cell intracellular antigen 1 (TIA-1) and
TIA-1 related protein (TIAR). Both AUF1 and the
TIA proteins were found to be overexpressed
in inflamed tissues, further supporting the idea
that proteins involved in posttranscriptional
regulation of gene expression are generally over­
expressed under conditions of inflammation,
which may lead loss of immune tolerance and the
induction of pathogenic autoimmune reactions.
Coworkers
Markus Hoffmann, PhD student (graduated
January 2008), currently working as PostDoc
Michael Müller, PhD student
Sylvie Trembleau, PostDoc
Brigitte Meyer, TA
Elisabeth Höfler, TA
Georg Stummvoll, MD
Esther Jimenez-Boj, MD
Relevant Publications
1. Fritsch-Stork R, Mullegger D, Skriner K,
Jahn-Schmid B, Smolen JS, Steiner G. The spli­
ceosomal autoantigen heterogeneous nuclear
ribonucleoprotein A2 (hnRNP-A2) is a major
T cell autoantigen in patients with systemic lupus
erythematosus. Arthritis Res Ther 8:R118. (2006)
2. Grisar JC, Aletaha D, Steiner CW, Kapral T,
Steiner S, et al. Endothelial progenitor cells
in active rheumatoid arthritis: Effects of TNF
and of glucocorticoid therapy. Ann Rheum Dis
66:1284–8. (2007)
3. Hoffmann MH, Tuncel J, Skriner K, Tohidast-
Akrad M, Türk B, et al. The rheumatoid arthritis-
associated autoantigen hnRNP-A2 (RA33) is a
major stimulator of autoimmunity in rats with
pristane-induced arthritis. J Immunol
179:7568–76. (2007)
4. Skriner K, Hueber W, Süleymanoglu E,
Höfler E, Krenn V, et al. AUF 1, the regulator of
tumor necrosis factor alpha messenger RNA
decay, is targeted by autoantibodies of patients
with rheumatic diseases. Arthritis Rheum
58:511–20. (2008)
5. Jimenez-Boj E, Kedersha N, Tohidast Akrad M,
Karlhofer FM, Stummvoll G, et al. Autoanti­
bodies to the translational suppressors TIA-1
and TIAR in patients with rheumatic diseases.
Arthritis Rheum, in press.
68 69
The First Drug Action and
Man and woman. Europe and America. CeMM In a talk that perhaps best exemplified the
and EMBO. Chemistry and Biology. These were integration of basic science and drug discovery,
the winning combinations that together went
Chemical Biology a goal of the meeting, Stephen Fesik (Abbott)

Conference
on to make the first CeMM research conference discussed how his team used his SAR by NMR
a resounding success. First, the organizers: Giulio
Superti-Furga and Ulrike Eggert. Giulio is the in the Post­ approach to discover inhibitors of anti-apoptotic
proteins. One of these compounds is now in
Scientific Director of CeMM and a visiting profes­
genomic Era clinical trials to treat leukaemia and other cancers.

of CeMM:
sor at the Medical University of Vienna. He has
been mainly based in Europe having studied in Small molecules can also be used to study entire
Zurich and the Institute for Molecular Pathology classes of proteins using activity-based profiling.
in Vienna (IMP), as well as heading his own In a beautiful and comprehensive example,

Synergy
research group at the European Molecular Biology
Laboratory in Heidelberg and being the scientific
leader of Cellzome, a biotech company, for five
years. Ulrike Eggert is Assistant Professor at the
Chemical biology and molecular pharmacology ­Benjamin Cravatt (Scripps) discussed how his
as scientific disciplines are evolving towards lab began with a screen and discovered a new
each other and profit from powerful advances role for specific metabolites in cancer.
in postgenomic, imaging and bioinformatic

in action
Dana Farber Cancer Institute and Harvard Uni­ technologies. Concurrently, diseases are being Ron Raines (U Wisconsin/Madison) illustrated
versity in Boston. Ulrike did her undergraduate better characterized at a molecular level and an example of how a protein itself can become
degree in Oxford in the UK, but moved to the the genetic basis for differential response of a drug by engineering a ribonuclease (RNAse)
USA shortly after, for both her PhD and Post- patients to therapeutics is being investigated. and showing that it can target and kill cancer cells.
23 — 26 August 2007 doctoral research. Together, they make an inter­
Austrian Academy of Sciences, Vienna, Austria national team and an ideal combination to Understanding and Exploiting Proteins Targeting the Kinome
organize a high-profile scientific conference. Historically, enzymes have been the main targets Small molecule inhibitors of tyrosine protein
of small molecules, both in drug discovery and kinases are a class of compounds that are both
The European Molecular Biology Organization in chemical biology. Designing effective small important research tools and a successful group
(EMBO) encourages scientists to organize work­ molecule inhibitors is dependent on understand­ of therapeutics. Imatinib (Gleevec), probably
shops, which are intended to give researchers ing the mechanism of an enzyme. The polymeriz­ the best characterized and most successful target­
from different but related fields the opportunity ing enzyme (GlfT) is involved in the biosynthesis ed therapeutic agent, has galvanised the field of
to meet and discuss common themes. Giulio of the bacterial cell wall in M. tuberculosis and signal transduction and formed the basis of new
and Ulrike come from different scientific back­ therefore a potential target for the development therapeutic approaches.
grounds but both use similar chemical and cell of urgently needed antibiotics. Laura Kiessling
biological approaches to do their research. This (U Wisconsin/Madison) discussed how they
prompted them to organize an EMBO workshop, discovered how this enzyme works, and there­
in collaboration with CeMM, designed to explore fore could design inhibitors, which have shown
the synergism between biology, chemistry some promise in killing mycobacteria.
and medicine. The goal was to foster interactions
between researchers of different backgrounds
who have a common interest in understanding
the effect of chemical compounds on biological
systems. Dining in the Kuppelhalle,
where the stage is set
for rockband Rocquette.
The organizers invited a range of internationally
renowned scientists from both chemistry and
biology to take part in the conference. All in all,
it was a recipe for success. Attendees commented
on the exceptionally high quality of the science,
and scientific discussions were made all the more
enjoyable by the extraordinary surroundings
of the National Historisches Museum in Vienna,
which was the venue for the event. The following
article is based on a meeting report written by
the two organizers, Ulrike Eggert and Giulio
Superti-Furga. The full version can be accessed
from Nature Chemical Biology, January 2008,
Vol. 4, 1, p7–11.

Ce — M­— M­— Research Report 2007 70 71

 The laboratories of Gerard Drewes (Cellzome)
and Superti-Furga (CeMM, Vienna) presented
chemical proteomics studies using imatinib, its
structurally related second generation cousin
nilotinib as well as the type I inhibitors dasatinib
and bosutinib. Both groups reported the sur­
prising finding that therapeutic drugs with the
same medical indication (chronic myelogenous
leukemia) display dramatically different interac­
tion profiles, with only a few targets in common.
Small Molecular Probes of Cell Division
Small molecules that target cell division have
a long and distinguished history, both as drugs
and as tool compounds. For example, the tubulin
binder taxol is a widely used anti-cancer drug.
Thomas Mayer (MPI Martinsried) and Ulrike
­Eggert (Dana-Farber Cancer Institute and Harvard
Medical School) discussed recent advances in this
field. Jan-Michael Peters (IMP Vienna) discussed
how they used BI2536, an inhibitor of a regulator
of cell division they discovered in collaboration
with Boehringer Ingelheim, to study both mitosis
and cytokinesis.
Drugs, Pathways and Networks
In a synthetic lethal relationship, a cell survives
if one protein of a synthetic pair is removed, but
dies if both are removed, implying a functional
cooperation between the two proteins. Synthetic
lethality can be assessed by removing combina­
tions of gene products or by combining gene
products and drugs. Mike Tyers (University of
Edinburgh) reported on more than 100 synthetic
lethality screens performed in his laboratory,
which is part of an effort to comprehensively
map the network of all possible chemical and
genetic synthetic interactions in yeast.
Ce — M­— M­— Research Report 2007
In a conceptually related approach, several groups
have developed tools to monitor changes in the Natural History Museum:
activity of drugs in mammalian cells using RNA Venue for the gala dinner.
interference. Julian Downward (Cancer Research
UK) discussed an RNAi screen to identify genes
that are involved in resistance to cancer chemo­
therapeutic drugs and Thijn Brummelkamp
(Whitehead Institute) reported on new shRNAi
technologies to evaluate synthetic interactions
in mammalian systems.
Drugs: Efficacy and Safety
Many scientists at the meeting shared the opin­
ion that extensive “physiome” measurements
on drug action as well as drug target interactions
will eventually allow accurate computational
predictions of the efficacy and safety of new drugs. Two of the speakers:
Jonathon Mason (Lundbeck, Copenhagen) is Michael Hoch, left,
and Randall Peterson.
clearly among the researchers who are already
trying to do this. Many drugs show “polyphar­
macology”, meaning that they clearly affect
distinct targets despite similarities in chemical
structure. For about 2,500 compounds Mason,
with colleagues at Pfizer, has obtained data
from a variety of functional assays (“biological
fingerprints”) and then clustered compounds
according to the similarity of their fingerprints.
Hans-Peter Fischer (Genedata), Klaus Weinberger
(Biocrates) and Robert McBurney (BG Medicine)
reported on other new “omics” approaches
to predict the molecular action of drugs and the
pathways affected. Robert McBurney, left,
discussing science (perhaps)
with Fabio Piano and
What next? Thijn Brummelkamp, right.
One conclusion of the conference was that the
time is coming to update the pharmacology
textbooks. We have now moved beyond the
point where we should focus solely on individual
drug-target relationships as the molecular basis
of therapeutics. It should be feasible to describe
entire “physiome” changes elicited by chemical
agents, including the details of how much certain
pathways are affected. At the same time, cell and
developmental biology are increasingly adopting
the use of creative chemistry that complements
classic and molecular genetics approaches. Cer­
tainly until all of these approaches have become The two organizers:
an essential part of the research repertoire of basic Ulrike Eggert and
Giulio Superti-Furga.
researchers and drug hunters, we will keep this
conference running with biannual occurrence.
We hope to attract more and more “fusionists”
and “trespassers” each time.
Ce — M­— M­— Research Report 2007 72 73
CeMM Karl Landsteiner:
The Austrian Founder of Blood Groups
Karl Landsteiner (1868 -1943) was an
Karl
Austrian biologist and physician. He was
awarded the Nobel Prize in Physiology
Landsteiner
or Medicine in 1930, for his groundbreak­
ing discovery that human blood could
be divided into specific blood groups,
Lectures
made when he was an assistant at the
University of Vienna in 1901. He worked
in the Department of Pathological Anat­
omy under Professor A. Weichselbaum,
who himself discovered the bacterial
cause of meningitis. Today, thanks to
Landsteiner’s pioneering work, all humans
are classified according to their blood
group: A, B, AB or O. His discovery has
had far reaching implications within
diverse fields of medicine and biology,
by providing a novel foundation for
human classification and the study of
heredity, and has been of fundamental
importance for the safe operation of
blood transfusions. To honor his achieve­
ments, CeMM has established the Karl
Landsteiner Lecture series, which will be
hosted annually at the Austrian Academy
of Sciences, and will be given by an invited
speaker who is also regarded as a pioneer
in molecular medicine.
John Kuriyan: Professor Kuriyan received his Bachelor of
Science undergraduate degree in chemistry
“Regulatory from the Juniata College in Pennsylvania, before
attaining a doctorate at the renowned Massa­
Mechanisms in chusetts Institute of Technology in Cambridge
with G­ regory Petsko and with Martin Karplus
Protein Tyrosine at Harvard University. After 14 years at the
Rockefeller University in New York, as Head
Kinase Signaling”. of the department for molecular biophysics and
Patrick E. and Beatrice M. Haggerty Professor,
3rd May, 2007 John Kuriyan moved to UC Berkley in s2002.
He has published so far more than 140 scientific
papers, a quarter of which can be found in the
highest impact journals, including Nature and
Cell. Many of the structures that were deter­
The Inaugural Speaker: Professor John Kuriyan mined in his laboratory are prominent in all
Professor John Kuriyan was invited by Professor standard molecular and cell biology textbooks,
Giulio Superti-Furga, the director of the CeMM- which just goes to show how fundamental
research center for molecular medicine of the his discoveries have been and how far reaching
Austrian Academy of Sciences as the first speaker his work will no doubt become.
of this new annual lecture series, “CeMM – Karl
Landsteiner Lectures”. For 10 years there has been
a close scientific collaboration between the groups
of Superti-Furga and Kuriyan, which led to new
discoveries on the mechanisms of enzyme activity
in relation to cancer formation. His Karl Land­
steiner Lecture was entitled: “Regulatory Mecha­
nisms in Protein Tyrosine Kinase Signaling”.
John Kuriyan is a Howard Hughes Investigator
and Chancellor’s Professor of Biochemistry and John Kuriyan on a tram
in Vienna, sightseeing
Molecular Biology at the University of California,
with Oliver Hantschel and
Berkley. He is one of the youngest selected mem­ Giulio Superti-Furga.
bers of the US National Academy of Sciences,
and received, amongst other things, the renowned
Lounsbery Award in 2005 in recognition of his
extraordinary scientific achievement. Professor
Kuriyan is one of the most prominent and suc­
cessful structural biologists in the world and has
solved the molecular structure of many proteins
associated with disease. His innovative work has
given important insights into the most funda­
mental cellular processes, most notably mecha­
nisms of signal transduction and DNA replication.
Some of his other important discoveries were
the first three-dimensional structure of the onco­ John Kuriyan talking
protein c-Src, and studies of Bcr-Abl, which causes to Peter Schuster,
President of the Academy
specific forms of leukemia. Many of Kuriyan’s
publications are considered to be milestones of
molecular medicine.
Ce — M­— M­— Research Report 2007 74 75
CeMM
Following a year of CeMM firsts (the first
CeMM conference and the first Landsteiner Photos from the CeMM
retreat, in Steinschaler
lecture), came the first CeMM scientific Dörfl.

Retreat
retreat; a two-day science and social get
together for everybody, held in Franken­
fels, a hiking paradise in the Alpine foot­
hills of the province of Lower Austria.

The schedule carefully interspersed the

science with the social, alternating student
talks and scientific discussions, allowing
time for outdoor walks along the snow
covered paths and outdoor drinks of
Glühwein (a sort of mulled wine) around
campfires, followed by a late-night party
for all who were up for it. There was even
room for a caricature artist to give his
visual interpretation of the individuals
at CeMM, some apparently better than
others, which are shown on the following
pages.

All the activities were accompanied by

a photographer to faithfully capture the
whole event. We considered getting some
participants to describe their personal
experience of the retreat, but all in all the
photos tell a much better story …

Ce — M­— M­— Research Report 2007 76 77

 Can you guess
who is who?
Christoph Baumann
Tiina Berg
Christoph Binder
Marc Brehme
Jacques Colinge
Gerhard Dürnberger
Anita Ender
A B C D Q R Nora Fernbach
Adriana Goncalves
Roland Jäger
Evren Karayel
Ines Kaupe
Robert Kralovics
Thomas Köcher
Sebastian Nijman
Damla Olcaydu
Mathew Sloane
Adrijana Stefanovic
Thomas Stranzl
Amrei Strehl
Giulio Superti-Furga
Sandrine Tonon
David Weismann
E F G H S T Carina Winkler

Answer at the end

> p. 99

I J K L U V

M —M­—M­—
Ce Research Report 2007 N O P W
Ce — M­— M­— Research Report 2007 X 78 79
CeMM
The first CeMM PhD program was
established in 2006 and the next round
is in 2008. For each yearly intake, the
PhD Program program is advertised internationally in
scientific journals such as Nature. The
applications are received and discussed
by all of the CeMM PIs, and a prelimi­
nary selection is made and those can­
didates invited for an interview before
the final PhD students are chosen.
The Medical University of Vienna is
the home academic institution for the
CeMM PhD program, and as such sets
several guidelines. The duration of the
PhD is 3 years and at the end the thesis
is defended in front of a committee of
around three members. The PhD thesis
is required to yield at least one publica-
tion in a peer-reviewed journal. There
is mandatory course work, particularly
in the first year taking around 6–7 hours
per week, including basic seminars
and introductory courses in molecular
medicine, cell biology and ethics, disser­
tation seminars and regular journal clubs.
Informal CeMM work discussions are
held every Friday and students will pres­
ent their work on a regular basis.
In the future, there will be a CeMM
PhD student symposium, which will be
organized by the CeMM PhD students.
They will be encouraged to invite speak­
ers of their choice, and host the talks
and mediate discussion. Of course, inter­
spersed between the science are regular
social activities including Happy Hours,
and the yearly scientific retreat.
Structure of
the CeMM
PhD Program
1st Year
Lab rotations: Students spend 2 weeks in each
of the 6 labs at CeMM, getting to know the people
and the science. This is designed to create the
sense of belonging to a program from the entire
institute, and of course to get to know everybody
and experience what is being done scientifically.
Kick-off lectures: These are given by a selection
of prominent leaders, scientists and medical pro­
fessors from the Viennese science and medical
community, as well as the biotech industry,
who speak to a very small group of students. The
goal is to provide students with a detailed and
up-­to-date introduction to the various topics of
Molecular Medicine.
End of 1st Year: Students are required to generate
a research proposal on a topic that is not directly
related to their own research, but involves the
research of at least two CeMM groups. The best
proposal is awarded a prize. This encourages
students to think independently and stimulate
discussions with other students and Post-Docs
from different labs.
2nd Year
Beginning of 2nd Year: Thesis proposals. This
is in accordance with the Medical University
of Vienna guidelines. Short abstracts are first
reviewed by all CeMM PIs, before the final pro­
posal is written and submitted to the university
and thesis committee.
3rd Year
End of 3rd Year: Thesis defense
Ce — M­— M­— Research Report 2007
The first
CeMM
PhD Students
The first CeMM PhD program began in October
2006. There were 267 applications, and only five
positions awarded. The outstanding candidates
that were eventually selected to join the program
were Irena Vlatkovic, Adriana Goncalves, Ana
Zivkovic, Roland Jäger and David Weismann.
Below, these first CeMM PhD students describe
in their own words how they found their first
year at CeMM.
PhD Students
(clockwise from top left):
Irena Vlatkovic
David Weismann
Ana Zivkovic
Roland Jäger
Adriana Goncalves
David Weismann (Supervisor: Christoph Binder)
More than one year has passed since I arrived
at CeMM for the PhD interview. Within this
year, although – or better, because – it happened
to be tough sometimes, I learned to appreciate
this institute as a place of high level research,
with fruitful, interdisciplinary discussions and
highly developed interactions between the dif­
ferent research groups. It is the latter that has
been completely new to me and is, to my mind,
the most prominent of CeMM’s merits. To be
able to call someone rather informally when­
ever I encounter problems and be sure that this
person will try her/his best to help me was a
revelation to me, but these are just a few of many
factors that make CeMM a unique platform and
highly recommendable to young scientists.
80 81

Ana Zivkovic (Supervisor: Sylvia Knapp)
During the interview for my PhD position,
I realized that CeMM was the right place to
start my scientific career, as discussions with
a group of successful, strong-background
principal investigators coupled with a great
chance to do research in a topic I was inter­
ested in during the last year of my studies in
Belgrade, seemed highly attractive to me.
After one long extensive year of hard work
(which seems a bit like a rollercoaster ride of
highs and lows), a lot of experiments and plenty
of new conclusions, I can see how much I have
both improved my scientific knowledge and
importantly developed my scientific judgment.
Particularly fulfilling was the great support for
my own ideas that I received from members
of both my immediate lab and the CeMM com­
munity in general. Together with other PhD
students, my great friends, I’m learning how to
overcome my difficulties and to approach my
scientific outlook in a positive and fun manner.
Being here, at the beginning of CeMM expanding
is a rare advantage and it gives me a chance to
take an active role in building this institute. I have
thoroughly enjoyed this first year and I hope
that the next couple of years will be as fulfilling
as my first.
Irena Vlatkovic (Supervisor: Denise Barlow)
My first year at CeMM as a PhD student showed
me that graduate study is hard work, but reward­
ing and enjoyable. CeMM gave me an opportu­
nity to experience the science, to learn how to
think globally taking into consideration different
sides of the problem no matter to which disci­
pline they belong. In CeMM I learned how
information, technical supports and ideas can
be shared at the level of the whole institute,
which became some kind of gestalt. The warm
familiar atmosphere of CeMM meetings, CeMM
retreats, CeMM parties and also good scientific
perspective with all technical, clinical and people
support make CeMM the perfect place to learn
and live. That is why I warmly recommend CeMM
to future generations of PhD students for whom
molecular medicine is the mystery of life.
Ce — M­— M­— Research Report 2007
CeMM
Roland Jäger (Supervisor: Robert Kralovics)
When I found the call for applications for the
CeMM PhD program, I was immediately fasci­
Principal
nated by the professional website, the idea of
CeMM and especially by the fact that CeMM tries
to bridge the gap between basic research and
the clinic. Up to now I do not regret sending my
Investigators
application. Although it is the first round of this
program and many things have to be built up,
organized and established, I think everything was
handled in a very professional way. Starting from
the interviews where we could get to know the
principal investigators really well, continuing
with the lab rotation in the first months, where
we came into close contact with every single
person at CeMM and got to know where to find
support, competence and friendship, up to
now where the CeMM PhD program really starts
to be in complete accordance with the require­
ments at the Medical University, taking away
from us a lot of the organizational burdens. I am
also glad that I can contribute to the very begin­
ning of the Kralovics lab at CeMM in Vienna,
learning every day about the difficult challenges
of starting a lab, but nevertheless feeling the
development in productivity and the increase
in technical and intellectual power, pillowed
by a strong support from the whole of CeMM.
Adriana Goncalves
(Supervisor: Giulio Superti-Furga)
As one of the first round CeMM PhD students,
I am glad to be able to give my impressions about
the first year experience at CeMM. It all started
with an eagerness to take a new challenge, give
a new and almost first step in science and enroll
in what was the first PhD program of an institute,
that was also taking its own very first steps and
the challenge of starting a fresh and innovative
scientific perspective. It feels good to look back
now and see how much we both grew up. At
CeMM I learned not only to overcome technical
problems and to develop scientific thinking,
but also to understand the dynamics of a scientific
culture and the people that make it. As an inter­
national, interdisciplinary and innovative insti­
tute that integrates basic and clinical research,
I can say that CeMM offers the ideal platform to
promote training of young researchers. It was not
always easy throughout this first year, but the
final feedback couldn’t be more positive and
it is with pleasure that now I can recommend
CeMM to the next generations of PhD students.
Giulio
Superti-Furga
Pathological Networks
in Leukemia and Immunity
Giulio Superti-Furga’s group
is renting lab space:
Vienna Competence Center
CeMM – Center for Molecular
Medicine of the Austrian Academy
of Sciences
Lazarettgasse 19
1090 Vienna, Austria
Ce — M­— M­— Research Report 2007
CEO and Scientific Director
gsuperti@cemm.oeaw.ac.at
PhD (Molecular Biology),
University of Zurich (CH),
IMP Vienna (A)
Post-doctoral fellow, Team Leader
EMBL – European Molecular
Biology Laboratory (D)
Scientific Director
Cellzome (D)
+ Italian nationality
+ Joined Cemm in January 2005
+ Group of 15 people
plus mass spectrometry team (4)
and bioinformatics team (3)
Main research interests
+ Mechanism of action of drugs
+ Molecular networks
affecting leukemias
+ Molecular basis of innate immunity
Giulio Superti-Furga, Scientific Director and CEO
of the Research Center of Molecular Medicine
of the Austrian Academy of Sciences and a visiting
professor at the Medical University of Vienna.
He performed his undergraduate and graduate
studies in molecular biology at the University
of Zurich, at Genentech Inc. and at the Institute
for Molecular Pathology in Vienna (I.M.P.).
Giulio Superti-Furga has been a post-doctoral
fellow and Team Leader at the European Molec­
ular Biology Laboratory (EMBL) until 2004.
For several years he has served as professor of
Biotechnology at the University of Bologna. In
2000, he co-founded the biotech company Cell­
zome Inc., where he has been Scientific Director
and responsible for the Heidelberg research site.
His most significant scientific contributions are
the elucidation of basic regulatory mechanisms
of tyrosine kinases in human cancers and the
discovery of fundamental organization principles
of the proteome of higher organisms.
An Italian national born 1962, Giulio Superti-­Furga
has an Austrian wife and two children.
Robert
Kralovics
Genetics of hematological
disorders
Robert Kralovics’ group
is hosted by:
Division of Hematology and
Hemastaseology
University Hospital of Vienna
Währinger Gürtel 18–20
1090 Vienna, Austria
Ce — M­— M­— Research Report 2007
CeMM Principal Investigator
robert.kralovics@cemm.oeaw.ac.at
PhD (molecular biology)
Czech Academy of Sciences
Post-doctoral fellow
University of Alabama
at Birmingham (USA)
Assistant Professor
Baylor Collage of Medicine,
Houston (USA)
Project Leader
University Hospital Basel (CH)
+ Czech nationality
+ Joined CeMM in June 2006
+ Group of 5 people, funded
by CeMM, MUW, and FWF
Main research objectives
and questions
+ Identify mutations in early
steps of disease development
in hematological malignancies
+ How mutant stem cells evolve
genetically, how they respond
to therapy?
+ What gene mutations cause
familial predisposition to
hematological malignancies?
+ How does genetic variability
contribute to disease?
+ How to diagnose the diseases
in early stages of development?
Robert Kralovics, born 1970, is Czech and joined
CeMM on June 1st 2006. He obtained his first
degree in Molecular Biology and Genetics in
Bratislava and later his Ph.D. in Biophysics at the
Academy of Sciences of the Czech Republic in
Brno. He did his postdoctoral work on the genetics
of myeloproliferative disorders working with Josef
Prchal at the University of Alabama at Birmingham,
USA. He followed Prchal as an Assistant Professor
at the Baylor College of Medicine in Houston. Since
mid 2001 Robert Kralovics has been Project Leader
with Radek Skoda in Basel. Robert Kralovics’
research interests are in chronic myeloproliferative
disorders (MPDs). His major achievement so far
has been the identification of a gain-of-function
mutation in the JAK2 kinase(V617F) that plays an
important role in MPD pathogenesis. Prominently
published in April 2005 inNew England Journal
of Medicine, the work has given Robert instant
celebrity in the hematooncological field and fos­
tered Robert’s interest in Jak2 as a potential target.
However, he believes that there is an “upstream”
mutation in a yet to be identified gene(s), that
predisposes patients to MPDs. One of his new
research tasks is to find new mutations using whole
genome deletion analysis and by mapping disease
associated genomic regions in MPD families. Robert
Kralovics has authored 20 scientific publications.
Robert Kralovics is housed and hosted by the
Hematology Department of the MUW (Ulrich
Jäger, Heinz Gisslinger).
84 85
Denise
P. Barlow
Epigenetic Mechanisms
in Development & Disease
Denise Barlow’s group
is renting lab space:
Institute of Genetics
Max F. Perutz Laboratories
Vienna Biocenter
Dr. Bohr-Gasse 9/4
1030 Vienna, Austria
Ce — M­— M­— Research Report 2007
CeMM Principal Investigator
denise.barlow@univie.ac.at
Honorary Professor of Genetics
at Vienna University
PhD, Warwick University (UK)
Post-doctoral Fellow, ICRF London
(UK), EMBL Heidelberg (D)
Group Leader, IMP Vienna (A),
NKI Amsterdam (NL)
Head Dept. Developmental Biology,
IMB-OeAW Salzburg (A)
+ British nationality
+ Joined CeMM in January 2004
+ Currently group of 12 people
Main research interests
+ Molecular basis and function
of genomic imprinting in mice
and humans
+ Identification and characterization
of macro non-coding RNAs
+ The potential of macro non-coding
RNAs as tumor biomarkers
Denise Barlow is Principal Investigator at CeMM
and an Honorary Professor at the Universityof
Vienna. Denise initially trained as a State Regi­
stered Nurse in the UK and afterwards completed
undergraduate studies at Reading University
(UK) and a Ph.D. at Warwick University (UK).
Post Doctoral work followed at ICRF (London
UK) and EMBL (Heidelberg,Germany). Group
leader positions were then held at the IMP
(Vienna) and NKI (Amsterdam). On returning
to Austria in 2000, Denise was appointed Head
of the Dept. of Developmental Genetics at the
Austrian Academy IMB Institute (Salzburg),
and then finally, returned to Vienna in 2003 as
a Principal Investigator with CeMM. Significant
contributions of the Barlow lab so far, are the
discovery of the first imprinted gene in mammals
and the elucidation of the epigenetic mechanism
underlying imprinted expression. A British
national, Denise has a passion for mountains and
enjoys very much living and working in Austria.
Sylvia
Knapp
Innate Immunity
and bacterial infections
Sylvia Knapp’s group
is hosted by:
Department of Internal Medicine I
Medical University Vienna
Währinger Gürtel 18—20
1090 Vienna, Austria
Ce — M­— M­— Research Report 2007
CeMM Principal Investigator
sknapp@cemm.oeaw.ac.at
MD, University of Vienna
Internist, Vienna General
Hospital, MUW
PhD (Experimental Medicine),
University of Amsterdam
+ Austrian nationality
+ Joined CeMM in April 2006
+ Currently group of 6 people
Main research interests
+ Identify the impact of
bacterial toxins
+ Exploit molecular mechanisms
of host-pathogen interactions
Sylvia Knapp was born in Innsbruck in 1968 and is
an Austrian Citizen. She studied Medicine first at
the Free University in Berlin and for the major part
at the University of Vienna Medical School, obtai­
ning her M.D. degree in 1993. In 2000 she obtained
her License in Internal Medicine and in 2004 she
obtained a “Habilitation” in Internal Medicine of
the MUW.
After several residencies, mostly in areas of Internal
Medicine like Infectious Diseases, AIDS and Inten­
sive Care Units, she became a Research Fellow in
Tom van der Poll’s laboratory at the University of
Amsterdam, for four years (Laboratory of Experi­
mental Internal Medicine). She intends to continue
her work on the innate immune response to bacteri­
al infections, focusing on the molecules involved
in the initiation and resolution of the innate immu­
ne response to clinically relevant pathogens and
on the role of bacterial virulence factors and their
interactions with host structures and pathways.
She is author of 60 scientific publications, reports
and book chapters, her most important achieve­
ments include the identification of the anti-
inflammatory role of alveolar (lung) macrophages
in Streptococcus pneumoniae pneumonia. Sylvia
Knapp is keeping her part-time responsibilities in
the intensive care unit (albeit at a very reduced
level) and her own research laboratory is hosted
by the MUW (Dept. of Internal Medicine I).
86 87
Sebastian
Nijman
Cancer Genomics
Sebastian Nijman’s group
is renting lab space:
Department of Medical
and Chemical Laboratory
Diagnostics (KIMCL)
Medical University of Vienna
General Hospital H5.J2.09
Währinger Gürtel 18–20
1090 Vienna, Austria
Ce — M­— M­— Research Report 2007
CeMM Principal Investigator
snijman@cemm.oeaw.ac.at
PhD (Molecular Biology),
Netherlands Cancer Institute
Post-doctoral fellow,
Broad Institute of Harvard
and MIT (USA)
+ Dutch nationality
+ Joined CeMM in October 2007
+ Currently group of 3 people
Main research interests
+ Identify novel strategies to treat
cancer (cancer vulnerabilities)
+ Unravel molecular mechanisms
that drive tumorigenesis
+ Functional genetic screens to
identify cancer-related genes
Sebastian Nijman was born in The Netherlands
(1975). He obtained his university training in
Utrecht where he specialized in Molecular Biol­
ogy and Biochemistry and acquired a Masters
of Arts degree from the University of Maastricht
(Science, Society and Technology Studies).
After a short “detour” through industry where
he was involved in clinical research, he started
his PhD in the lab of Rene Bernards at the Nether­
lands Cancer Institute in Amsterdam. With the
help of the first RNAi screen in mammalian cells
he assigned a function to the familial tumor sup­
pressor gene CYLD. This work has led to a rational
therapeutic approach for treating the tumor
syndrome that is caused by mutations in this
gene. Furthermore, his work on CYLD and other
deubiquitinating enzymes has had a significant
impact on various fields of research.
In 2006 he joined the lab of Todd Golub at the
Broad Institute of Harvard and MIT. Here he
developed novel genomic approaches to dis­
cover the functions of genes and identify new
angles for cancer treatment. Much of Sebastian
Nijman’s research can be considered as techno­
logy driven which allows the interaction with
scientists from many different backgrounds.
At CeMM and the KIMCL, where also principal
investigator Christoph Binder is located, he
hopes to find an exciting scientific environment
at the interface of basic research and the clinic.
Christoph
J. Binder
Atherosclerosis
and Immunity
Christoph Binder’s group
is hosted by:
Department of Medical
and Chemical Laboratory
Diagnostics (KIMCL)
Medical University of Vienna
Währinger Gürtel 18­—20
1090 Vienna, Austria
Ce — M­— M­— Research Report 2007
CeMM Principal Investigator
cbinder@cemm.oeaw.ac.at
MD, University of Vienna
PhD (Molecular Pathology),
University of California San Diego
Post-doctoral fellow,
University of California San Diego
+ Austrian nationality
+ Joined CeMM in April 2006
+ Currently group of 5 people
Main research interests
+ Role of natural immunity in
inflammation and oxidative stress
+ Elucidate the protective
capacities of natural antibodies
in atherosclerosis
+ Discover ways to boost natural
immunity as therapy for cardio­
vascular diseases
Christoph Binder was born in 1973 in Vienna. He
first obtained his M.D. degree from the University
of Vienna Medical School in 1997, working as an
intern in the Clinical Pathology department (Prof.
Dontscho Kerjaschki). Later, he entered a Ph.D.
program at the University of California in San Diego,
working with world-famous atherosclerosis resear­
cher Joseph Witztum.
In 2002, Christoph obtained his Ph.D. degree for
the thesis entitled: “Defining Innate and Adaptive
Immune Mechanisms in the Atheroprotective
Effect of Immunization with Oxidized Low-
Density Lipoproteins”. His interests are clearly
interdisciplinary and span vascular biology, lipid
oxidation, natural antibodies and innate immunity.
Christoph Binder has won numerous prestigious
fellowships and awards and has authored 15 publi­
cations in important journals, including Nature
Medicine and Nature. His main research achieve­
ments include the discovery of IL-5 as an athero­
protective cytokine. In the future, he would mainly
like to define the role of IL- 5 and of natural anti­
bodies in atherogenesis and autoimmunity
and to exploit findings for therapy and diagnosis.
Christoph Binder still holds a faculty position
as Assistant Professor of Medicine at UCSD and
works at the Department of Medical and Chemical
Laboratory Diagnostics (KIMCL) of the MUW.
He recently obtained his “Habilitation”.
88 89
Keiryn
Bennett
Keiryn Bennett’s group
is renting lab space:
Vienna Competence Center
CeMM – Center for
Molecular Medicine
of the Austrian Academy Head of Mass Spectrometry
of Sciences kbennett@cemm.oeaw.ac.at
Lazarettgasse 19
1090 Vienna, Austria
PhD, Department of Chemistry,
University of Wollongong, Australia
Director of Analytical Applications,
Protana AS, later called
MDS Proteomics, Denmark
+ Australian nationality
+ Joined CeMM in October 2004
+ Group of 3 people
Main research interests
+ Proteomics
+ Mass Spectrometry
+ Integration of mass spectrometry
with Biology and Bioinformatics
Ce — M­— M­— Research Report 2007
Keiryn Bennett, PhD., heads the mass spectrom­
etry unit at CeMM. She obtained her Bachelor
of Science with Honours at the University
of Tasmania and her PhD at the Department of
Chemistry, University of Wollongong, Australia,
under the supervision of Professor Margaret
Sheil. She further trained in some of the most
renowned mass spectrometry laboratories,
includ­ing Professor Peter Roepstorff in Denmark.
Keiryn Bennett has been Director of Analytical
Applications at Protana AS in Denmark (now
MDS Proteomics) and has experience with many
different systems. Author of around 30 publi­
cations, Keiryn Bennett was also involved in the
large-scale analysis of yeast protein complexes
published in Nature along with the analogous
effort from Cellzome. She is respected worldwide
in the field of protein mass spectrometry. She
brought to CeMM more than 15 years of expe­
rience in protein mass spectrometry and 7 years
experience managing a high-throughput indus­
trial proteomic laboratory. Keiryn Bennett has
established CeMM’s protein mass spectrometry
capability.
Jacques
Colinge
Jacques Colinge’s group
is renting lab space:
CeMM – Center
for Molecular Medicine
of the Austrian Academy
of Sciences
Mariannengasse 14 Head of Bioinformatics
1090 Vienna, Austria
jcolinge@cemm.oeaw.ac.at
PhD, Swiss Institutes
of Technology Bioinformatician,
Serono Pharmaceutical
Research Institute
Head of Bioinformatics,
GeneProt Inc
Professor of Bioinformatics,
Upper Austrian University
of Applied Sciences, Hagenberg
+ Swiss and French nationality
+ Joined CeMM in September 2006
+ Group of 4 people
Research Interests
+ Computational Proteomics
+ Computational Statistics
and Statistical Learning
+ Systems Biology Data Analysis
Ce — M­— M­— Research Report 2007
Jacques Colinge PhD, heads the bioinformatics
team at CeMM since September 2006. He perfor­
med mathematics graduate studies in Geneva,
Switzerland. He then did his PhD with Professor
G. Wanner, also in Geneva, in the field of numerical
analysis of partial differential equations. This was
a joint project with both Swiss Institutes of Tech­
nology. After completing his PhD, Jacques Colinge
joined Serono Pharmaceutical Research Institute
as a bioinformatician to work mainly on differential
gene expression data analysis. In 2000 he moved
to GeneProt Inc. to head a group of 9 in charge
of mass spectrometry-related bioinformatics. Four
years later, he joined the Upper Austrian University
of Applied Sciences at Hagenberg to serve as a
Professor of Bioinformatics. Jacques Colinge’s main
contributions are solution methods for strongly
nonlinear elliptic PDEs arising in glaciology, stati­
stical models for SAGE data analysis, MS data
identification, and MS-based quantitation analysis.
A Swiss and French national, he is married and has
3 children.
90 91
CeMM Directory
Management Thomas Köcher (A) Agnes Gstöttenbauer (A) Technical Assistants
Giulio Superti-Furga (I) OeNB OeNB Tiina Berg (FIN)
CEO and Scientific Director Paulina Latos (PL) Adriana Goncalves (P) CEMM
Gerhard Schadler (A) CEMM/EUP0002 (Heroic) OeNB Romana Bittner (A)
CEO and Administration FWF1718 Ru Huang (CN) CEMM, FWF1718
Markus Müllner (A) EUP0001 (Epigenome); Nils Craig-Müller (D/USA)
ÖAW EUP0002 (Heroic) CEMM
Administration
Lily Remsing-Rix (USA) Roland Jäger (A) Nora Fernbach (A)
Anita Ender (A) PRI0001 LLS Fellowship FWF20033 BWK0004 (GENAU DRAGON)
Alexandra Gossner* (A) Uwe Rix (D) Evren Karayel (TR) Tanja Furtner (A)
Xenia Taschner-Weissmann BWK0004 (GENAU DRAGON) FWF W1204B09 (CCHD) CEMM
(A) Omar Sharif (UK) Martha Körner (A) Laura Göderle (A)
Carina Winkler (A) CEMM CEMM, EUP0002 (Heroic) CEMM
Mathew Sloane (AUS) Ulrich Matt (A) Hanna Jahn (A)
Principal Investigators ÖAW CEMM OeNB
Denise Barlow (UK) Laura Steenpaß (D) Damla Olcaydu (TR) Ines Kaupe (A)
EUP0001 (Epigenome) CEMM FWF18737
Christoph Binder (A)
Amrei Strehl (D) Florian Pauler (A) Martin Krammer* (A)
Sylvia Knapp (A) FWF20033 EUP0002 (Heroic) OeNB
Robert Kralovics (CZ) Iveta Yotova (B) Frederica Santoro (I) André Müller (D)
Sebastian Nijman (NL) FWF1718 CEMM CEMM
Giulio Superti-Furga (I) Basak Senergin (TR) Maria Ozsvar Kozma (H)
PhD and Diploma Students EUP0002 (Heroic)/FWF1718 KIMCL-MUV/CeMM
Marc Brehme (D) Amir Shahzada (PK) Melanie Planyavsky (A)
Department Heads
FWF18737 FWF W1204 (CCHD) OeNB
Keiryn Bennett (AUS)
Larissa Cardilo dos Reis (BR) Ana Zivkovic (SRB/CG) Gregor Schütze* (D)
OeNB
CEMM CEMM OeNB
Jacques Colinge (CH/F)
Evelyn Dixit (A) Thomas Stranzl (A) Adrijana Stefanovic (A)
GEN-AU APPII
OeNB FWF W1204 (CCHD) OeNB OeNB
Gerhard Dürnberger (A) Stefan Stricker (D) Katarzyna Warczok (PL)
Postdoctoral Fellows EUP0001 (Epigenome)
OeNB CEMM
Christoph Baumann (D) Sandrine Tonon (B)
Emanuel Gasser (A)
OeNB CEMM
OeNB
Tilmann Bürckstümmer (D) Irena Vlatkovic (SRB/CG)
DFG Fellowship EUP0002 (Heroic)
Oliver Hantschel (D) David Weismann (A) name (nationality)
FWF18737 CEMM funding
Quanah Hudson (NZ) * left CeMM in 2007
EUP0001 (Epigenome)
EUP0002 (Heroic)

Austria, Australia, Belgium,

Brazil, China, Czech Republic,
Finland, France, Germany,
United Kingdom, Hungary,
Italy, The Netherlands,
New Zealand, Pakistan, Poland,
Portugal, Serbia/Montenegro,
Switzerland, Turkey, USA
= 21 Nationalities Ce — M­— M­— Research Report 2007 92 93
Ce — M­— M­— Research Report 2007 Ce — M­— M­— Research Report 2007
 CeMM
Publications
2007
Barlow DP, Bartolomei MS. Genomic imprinting
in mammals. Chapter 19 in EPIGENETICS Edited
by D. Allis, T. Jenuwein D. Reinberg. CSH Press
2007. ISBN 978-087969724–2. Book Chapter.
Binder CJ, Hartvigsen K, Witztum JL. Promise of
immune modulation to inhibit atherogenesis.
J Am Coll Cardiol. 2007, 50(6):547–50. (Editorial).
Bro S, Binder CJ, Witztum JL, Olgaard K, Nielsen
LB. Inhibition of the Renin-Angiotensin System
Abolishes the Proatherogenic Effect of Uremia
in Apolipoprotein E-Deficient Mice. Arterioscl
Thromb Vasc Biol. 2007, 27(5):1080–6.
Colinge J. Peptide fragment intensity statistical
modelling. Anal Chem 2007, 79, 7286–7290.
Colinge J, Bennett KL. Introduction to computa­
tional proteomics. PLoS Comput Biol 2007, 3:e114.
Dessing M, Knapp S, Florquin S, de Vos AF, van
der Poll T. CD14 facilitates invasive respiratory
tract infections by Streptococcus pneumoniae.
Am J Respir Crit Care Med. 2007, 175:604–611.
Gattringer R, Lagler H, Gattringer KB, Knapp S,
Burgmann H, et al. Anakinra in two adolescent
female patients suffering from colchicine-
resistant familial Mediterranean fever: effective
but risky. Eur J Clin Invest. 2007, 37:912–914.
Hantschel O, Rix U, Schmidt U, Burckstummer T,
Kneidinger M, Schutze G, Colinge J, Bennett KL,
Ellmeier W, Valent P, Superti-Furga G. The Btk
tyrosine kinase is a major target of the Bcr-Abl
inhibitor dasatinib. Proc Natl Acad Sci USA. 2007,
104:13283–13288.
Hartvigsen K, Binder CJ, Hansen LF, Rafia A,
Juliano J, et al. A diet-induced hypercholester­
olemic murine model to study atherogenesis
without obesity and metabolic syndrome.
Arterioscl Thromb Vasc Biol. 2007, 27(4):878–85.
Ce — M­— M­— Research Report 2007
Kakkad R, Sloane MA, Huang R, Pauler FM,
Warczok KE, Melikant B, Radolf M, Martens JHA,
Schotta G, Jenuwein T, Barlow DP. Active and
Repressive Chromatin Is Interspersed without
Spreading in an Imprinted Gene Cluster in the
Mammalian Genome. Mol Cell. 2007, 27(3):353–66.
Knapp S. Innate recognition of bacteria. Expert
Rev Clin Immunol. 2007, 3:443–445 (Editorial).
Knapp S, Matt U, Leitinger N, van der Poll T.
Oxidized phospholipids inhibit phagocytosis
and impair outcome in gram-negative sepsis
in vivo. J Immunol. 2007, 178:993–1001.
Kocher T, Superti-Furga G. Mass spectrometry-
based functional proteomics: from molecular
machines to protein networks. Nat Methods.
2007, 4(10):807–15.
Orchard S, Salwinski L, Kerrien S, Montecchi-
Palazzi L, Oesterheld M, Stumpflen V, Ceol A,
Chatr-aryamontri A, Armstrong J, Woollard P,
Salama JJ, Moore S, Wojcik J, Bader GD, Vidal M,
Cusick ME, Gerstein M, Gavin AC, Superti-Furga
G,et al. The minimum information required
for reporting a molecular interaction experiment
(MIMIx). Nat Biotechnol. 2007, 25(8):894–8.
Pauler FM, Koerner MV, Barlow DP. Silencing
by imprinted noncoding RNAs: is transcription
the answer? Trends Genet. 2007, 23(6):284–92.
Pitzer E, Masselot A, Colinge J. Assessing peptide
de novo sequencing algorithms performance
on large and diverse data sets. Proteomics 2007,
7:3051–3054.
Rix U, Hantschel O, Dürnberger G, Remsing Rix
LL, Planyavsky M, Fernbach NV, Kaupe I, Bennett
KL, Valent P, Colinge J, Köcher T, Superti-Furga
G. Chemical proteomic profiles of the BCR-ABL
inhibitors imatinib, nilotinib and dasatinib reveal
novel kinase and non-kinase targets. Blood.
2007, 110:4055–4063.
Schuster C, Fernbach N, Rix U, Superti-Furga G,
Holy M, et al. Selective serotonin reuptake
inhibitors – A new modality for the treatment
of lymphoma/leukaemia? Biochem Pharmacol.
2007, 74(9):1424–35.
Additional references
Characterization of Protein Networks
and Proteomics Approaches
Burckstummer T, Bennett KL, Preradovic A,
Schutze G, Hantschel O, Superti-Furga G,
Bauch A. An efficient tandem affinity purification
procedure for interaction proteomics in mam­
malian cells. Nat Methods. 2006, 3(12):1013–9.
Gavin AC, Aloy P, Grandi P, Krause R, Boesche
M, et al. Proteome survey reveals modularity
of the yeast cell machinery. Nature. 2006,
440(7084):631–6.
Ho Y, Gruhler A, Heilbut A, Bader GD, Moore L,
et al. Systematic identification of protein
complexes in Saccharomyces cerevisiae by mass
spectrometry. Nature. 2002, 415:180–183.
Genetic Screens and Genomic Approaches
Hartwell LH, Szankasi P, Roberts CJ, Murray AW,
and Friend, SH. Integrating genetic approaches
into the discovery of anticancer drugs. Science.
1997, 278:1064–1068.
Lum PY, Armour CD, Stepaniants SB, Cavet G,
Wolf MK, et al. Discovering modes of action
for therapeutic compounds using a genome-
wide screen of yeast heterozygotes. Cell. 2004,
116:121–137.
Nijman SM, Huang TT, Dirac AM, Brummelkamp
TR, Kerkhoven RM, D’Andrea AD and Bernards
R. The deubiquitinating enzyme USP1 regulates
the Fanconi Anemia pathway. Molecular Cell,
2005, 17(3):331–9.
Molecular Mechanisms of Cancer
Hantschel O and Superti-Furga G. Regulation
of the c-Abl and Bcr-Abl tyrosine kinases. Nature
Molecular Biology. 2004, 5:33–44.
Kralovics R, Teo SS, Li S, et al. Acquisition of the
V617F mutation of JAK2 is a late genetic event
in a subset of patients with myeloproliferative
disorders. Blood. 2006, 108:1377–1380.
Ce — M­— M­— Research Report 2007
Kralovics R, Passamonti F, Buser AS, et al. A gain-
of-function mutation of JAK2 in myeloprolifera­
tive disorders. N Engl J Med. 2005, 352:1779–1790.
Nijman SM, Hijmans EM, El Messaoudi S,
van Dongen MW, Sardet C, Bernards R. A func­
tional genetic screen identifies TFE3 as a gene
that confers resistance to the anti-proliferative
effects of the retinoblastoma protein and
TGFbeta. J Biol Chem, 2006. 281(31):21582–7.
Non-coding RNAs and Imprinting
Seidl CI, Stricker SH, Barlow DP. The imprinted
Air ncRNA is an atypical RNAPII transcript
that evades splicing and escapes nuclear export.
EMBO J. 2006, Aug 9;25(15):3565–75.
Sleutels F, Zwart R, Barlow DP. The non-coding
Air RNA is required for silencing autosomal
imprinted genes. Nature. 2002, 415(6873):810–3.
Barlow DP, Stoger R, Herrmann BG, Saito K,
Schweifer N. The mouse insulin-like growth
factor type-2 receptor is imprinted and closely
linked to the Tme locus. Nature. 1991, 349(6304):
84– 7.
Inflammation, Immunity and Disease
Binder CJ, Shaw PX, Chang MK, Boullier A,
Hörkkö S, Miller YI, Hartvigsen K, Woelkers DA,
Corr M, Witztum JL. The Role of Natural
Antibodies in Atherogenesis. J Lipid Res. 2005,
46(7):1353–63.
Gonzalez MR, Bischof berger M, Pernot L,
van der Goot FG, Frêche B. Bacterial pore-form­
ing toxins: the (w)hole story? Cell Mol Life Sci.
2008, 65(3):493–507.
Hansson GK. Inflammation, atherosclerosis,
and coronary artery disease. N Engl J Med. 2005,
352(16):1685–95.
Hood L, Heath JR, Phelps ME, Lin B. Systems
biology and new technologies enable predictive
and preventative medicine. Science. 2004,
306(5696):640–3.
Rader DJ, Daugherty A. Translating molecular
discoveries into new therapies for atherosclerosis.
Nature. 2008, 451(7181):904–13.
96 97
Scientific
Prof. Dr. Richard Flavell
Chairman, Section of Immunobiology,
Yale University School of Medicine,
Advisory
New Haven, USA
Prof. Dr. James D. Griffin
Chair, Department of Medical Oncology,
Board
Dana Farber Cancer Institute, Boston, USA
Prof. Dr. Carl-Henrik Heldin
Director, Ludwig Institute for Cancer
Members
Research, Uppsala University, SE
Prof. Dr. Denis Hochstrasser
Head, Central Clinical Chemistry Laboratory,
Geneva University Hospital, CH
Prof. Dr. David Livingston
Deputy Director, Dana-Farber/­
Harvard Cancer Center, Boston, USA
Prof. Dr. William E. Paul
Chief, Laboratory of Immunology,
National Institute of Allergy and
Infectious Diseases, Bethesda, USA
Prof. Dr. Hidde Ploegh
Member, Whitehead Institute for
Biomedical Research, Cambridge, USA
Prof. Dr. Nadia Rosenthal
Head, EMBL- European Molecular Biology
Laboratory, Monterotondo Outstation, Rome, I
Prof. Dr. Louis M. Staudt
Head, Molecular Biology of
Lymphoid Malignancies Section
National Institutes of Health,
National Cancer Institute, Bethesda, USA
Dame Prof. Dr. Janet Thornton
Director, European Bioinformatics Institute
in Cambridge, UK
Group Leader, EMBL- European Molecular
Biology Laboratory, Hinxton Outstation,
Cambridge, UK
Ce — M­— M­— Research Report 2007
Acknowledgements
Zoran Almanzan, Stefan Amatschek, Mehran Ansari, Georg Anzenberger, Christian Arthaber, Amanda Baker,
Christian Balluch, Angela Bauch, Gerhard Bauer, Hemma Bauer, Matthias Beck, Christina Bergmeister,
Martin Bilban, Christoph Block, Matthew Bogyo, John Bohannon, Stefan Böhm, Günther Bonn, Stu Borman,
Oliver Brandt, Robert Brown, Eva Bruckner, Thijn Brummelkamp, Herbert Burger, Maria Bürgermeister,
Eugene Burns, Horst Bursik, Meinrad Busslinger, Jon Clardy, Benjamin Cravatt, Birgit Dalheimer, Rainer
De Martin, Jan de Vries, Thomas Decker, Helmut Denk, Barry Dickson, Julian Downward, Gerard Drewes,
Gerhard Ecker, Riki Eggert, Hans Georg Eichler, Adelheid Elbe-Bürger, Wilfried Ellmeier, Heinz Engl, Michelle
Epstein, Harald Esterbauer, Stephen Fesik, Katja Fiala, Hans-Peter Fischer, Mischa Freissmuth, Herwig
Friesinger, Christian Fritzsche, Michael Füchsl, Helmut Gadner, Christoph Gasche, Manfred Gengler, Edith
Gindel, Nathanael Gray, Karin Hagenbichler, Brigitte Haidl, Bernhard Hain, Hans Tuppy, Claudia Heilmann-
Sennhenn, Katharina Heiss-Kienberger, Markus Hengstschläger, Wilhelm Henrich, Anke Heynoldt, Michael
Hoch, Elisabeth Hochleitner, Erhard Hofer, Astrid Hofstätter, Martin Hohenegger, Eveline Holzmeier,
Lukas Huber, Ylva Huber, Liu Huchi, Heidemarie Hurtl, Monika Hutter, Sandrine Imbeaud, Harald Isemann,
Alain Israel, Ulrich Jäger, Erika Jensen-Jarolim, Kai Johnsson, Luzi Josipovic, Veronika Josipovic, Andrea
Kainz, Tarun Kapoor, Oliver Kemper, Dontscho Kerjaschki, Michael Kiebler, Hans Kiener, Laura Kiessling,
Melitta Kimbacher, Michael Kneidinger, Guido Korlath, Barbara Kornmüller, Ursula Kosir, Peter Kowalski,
Christoph Kratky, Michael Krebs, Reinhard Krepler, Dragan Krstic, Andreas Kungl, Tamar Kurtskhalia,
Christoph La Garde, Kirsten Larsen-Becker, Hans Lassmann, Klaus Lechner, Gerhard Leder, Kriso Leinfellner,
Alexander Leitner, Hans-Joachim Lipp, Melanie Lobner, Jutta Löffler, Silvia Lossgott, Dieter Lutz, Wolfgang
Machal, Christine Mannhalter, Marianne Pöschko-Laczkovics, Javier Martinez, Jonathan Mason, Herbert Matis,
Thomas Mayer, Robert McBurney, Karl Mechtler, Claudia Mick, Michael Micksche, Martina Milletich, Wolfgang
Mlecnik, Maria Magdalena Mosgan, Markus Müller, Mathias Müller, Johann Mulzer, Alexander Nagler,
Gabriele Nestyak, Waltraud Niel, Harald Niessner, Mamuka Nikolaishvili, Lars Nitschke, Christian Nordberg,
Peter Oefner, Markus Otte, Markus Pasterk, Josef Penninger, Jan-Michael Peters, Randall Peterson, Anna
Peutl, Fabio Piano, Helen Pickersgill, Katharina Pluner, Bernhard Plunger, Marie-Therese Porzer, Roberto
Raggiaschi, Ron Raines, Meinhard Rauchensteiner, Kurt Redlich, Markus Reicher, Caetano Reis e Sousa,
Georg Reithofer, Ingrid Riedel-Taschner, Jagoda Ristic, Hildi Rowland, Peter Roy, Philip Santoll, Michael
Sazel, Clemens Scheinecker, Otto Scheiner, Ursula Schmidt-Erfurth, Maria Schreiber, Rene Schröder, Peter
Schuster, Reinhard Schwarz, Dieter Schweitzer, Veronika Sexl, Maria Sibilia, Werner Sieghart, Reya Silao,
Maria Siomos, Uwe Sleytr, Josef Smolen, Hans-Joachim Sorger, Peter Soswinski, Didier Soulat, Nikolaus
Spieckermann-Hutter, Holger Stalz, Michael Stampfer, Edda Starzer, Georg Stingl, Hannes Stockinger,
Gitte Stoilov, Sepp Strasser, Erich Streissler, Herbert Strobl, Carl-Wolfgang Stubenberg, Tada Taniguchi,
Elisabeth Tischelmayer, Zlatko Trajanoski, Jasmin Turtenwald, Michael Tyers, Mohien Ceereena Ubaida,
Peter Valent, Marc Vidal, Alexander von Gabain, Sasha Vukovic, Oswald Wagner, Stephan Wagner, Jürgen
Walkenhorst, Elisabeth Wegmann, Karin Wihsböck, Tanja Winkler, Anke Wittig, Evelyn Zaininger-Reiterer,
Pavel Zavodny, Rudolf Zechner, Silvia Zendron, Elke Ziegler, Christoph Zielinski, Klaus Zinöcker, Gerhard
Zinsberger, Stephanie Zorn, Elke Zuckermann
Solution to caricature quiz
p 78—79
A Christoph Binder I Tiina Berg Q Marc Brehme
B Giulio Superti-Furga J Christoph Baumann R Nora Fernbach
C Amrei Strehl K Jacques Colinge S Roland Jäger
D Gerhard Dürnberger L Damla Olcaydu T Mathew Sloane
E Anita Ender M Ines Kaupe U Thomas Stranzl
F Sandrine Tonon N Thomas Köcher V Carina Winkler
G David Weismann O Adrijana Stefanovic W Robert Kralovics
H Adriana Goncalves P Evren Karayel X Sebastian Nijman
Ce — M­— M­— Research Report 2007 98 99
Copyrights
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Center for Molecular Medicine
of the Austrian Academy of Sciences
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www.cemm.at

Scientific Writer and Editor

Helen Pickersgill, PhD
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helenpickersgill@mac.com
Overall responsibility for content
Giulio Supteri-Furga
Art Direction and Design
Lichtwitz — Büro für
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Photography
(Cover, Back, p. 2—5,
p. 36—37, p. 46—47, p. 56—57,
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Caricature Artist
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