connecting excellence for health€¦ · holistic research – bridging the gap between basic molecular research and patient care. Cooperation is a crucial factor for the remarkable

2009connecting excellence for health

5

6

7

8

9

10

11

12

1314

1516 17 18

19

7.1.1

7.2.1

7.3.1

7.4.1

8.1.1

8.2.1

5.35.4

5.55.12

6.16.2

7.1

7.2

7.3

8.1

8.2

9.1

9.2

9.3

10.1

10.2

11.1

12.1

12.2

13.1

14.1

15.115.2 15.3

16.1 17.1 18.1

18.1.1

19.1.1

18.219.1

20.1

17.1.1

16.214.1.1

15.1.115.2.1

15.3.116.1.1

12.1.1

12.2.1

11.1.1

10.1.1

7.4

9.1.1 – 9.1.2

9.2.1 – 9.2.2

9.3.1

13.1.1 – 13.1.2

16.2.1 – 16.2.218.2.1 – 18.2.2

Infographics

Authors and Cooperation Partners

At the beginning of each research highlight in this annual report there

is an infographic in the upper left corner of the page (example on the

right). It depicts the respective connections of all cooperation partners

and authors involved in the original publication.

Level 1 shows the responsible author or the authors, level 2 the

coope rating institutes and level 3 the respective co-authors. The info-

graphics provide a quick overview of how many authors have contrib-

uted to each respective publication.

Cooperations of Helmholtz Zentrum München

Five infographics between the individual chapters of the annual report

visualize the various cooperation structures through which Helmholtz

Zentrum München is connected internally and externally.

Starting from Helmholtz Zentrum München, three rings show the

various levels of the cooperation chain, such as the network between

Helmholtz Zentrum München and research institutions in other coun-

tries. The respective numbers indicate the institutions listed on the op-

posite page.

level 1

level 2

level 3

Helmholtz Zentrum München

Numbering (index for the respective table)

1st cooperation level

2nd cooperation level

3rd cooperation level

10.1.1 – 10.1.2

1

2

3

4

20

1.1

2.1

2.2

2.3

3.1

4.1

5.1

5.1.1

5.2

5.35.4

19.1.1

20.1.120.2.1

20.3.1

20.4.1

20.5.1

20.6.1

20.8.1

20.7.1

20.9.1

20.10.1

20.11.1

20.12.1

20.120.2

20.320.4

20.5

20.6

20.7

20.8

20.10

20.11

20.12

20.9

4.1.1 – 4.1.3

18.2.1 – 18.2.2

3.2 3.1.1

3.2.1

2.2.1

2.3.1

2.1.1

1.1.1

Generative Design

So-called tree diagrams branch out from

one point into different branches and are

an easy way to visually display hierarchi-

cal structures.

Generative design means the translation of complex data structures into a visual pre-

sentation. A computer program converts data or formulas into a graphic representation.

Depending on the underlying rules, a wide range of different shapes and visual worlds

can be created – each data set generates its own distinctive “fingerprint”.

For this annual report the programming language “Processing” was used to dis-

play the various types of networks and multilevel cooperations of Helmholtz Zentrum

München in a concise and well-structured manner.

Helmholtz Zentrum München –

German Research Center for Environmental Health

At a glance:

3 research programs within the program-oriented funding (POF)

framework of the Helmholtz Association of German Research Centres

781 publications in international journals (2009)

125 patent families

12 spin-offs and joint venture companies

1,792 employees (2009)

40 trainee positions

30 independent research institutes and departments

160 million euros financial volume (2009)

52 hectare research campus to the north of Munich

Helmholtz Zentrum München belongs to the largest German scientific

organization: The Helmholtz Association of German Research Centres has

30,000 employees and an annual budget of approximately 3 billion euros.

It pursues long-term research goals on behalf of the state and society and,

through its findings, helps to preserve and improve the foundations of

human life.

Annual Report 2009

Helmholtz Zentrum MünchenCooperation at Every Level

56

32

78

46

68

For an overview and explanation of the infographics, see the appendix.

Cooperation with HospitalsContinual exchange in translational centers and clinical cooperation groups with various

Munich university hospitals

International CooperationMore than 400 cooperation agreements with research institutions and university

institutes, scientific organizations and agencies worldwide

Cooperation in the Munich RegionClose collaboration with Ludwig-Maximilians-Universität (LMU) Munich and Technische

Universität München (TUM), clinical institutions and biotech and pharmaceutical companies

Cooperation through Platforms and Service Facilities Biomedical research infrastructure for the formation of science networks in Germany and in Europe

Cooperation in Centers and AssociationsPartnerships in future-oriented bioscience fields on a national, European and

international level

16 17 18 19

26 27

82 83 84 85 86 87 88 89 90 91

96 97 98 99 100 101 102 103 104 105

48 49 50 51 52 53

28 2924 25

58 59 60 61 62 63 64 65

42 4334 35 36 37 38 39 40 41

Contents

8 9 10 116 7

76 7772 73 74 7570 71

16182024262832

NetworksCooperations and NetworksResearch in Three Priority ProgramsTranslational Research and Personalized MedicineTechnology Transfer and Translational ResearchEpidemiology and Cohort Studies International Cooperation

68

12

2009 in RetrospectA Step ForwardTimeline 2009

343646

Lung Diseases Research Highlights Lung DiseasesCooperation in Centers and Associations

485056

Metabolic DiseasesResearch Highlights Metabolic DiseasesCooperation in the Munich Region

586068

Neurological DiseasesResearch Highlights Neurological DiseasesCooperation with Hospitals

70727880

Health and the Foundations of LifeResearch Highlights Health and the Foundations of LifeCooperation through Platforms and Service FacilitiesClinical Networks for Cancer Research

82 Further Research Highlights

9698

100102104106

Inside CoverInside Cover

FactsManagement in Networked StructuresStaffFinances Project FundingOrganizationResearch Institutes and DepartmentsImprint

20 21

30 31

22 23

92 93 94 95

106 Inside Cover

56 5754 55

32 33

80 81

66 67 68 69

44 45 46 47

12 13 14 15

78 79

Helmholtz Zentrum München is the German Research Center for Environ-

mental Health. It investigates common complex diseases which develop from

the interaction of environmental factors, lifestyle and individual genetic

disposition. The Center’s research activities focus on three main areas: meta-

bolic disorders, diseases of the respiratory system and neurodegenerative

diseases. The Center is developing the fundamental concepts for a personal-

ized medicine focused on addressing the causes of disease.

2009 in Retrospect

8

A Step Forward

During 2009 we strengthened our center’s research in common diseas-

es and their causes, intensifying our focus on lung diseases and diabe-

tes mellitus. The prerequisites for this are excellent scientific work and

training as well as cooperation with other top-level scientists and re-

search institutions. Two key aspects of the Center’s strategy are trans-

lational research and technology transfer. Both elements are essential

to make research results available for commercial use. They are also

crucial in enabling patients to benefit from the latest findings in medi-

cal research.

On June 24, 2009, the German Center for Diabetes Research (DZD) was

founded in Munich; Helmholtz Zentrum München is a founding mem-

ber. The German Institute of Human Nutrition (DIfE), the German Dia-

betes Center (DDZ), the University of Tübingen, Dresden University

Hospital, and the Helmholtz and Leibniz Associations are the other re-

search partners. The DZD harnesses knowledge and expertise to devel-

op innovative approaches for the prevention and therapy of dia betes

mellitus. Professor Martin Hrabe de Angelis, director of the Institute of

Helmholtz Zentrum München is one of Germany’s foremost health research

centers and is a member of the renowned Helmholtz Association. As German

Research Center for Environmental Health, we study the pathogenic mecha-

nisms of complex common diseases which develop from the interaction of

environmental factors, lifestyle and individual genetic disposition. Our re-

search focuses on lung diseases and diabetes mellitus as well as on patho-

genic mechanisms occurring in the central nervous system, in the cardiovas-

cular system, in cancer and infections.

Experimental Genetics at Helmholtz Zentrum München and chair of

Experimental Genetics at Technische Universität München (TUM), was

elected one of three members of the board of the newly established

center. With the federal funding through the DZD, we will further ex-

pand our research in this field and also found new institutes.

The translational approach of the Comprehensive Pneumology Center

(CPC) opens up new avenues in the therapy of respiratory diseases.

Helmholtz Zentrum München, Ludwig-Maximilians-Universität (LMU)

Munich and the Asklepios Pulmonary Hospital in Munich-Gauting are

co-founders of the CPC. The new center allows the researchers and

physicians from the different participating institutions to complement

one another’s capabilities. The CPC took shape in 2009: The laborato-

ries, which are close to the university hospital, were renovated, and

the researchers were able to move into them at the end of the year.

Two factors will ensure the success of the CPC: the outstanding scien-

tific work of the researchers within the CPC itself and their cooperation

with scientists from other top-level institutions. To mention several

9

examples: Professor Oliver Eickelberg, institute director at Helmholtz

Zentrum München and chair (W3) of Experimental Pneumology at

LMU, was appointed conference and seminar director of the European

Respiratory Society. The CPC also cooperates with the French Nation-

al Institute for Healthcare and Medical Research (INSERM), Paris, and

the American healthcare organization UPMC, Pittsburgh. Within the

framework of the Helmholtz Graduate School of Environmental Health

(HELENA), the Helmholtz Research School “Lung Biology and Diseas-

es”, planned for 2010, will provide our young researchers with in-depth

knowledge in this research field. Together with Münchner Bank, Helm-

holtz Zentrum München established the foundation “AtemWeg” (Air-

Way) in order to gain the support of the general public for important

research activities and the promotion of young scientists.

Neurological and psychiatric diseases constitute an ever-increasing

challenge for our society. Helmholtz Zentrum München coordinates

the Helmholtz Alliance “Mental Health in an Aging Society”, which

will eventually merge with the newly established German Center for

Neurodegenerative Diseases (DZNE) in Bonn. As of November 5, 2009,

Helmholtz Zentrum München also officially supports the Munich part-

ner site of the DZNE and contributes its expertise. The DZNE is being

established as an interdisciplinary research institute which enables

holistic research – bridging the gap between basic molecular research

and patient care.

Cooperation is a crucial factor for the remarkable progress we have

made: We have cooperation agreements with the best partners in ac-

ademic and industrial research. This also applies to our other large-

scale research projects that have made good progress in 2009:

– Successful translational research is an essential element of Helm-

holtz Zentrum München. In addition to eleven clinical coopera-

tion groups and the translational Comprehensive Pneumology

Center (with LMU and Asklepios Pulmonary Hospital), Helmholtz

Zentrum München and Technische Universität München are es-

tablishing a second translational center, the Munich Allergy Re-

search Center (MARC). Research is set to begin in April 2010 with

Prof. Dr. Günther Wess CEO and President

Dr. Nikolaus Blum CFO

A Step Forward

10

the establishment of the first German university chair for Allergy

and Environmental Research.

– To carry out research on the most common diseases, mouse mod-

els, epidemiology and structural biology are decisive cross-sec-

tional technologies in which Helmholtz Zentrum München has a

leading role. In the field of epidemiology we work together with

the German Cancer Research Center in Heidelberg in building

the Helmholtz cohort, a national cohort of 200,000 persons. The

central biorepository will be located here in Munich.

– The long-standing competence of Helmholtz Zentrum München

in the field of radiation research will be preserved. To this end,

we have realigned our activities in coordination with the Federal

Minis try of Education and Research (BMBF) and the Federal Min-

istry for the Environment, Nature Conservation and Nuclear Safety

(BMU). At the World Congress for Medical Physics and Biomedi-

cal Engineering, innovative technologies for radiation protection

in medicine – based on developments at our center – were pre-

sented. This knowledge and expertise will enable us to become an

important cooperation partner nationally and internationally, also

in the long term.

Two of the most important yardsticks of success for Helmholtz Zentrum

München are value creation and the further development of basic re-

search findings for applications. As a strong partner in science, we

take our research to its ultimate goal – to applications which benefit

patients. On April 23, 2009, the European Medicines Agency (EMEA)

approved the new medication Removab®. The scientific basis for this

innovative cancer drug was developed and patented at what is now

Helmholtz Zentrum München in the 1990s. The licenses were granted

to the Center’s spin-off Trion Pharma, which obtained approval for the

antibody in collaboration with the firm Fresenius Biotech. Helmholtz

Zentrum München thus proved that it can make a significant contribu-

tion to innovative therapies. In many different ways Removab® is a

great success and an example for successful cooperation: It is the first

approved therapeutic antibody that was completely developed in Ger-

many and thus the only new drug in the past 15 years that was fully de-

veloped by the German biotech sector – from basic research to clinical

trials and finally to marketing authorization. Removab® underscores

the importance of industrial cooperation, which we have expanded

further in 2009.

Helmholtz Zentrum München enhanced its performance and attrac-

tiveness in 2009, and the structure of our excellent training concept

was further developed. This represents an advantage in the competi-

tion to attract the best scientific minds.

– The number of publications and citations increased again com-

pared with the previous year. With 781 publications in ISI-refereed

journals and a total impact factor of 4400, the Center is one of the

world’s leading research institutes in the field of Environmental

Health. In the latest funding ranking published by the German Re-

search Foundation (DFG) in September 2009, Helmholtz Zentrum

München was ranked first in the Sixth EU Framework Program on

Research, second in receiving federal grants, and fourth in receiv-

ing DFG funding among non-university institutions in Germany.

– A central commitment of our center is to promote the careers of

young scientists. To provide optimal guidance, we established a

graduate student office and thesis committees to supervise the

individual doctoral thesis projects. We also initiated a lecture

series on Environmental Health to deepen and expand our young

research ers’ theoretical knowledge. Last year, the first components

of the Helmholtz Graduate School of Environmental Health were

established, which is due to begin in 2010. Likewise, the “Petten-

kofer School of Public Health München” (PSPH-LMU) was estab-

lished as regional center for interdisciplinary health research and

education in public health. Supported by LMU, the Bavarian Office

for Health and Food Safety in Erlangen and Helmholtz Zentrum

München, it will encourage networking between research and

practice and open up new perspectives in the field of public health.

– Moreover, with the establishment of a café for doctoral students

and the improvement of bus connections, the campus became

more attractive in 2009.

On our way towards becoming the world’s leading research center

in the field of Environmental Health, we have taken important steps

forward. To this end, we are pooling our resources and efforts under

the motto “one2013 – one center, one goal”. The endeavor one2013 can

only be achieved together: as a research center with a common focus,

a common goal and a common strategy.

Excellent science needs efficient support through smooth administra-

tive processes. One of our objectives in 2009 was to optimize the in-

ternal processes and to establish a modern governance structure. In

11

November the Supervisory Board and the Assembly of Partners ap-

proved the new regulations which meet these requirements. At the

same time, scientific co-determination was strengthened: It now also

takes place in the central decision-making body at management level,

the Management Committee. The new committee convened for the first

time on November 24, 2009. These changes create the essential pre-

requisite for short decision-making paths and fast, efficient implemen-

tation – factors which maximize scientific success.

Our success would not have been possible without cooperative re-

search in interdisciplinary teams. The ability to work in a team is one

of our five values that guide us at Helmholtz Zentrum München. They

also include respect, integrity, responsibility, and commitment. Our

staff members show the latter with their continual dedication in their

daily work and thus lay the foundation for the success of our center.

Here we would like to express our most sincere gratitude to all of them.

We would also like to extend our thanks to the Supervisory Board

and the Scientific Advisory Board for supporting our activities in such

a constructive manner, to the Federal Ministry of Education and Re-

search (BMBF) and the Bavarian State Government for providing fund-

ing, and to the President and Central Office of the Helmholtz Associa-

tion for their support.

The successes of the year 2009 illustrate that scientific results can only

be achieved through cooperation. This is true not only for our work

within Helmholtz Zentrum München, but also for our cooperation with

outstanding scientists throughout the world. With this annual report,

we therefore focus our special attention on cooperations and networks

and present a selection of outstanding scientific results of the past

year: “Connecting excellence for health!”

A Step Forward

Dr. Nikolaus Blum CFO

Prof. Dr. Günther Wess CEO and President

Excellent Research

Excellent Training

Excellent Platforms

Use in Society

Common diseases: lung diseases, diabetes, neurodegenerative diseases

New approaches for prevention, diagnosis and therapy

Leitmotif Environmental Health

Cooperations

Translational Research,Technology Transfer

From basic research to use in society: Cooperation is the central factor for successful research in the area of Environmental Health.

12

2 The Center is partner in the Alps Bio

Cluster: Here six alpine regions pool their

resources in research, industry and training

in the biotech and medtech sectors.

8 Genetic components of overweight:

As part of an international research team,

Center scientists identify six new genes

that have an impact on weight regulation.

29 Symposium on Environmental Allergy

and Allergotoxicology: Scientists of

Helmholtz Zentrum München and Technische

Universität München discuss the impact of

climate change on allergic diseases.

9 Expert training in radiation protection:

Scientists of the Center organize the

WE-Heraeus Physics Winter School.

17 Chemical biology project gets green

light: The Life Science Foundation approves

funding of a development platform for new

screening approaches at the Institute of

Structural Biology.

18 First German chair for Allergy and Envi-

ronmental Research: Technische Universität

München and Helmholtz Zentrum München

announce the establishment of the Munich

Allergy Research Center (MARC). — 1

10 Cooperation agreements with China:

The Shanghai Center for Bioinformation

Technology (SCBIT) and Helmholtz Zentrum

München intensify their collaboration in the

fields of epidemiology and systems biology.

— 2

12 Contact point for graduate students: With

the opening of the Graduate Student Office,

the Center continues to expand its promotion

and support of graduate students.

17 Chromatin structures are analyzed:

With four research groups, the Center

participates in the third phase of the DFG

Transregional Collaborative Research Center

SFB Transregio 5 “Chromatin: Assembly and

Inheritance of Functional States”.

18 Industrial robot for tomographic

imaging: The Federal Ministry of Economics

and Technology supports a new joint project

at the Center for the development of dose-

efficient instruments in human and veteri-

nary medicine.

Timeline 2009

January February March

1

2

13 Timeline 2009

1 Focus on neurodegenerative diseases:

The Federal Ministry of Education and Re-

search promotes the joint project “Integration

of Stem Cell Based Neurons” which is coordi-

nated at the Center together with university

institutes in Dresden, Jena, Munich, Regens-

burg and Erlangen-Nuremberg.

20 Graduate program commences lecture

series: The new lecture series provides grad-

uate students with a survey of the research

area “Environmental Health”.

23 Institutional framework for doctoral

training: The Center decides on guidelines on

the supervision of doctoral students.

23 European Medicines Agency EMEA

approves the first therapeutic antibody

“made in Germany”: The drug is the result of

research at the Center.

24 Research topics in focus: local politicians

of the communities surrounding Munich visit

the Center together with the mayor of Ober-

schleißheim, Elisabeth Ziegler, and District

Administrator Johanna Rumschöttel. — 3

4 4th EU funds innovative biomarkers:

The Center participates in the public-private

partnership project (Innovative Medicines

Initiative, IMI) for the development of new

diagnostic approaches for secondary diseases

of type 1 and type 2 diabetes.

6 6th Workshop on Steroid Analytics:

International experts discuss new techniques

and clinical applications.

15 From Neuherberg to Munich-Perlach:

The largest European monitoring station for

personal dose monitoring, which is affiliated

with the Center, moves to new premises. — 4

18 One hundred years after Marie Curie:

The workshop “Women in Radiation Science”

focuses on current contributions to radiation

science by female researchers.

27 Workshop discusses new research

approaches: More accurate assessment of the

risks of small radiation doses with methods

of radiation proteomics.

29 Perspectives for the translation of

basic biomedical research: Pilot projects are

selected for the establishment of the Depart-

ment of Chemical Biology at the Center.

15 A comparison of metabolic diseases in

different ethnic groups: The Federal Minis-

try of Education and Research promotes a

German-Chinese study on type 2 diabetes un-

der the aegis of the Institute of Epidemiology.

20 Simplifying risk assessment for chemi-

cals: The Center participates in a new Euro-

pean project for the development of a system

of substance classification (CADASTER).

23 Munich company B2Run:

70 runners compete for Helmholtz Zentrum

München. — 5

24 Concentrating diabetes research

nationally and internationally: Partners of

the newly established German Center for

Diabetes Research (DZD) are Helmholtz

Zentrum München, the German Institute of

Human Nutrition (DIfE), the German Diabe-

tes Center (DDZ), the University of Tübing en,

the University Hospital Dresden, and the

Helmholtz and Leibniz Associations. — 6

25 Solution proposals presented by the

Octrahedron Workshop: Staff members in ad-

ministration develop new approaches to opti-

mize processes and structures at the Center.

April May June

4

5

6

3

14

1 Restoring impaired brain and spinal cord

functions: The Bavarian Research Association

“Adult Neural Stem Cells” receives funding

for new therapeutic approaches to regenerate

damaged cells in the nervous system.

10 Striving for leadership in international

research on environmental health: Supervi-

sory board and Scientific Advisory Board of

Helmholtz Zentrum München give green light

for the next steps toward one2013.

29 On the move: Under the motto “Tour de

Sport”, the first sports day takes place on the

Neuherberg campus. — 7

3 Young researchers conquer the campus:

Employees’ children start their long holidays

with a week full of scientific experiments.

— 8

6 New department is created: At the Insti-

tute of Ecological Chemistry, the new Depart-

ment of BioGeoChemistry and Analytics

comes into being under the leadership of PD

Dr. Dr. Philippe Schmitt-Kopplin.

15 In the service of the community:

The social welfare organization at Helmholtz

Zentrum München celebrates its tenth anni-

versary.

1 Start of training in professions of the

future: 17 new trainees begin their appren-

ticeship at the Center. — 9

7 Top-quality training: At the Neuherberg

training laboratory, the Bavarian Minister of

Social Affairs, Christine Haderthauer, praises

the high quality of the vocational training at

the Center. —10

7 World Congress for Medical Physics and

Biomedical Engineering convenes in Munich:

The Center presents innovative technology

for radiation protection in medicine.

10 Making use of research approaches: New

project field “Translational Biomedical Phys-

ics and Technology” connects research activi-

ties at Helmholtz Zentrum München with clin-

ical applications.

15 Securing drinking water quality in

Europe: Young researchers learn innovative

methods for sustainable ground water use

and environmentally-friendly decontamina-

tion at the Center. 7

8

9

10

July August September

Timeline 2009 15

5 Successful track record is presented:

For the past ten years, the American Envi-

ronmental Protection Agency (EPA) and the

Center have been working together to assess

the effects of nanoparticles and particulate

matter on health. — 11

21 Living the values of the center: Among

staff members, the “marketplace of values”

starts the discussion process about the guid-

ing principle and values of the Center.

26 ERC-Starting grant for young research-

ers at the Center: Dr. Heiko Lickert receives

1.5 million euros in funding from the Euro-

pean Research Council (ERC) to conduct

research on ciliopathies.

5 Cooperation agreements concluded:

Munich is official partner site of the German

Center for Neurodegenerative Diseases

(DZNE) in the Helmholtz Association.

9 New start-up company founded: On the

basis of mass spectrometry methods invent-

ed at Helmholtz Zentrum München, Photo-

nion GmbH develops devices that enable

straightforward analysis of complex organic

materials, liquids or gases. — 12

25 Science Day as communication platform:

After presentation of research highlights,

staff members develop new approaches and

ideas across institute boundaries.

26 Forum for networking activities and

interdisciplinary work: Within the frame-

work of Graduate Students’ Day, the new

doctoral students’ café opens in the central

library.

26 Excellent doctoral theses receive

awards: Three doctoral students receive

the prize of the Association of Friends and

Sponsors.

2 Improving leukemia treatment: The José

Carreras Leukemia Foundation promotes

a research project at Helmholtz Zentrum

München to improve treatment of complica-

tions after bone marrow transplantations.

9 Success factor for the Science Region

Bavaria: During an informative visit, Bavar-

ia’s Science Minister Dr. Wolfgang Heubisch

assures his support for the expansion of the

Center’s leading position in science. — 13

10 Helmholtz President visits translational

center for lung research: Prof. Dr. Jürgen

Mlynek visits the Comprehensive Pneumol-

ogy Center (CPC) in Grosshadern and gathers

information on the planned Graduate School

for Environmental Health.

15 Joint research on lung diseases: The

Comprehensive Pneumology Center (CPC)

and the Institut National de la Santé et de la

Recherche Médicale in Paris (INSERM) enter

into a strategic partnership.

20 Fostering education and prevention:

Ludwig-Maximilians-Universität, Helmholtz

Zentrum München and the Bavarian Office for

Health and Food Safety together found the

Pettenkofer School of Public Health Munich.

11

12

13

October November December

16

Global cooperation and networks are critical success factors for research at

Helmholtz Zentrum München. Networks facilitate scientific exchange and

promote a diversity of research approaches.

Networks

18

Cooperations and Networks

At Helmholtz Zentrum München, we have established a tradition of success through

networking. Thinking in networks is an expression of our core concept ‘Environmental

Health’, which interconnects health research and environmental research. At our center

we investigate the complex interaction between individual genetic predisposition, envi-

ronmental influences and lifestyle. By combining basic research with clinical research, we

are able to develop new and promising approaches to diagnosing, treating and preventing

common complex diseases such as diseases of the respiratory system and diabetes.

Global cooperation and networks are an important success factor for our research at Helm-

holtz Zentrum München. We can only meet great challenges and achieve outstanding suc-

cess if our cooperation partners complement our capabilities and contribute to our shared

research goals. Working within networks means joining forces to facilitate the achievement

of shared goals. In line with our center’s strategy, we participate in high-performance re-

search networks with internationally renowned partners. We thus broaden and strengthen

our competence and provide greater benefit to society.

Acknowledged researchers and cutting-edge technology in important fields of biomed-

icine make Helmholtz Zentrum München a source of innovation in domestic and interna-

tional networks. By coordinating large German and European projects, we assume respon-

sibility beyond the scope of our center and set scientific standards.

Our collaborations range from basic, bilateral cooperation between individual scien-

tists to complex, international associations. Here trust is a keystone: Only in an honest and

responsible partnership can new ideas be developed and commonalities be recognized and

strengthened. Both the ‘ivory tower’ and the ‘industrial silo’ approaches to research have

become outmoded. In order to create innovation, there must be a shared and unimped-

ed flow of knowledge. This is why networks not only require good management, but even

more importantly, a culture of cooperation.

This is a major reason why respect, integrity and the ability to work in a team are among

our core values. Knowledge management is also an indispensable element of working in

large networks. As a capable partner, we formulate clear offers to the scientific community

and create transparency, multiple interfaces and options for cooperation.

Successful collaborations and networks help to set in motion continuous processes of

change. They help us replace our ingrained thought patterns and increase the number of

interfaces, both within and outside a research organization. By participating in effective

networks, we can further strengthen our profile as a center and can seize new opportuni-

ties together with new partners. This strategy will secure a sustainable competitive advan-

tage for our center.

In this annual report, some of our networks and partnerships are visualized graphically.

The examples provide an impression of the diversity of research approaches encompassed

by our core concept ‘Environmental Health’. Some networks have developed during the

course of many years, while others are still emerging and evolving dynamically.

19 Cooperations and Networks

The interconnectedness of Helmholtz Zentrum München is displayed in this annual report,

using prominent examples. These include graphics showing the respective levels of cooper-

ation that connect Helmholtz Zentrum München both internally and externally, the person-

al publication networks of individual scientists and – in the research highlights sections –

the connections between publications of all cooperation partners and authors involved in

the respective original publication. (Please find a detailed explanation on the inside front

cover flap).

Acampora D

Rathkolb B

Schmidt MV

Refojo D

Wolf E

Puelles E

Schnütgen F

Ohl F

Naserke T

Tuorto F

Sillaber I

Zieglgänsberger W

Prakash N

Steckler T

Simeone A

Partanen J

Paez-Pareda M

Wojtak CT

Ruiz P

Stalla GK

Renner U

Zimmermann S

Spanagel R

Vogt Weisenhorn DM

Reul JM

Seisenberger C

Rein J

20

Research in Three Priority Programs

Helmholtz Zentrum München obtains its basic funding through the program-oriented

funding (POF) of the Helmholtz Association. Its second phase runs from 2009 to 2013. The

three POF programs at the Center are guided by the strategic orientation towards envi-

ronmental health. In the program “Environmental Health” (EH), the main research focus

is on lung diseases and on reactions of the immune system to environmentally related

diseases such as allergies, specific types of tumors as well as risk factors for important

common diseases. In the program “Systemic Analysis of Multifactorial Diseases” (SAM),

diabetes and neurological diseases are at the center of interest. Cross-program projects

in the fields of allergy, immunity and aerosol research represent interfaces between the

program “Terrestrial Environment – Strategies for a Sustainable Response to Climate and

Global Change” (TE) and the health sector, especially the EH program.

Environmental Health (EH)

Environmentally related diseases are among the great medical and socio-economical chal-

lenges for the Western world. An increasing life expectancy of the population and global

environmental changes will lead to a dramatic increase in diseases such as diabetes, respi-

ratory and cardiovascular diseases, cancer and allergies that arise from the complex inter-

action of environmental factors, lifestyle and individual genetic disposition.

The Environmental Health program contributes to a better understanding of the inter-

action between environmental factors and health. It develops new, effective strategies for

prevention, early detection and therapy of chronic diseases.

Research in Three Priority Programs 21

Special Emphases within the Environmental Health Program: Lung Diseases

Helmholtz Zentrum München is conducting research to develop new therapies for chronic

lung diseases. It is committed to providing faster utilization of research results for the ben-

efit of patients through a translational research approach. Helmholtz Zentrum München

founded the Comprehensive Pneumology Center (CPC), a translational center for lung

research, together with Ludwig-Maximilians-Universität (LMU) Munich and Asklepios Pul-

monary Hospital Munich-Gauting. The CPC is located on the high-tech Grosshadern cam-

pus and is embedded in modern research and clinical infrastructures. The CPC laboratories

and research clinic cooperate with Asklepios Pulmonary Hospital in Munich-Gauting and

the University Hospital of LMU.

Allergies

Together with Technische Universität München, Helmholtz Zentrum München has founded

a new allergy center to elucidate the causes of allergic diseases and to develop new ap-

proaches for their treatment.

Disease Risks

Together with the German Cancer Research Center (DKFZ), Helmholtz Zentrum München

has assumed the leading role in the planning of a major national cohort for the analysis of

disease risks in the population. This nation-wide cohort, which will be in place for a period

of up to twenty years, will examine risk factors in 200,000 individuals for common diseas-

es such as diabetes, cancer, neurological diseases and cardiovascular diseases. It will open

new avenues for prevention.

“ We are researching how environmental factors and genetic disposition inter-

act in the pathogenesis of chronic diseases such as lung diseases. Based on

our research, we are developing individualized strategies for prevention, early

diagnosis and therapy.”

Coordination


Program Spokesperson

Prof. Dr. Martin Göttlicher

Participating Centers (share in %)

Helmholtz Zentrum München (90%)

Helmholtz Centre for Environmental Research –

UFZ, Leipzig (10%)

Prof. Dr. Martin Göttlicher

22

Systemic Analysis of Multifactorial Diseases

Multifactorial diseases have a major impact on the disease and mortality numbers of a

society. They arise from the complex interaction of an individual genotype with environ-

mental and lifestyle factors.

The program “Systemic Analysis of Multifactorial Diseases” (SAM) combines functional

genomics in model systems – studies in cell systems and animal models – with human ge-

netics. Through research approaches of systems biology, it searches for “functional mod-

ules”: biological functional units that cause diseases when disrupted. The German Mouse

Clinic, an open access platform that serves as an instrument for the standardized analysis

of mouse models for human diseases, is run under the aegis of the SAM program.

Special Emphases in the Systemic Analysis of Multifactorial Diseases Program:

Diabetes Mellitus

In diabetes research Helmholtz Zentrum München has teamed up with Ludwig-Maximil-

ians-Universität (LMU) and Technische Universität München (TUM) in a strategic part-

nership. It participates in the German Center for Diabetes Research (DZD), which unites

national research competence with the aim of rapidly translating basic research findings

into clinical applications to benefit patients with diabetes.

Neurological and Psychiatric Disorders

At Helmholtz Zentrum München two institutes conduct research on the brain and the ner-

vous system, neurodegeneration and neuroregeneration. The Center also coordinates the

Helmholtz Alliance “Mental Health in an Aging Society”. Helmholtz Zentrum München

participates in the Munich partner location of the German Center for Neurodegenerative

Diseases (DZNE) in Bonn.

“ The next great challenge for research will be to find out how genetic factors

contribute to the development of multifactorial diseases and under which pre-

conditions and environmental conditions systemic diseases arise. Our aim is

to analyze the essential genetic factors and biomolecular principles that lead

to multifactorial diseases – for example, in diabetes mellitus.”

Coordination



Prof. Dr. Martin Hrabe de Angelis

Participating Center



23 Research in Three Priority Programs

Terrestrial Environment – Strategies for a Sustainable Response to Climate and Global Change

Terrestrial systems are where human activities propel global change. At the same time

they are the habitat in which humans are directly affected in their living and economic

conditions. Therefore, terrestrial systems are the decisive starting point for the develop-

ment and implementation of strategies for a sustainable development. The aim of research

in the Helmholtz program “Terrestrial Environment” is to secure the natural foundations

for life and health and to create opportunities for social and economic developments at the

same time.

Environmental research at Helmholtz Zentrum München is embedded in the program

“Terrestrial Environment – Strategies for a Sustainable Response to Climate and Glob-

al Change” (TE). It is coordinated by the Helmholtz Centre for Environmental Research –

UFZ, Leipzig. The participating centers are the Helmholtz centers in Leipzig, Jülich (FZJ)

and Munich.

At Helmholtz Zentrum München the main objectives are the following: to make innova-

tive and effective contributions to the optimized utilization of microorganisms and plants;

to define and optimize ecosystem services such as food and drinking water; to gain knowl-

edge about the prevention of environmentally related diseases such as allergies or in-

fectious diseases; to elucidate biological mechanisms and guide processes, ranging from

molecules to organisms and environmental habitats; and finally, to explain sensitivity or

disposition towards various influential factors.

A Special Focus of the Terrestrial Environment Program: Preserving Water Quality

Helmholtz Zentrum München is pursuing research on how water quality can be measured

and preserved. In cooperation with the chairs for Analytical Chemistry and Hydraulic En-

gineering at Technische Universität München, the chair for Hydrology at the University of

Bayreuth and the Water Resources Authority in Hof, Bavaria, Helmholtz Zentrum München

is in the process of establishing a Bavarian Center for Water Research.

“ The idea of ecosystem services is a key aspect of the program ‘Terrestrial En-

vironment’. The question of how the components soil, water and plants can be

utilized for human benefit is of prime importance.”

Coordination


UFZ, Leipzig


Prof. Dr. Bernd Hansjürgens, Leipzig

Program Spokesperson within Helmholtz

Zentrum München

Prof. Dr. Jörg Durner, München

Participating Centers (share in %)


UFZ, Leipzig (55%)

Research Center Jülich (23%)

Helmholtz Zentrum München (22%)

Prof. Dr. Jörg Durner

Engels B

Roskrow MA

Riethmüller G

Pezutto A

Schüler T

Endl J

Buchner A

Reinhardt D

Siebels M

Nössner E

Falk CS

Reinhardt C

Oberneder R

Djafarzadeh R

Konstantopoulus N

Hofstetter AG

Jantzer P

Dörken B

Nelson PJ

Frankenberger B

Cayeux S

Griese M

Raffegerst SH

Prell C

Kriegmair M

Willimsky G

Maget B Krauss-Etschmann S

Stief CG

Hartl D

Kolb HJ

Pohla H

Weiss EH

Uckert W

Segurado OG

Javorovic M

Blankenstein T

This graphic shows a publication-based social network.Source: www.biomedexperts.com

The Immune Monitoring Platform is an important link between clinical and research activi-

ties. It monitors patients’ immune response in the context of clinical trials of new immunologi-

cal therapy approaches against infectious diseases and malignant tumors. The platform is a

cooperation between highly qualified scientists of Helmholtz Zentrum München, the Univer-

sity Hospital rechts der Isar of Technische Universität München and the University Hospital

of Ludwig-Maximilians-Universität Munich.

Translational Research and Personalized Medicine

“ The aim of our work is to help patients in

an effective and individualized manner.

Due to the collaboration of highly motivated

scientists from leading institutions within

the Immune Monitoring Platform, we can

immediately verify successes.”

Prof. Dr. Dolores Schendel

is the director of the Institute of Molecular Immunology at Helmholtz Zentrum München. She was the

Center’s first female institute director and is considered to be one of the leading researchers in the field

of immune and cell therapy. Professor Schendel combines basic research with clinical applications in

various cooperative research initiatives – e. g. as coordinator of the platform for monitoring immune

response within the Helmholtz Alliance for Cancer Immune Therapy. Her institute is part of BayImmuNet,

a Bavarian network for the advancement of new immunotherapeutic approaches.

26

Technology Transfer

Helmholtz Zentrum München has a broad range of new and competitive technologies,

especially in the fields of biotechnology, pharmaceuticals, medical technology and envi-

ronmental analytics. These are offered to industry for utilization by the Legal and Technol-

ogy Transfer Department in cooperation with Ascenion GmbH, which was founded on the

initiative of Helmholtz Zentrum München. Ascenion GmbH supports the Center in the com-

mercialization of technologies and patents developed at the Center. The foremost goal of

this technology transfer is to make the results of our research work available for develop-

ment of a concrete application as soon as possible with the help of our industrial partners.

Patenting or out-licensing as well as spin-offs constitute an important basis for tech-

nology transfer at Helmholtz Zentrum München. Photonion GmbH was founded in 2009.

A Success Story

The first therapeutic antibody “made in Germany” was approved under the trademark

Removab® in April 2009 and is based on immunological research at Helmholtz Zentrum

München. The production processes and the underlying active principle of the antibody

were developed and patented in the mid 1990s. Trion Pharma GmbH, a spin-off of Helm-

holtz Zentrum München, acquired the license in 1998 and brought the drug to market

together with Fresenius Biotech GmbH, a subsidiary of the Fresenius Health Care Group.

The success story of the antibody affirms the models for technology transfer and trans-

lational research that are consistently applied at Helmholtz Zentrum München. Results

with high application potential are further developed in close cooperation between re-

searchers in the laboratory and physicians in the hospital and brought to clinical trials.

Spin-offs and cooperations enable development to market maturity. Helmholtz Zentrum

München is entitled to a share of the revenues or the royalties generated by commercial-

ization of the research results. The generated revenue is then reinvested in the promotion

of innovative research projects or respective development projects.

ACTIVAERO GmbH founded as Inamed GmbH in 1998 – since2006 device development division under the name of Acti-vaero GmbH – a competence center for inhalation technology and aerosol medicine www.activaero.de

Biomax Informatics AG founded in 1997 – development of bioinformatics software for the life science sector www.biomax.com

Genomatix Software GmbH founded in 1997 – programs to elucidate mechanisms and pathways in biological systems www.genomatix.de

Inamed Research GmbH & Co. KG studies on drug inhalation www.inamed.de

Ingenium Pharmaceuticals GmbH founded in 1997 – inte-grated into Probiodrug AG in 2007 – development of small molecules for the treatment of neuronal and autoimmune diseases Probiodrug AG, www.probiodrug.de

Isodetect GmbH founded in 2005 – isotope analyses in the environmental sector www.isodetect.de

MedTherm GmbH founded in 2008 – hyperthermia as treat-ment method for cancer diseases

Photonion GmbH founded in 2009 – development of mass spectrometry devices for the direct analysis of complex organic gases, liquids and materials www.ascenion.de

Sirenade Pharmaceuticals AG founded in 2005 – taken over by KeyNeurotek AG – for the direct analysis of complex organic substances www.keyneurotek.de

TRION Pharma GmbH founded in 1998 – trifunctional anti-bodies for cancer immunotherapy www.trionpharma.de

Vaecgene GmbH founded in 2000 – drugs for therapy of tumor diseases and infectious diseases www.vaecgene.de

Vivacs GmbH taken over by Emergent Biosolutions in 2005 –vaccine vector technologies www.emergentbiosolutions.com

Spin-offs of Helmholtz Zentrum München

In recent years 11 spin-off companies with cur-

rently around 320 employees have been found-

ed. In 2009 the spin-off company Photonion

GmbH was founded as joint venture with two

mid-sized companies.

Technology Transfer and Translational Research

Translational Research

New findings about the interaction of genetic predisposition and the living conditions of

humans must be quickly translated into new and individually effective therapy and pre-

vention measures. In order to achieve this, clinical researchers and physicians cooperate

closely at the Comprehensive Pneumology Center (CPC), a translational center for lung

research, and in eleven clinical cooperation groups. Current experimental findings, clini-

cal observations and diagnoses as well as state-of-the-art technology are available to find

answers to relevant medical questions.

At the CPC, Helmholtz Zentrum München collaborates with its partners at the medical

school of Ludwig-Maximilians-Universität Munich, the University Hospital of LMU and the

Asklepios Pulmonary Hospital in Munich-Gauting to improve therapeutic and diagnostic

methods for patients with chronic lung diseases.

The fact that the laboratories and the research clinic are under one roof makes the pa-

tient-oriented research approach of the CPC possible.

New models for therapy and diagnosis are developed in clinical cooperation groups in

cooperation between the University Hospital of Ludwig-Maximilians-Universität Munich,

Technische Universität München and the Max Planck Institute of Psychiatry, with an em-

phasis on personalized concepts. The existing projects include identifying and validating

new target structures for the therapy of chronic diseases and tumor diseases, proof-of-con-

cept studies for cell therapy and the implementation of new therapy modalities, such as

hyper thermia in patient care.

Project status as of December 2009

Osteosarcoma

Molecular Oncology

Pathogenesis of Acute Myeloid Leukemia

Molecular Neurogenetics

Immune Regulation in Childhood

Environmental Dermatology and Allergology

Antigen-specific Immunotherapy

Hematopoietic Cell Transplantation

Innate Immunity in Tumor Biology

Tumor Immunology in Childhood

Tumor Therapy with Hyperthermia

Basic Preclinical Clinical Trials

Clinical Cooperation Groups (CCG)

27

Borte M

Jöckel KH

Kreuzer M

Reinhardt D

Herbarth O

Kuhn K

Peters A

Boffetta P

McCarthy M

Von Berg A

Baur M

Kaaks R

Kronenberg F

Reiser MJ

Hoek CLöffler M

Thorand B

Heier M

Kääb S

Rückerl R

Meisinger C

Zatloukal K

Brennan P

Jäger L

Heinrich J

Berdel D

Linseisen J

Sunyer J

Elliott P

Darby S

Dockery D

Bickeböller H

Ahrens W

Hirschhorn J

Brunekreef B

Behrendt H

Künzli N

Sausenthaler SBrüske-Hohlfeld I

Illig THolle R

Meitinger T

Weidinger S

Giani G

Kreienbrock L

Rathmann W

Grallert H

Gehring U

Leidl R

Schäfer T

Kreyling W

Pope A

Gieger C

Peltonen L

Cyrys J

Heid IM

Ladwig KH

Schneider A

Mansmann U

Vineis P

Herder C

Koletzko S

Pramstaller P

Krämer U

Ring J

Koenig W

Pfeufer A

This graphic shows a publication-based social network.Source: www.biomedexperts.com

The KORA study center in Augsburg is the nucleus of the internationally renowned research

platform on the pathogenesis and course of chronic diseases. In a large population-based

cohort study relationships are investigated between environment, lifestyle and genetic dis-

position. The aim of KORA is to detect early signs of disease risks and to identify approaches

to prevention.

Epidemiology and Cohort Studies

“ Research networks are an important part

of my epidemiological research, which

consists of collating data from large-scale

studies in order to gain insights which

cannot be provided by single studies. Here

KORA plays a key role.”

is the director of the Institute for Epidemiology at Helmholtz Zentrum München and holds the chair

of Epidemiology at Ludwig-Maximilians-Universität (LMU) Munich. He is one of the world’s leading

experts in the field of environmental epidemiology and environmental health research. As head of the

Cooperative Health Research Platform in the Augsburg Region (KORA), Professor Wichmann is part of

a large network of international research studies on common complex diseases.

Prof. Dr. Dr. H.-Erich Wichmann

30


Helmholtz Zentrum München has extensive expertise in the field of epidemiology. Epi-

demiological approaches play an increasingly significant role in modern health research.

They provide essential data on the incidence and distribution of diseases and the under-

lying influence factors. Population-based studies are an important basis for research at

the interface of health and environment. Furthermore, genetic risks can be identified and

analyzed in their interaction with environmental and lifestyle factors.

Through their participation in the KORA

studies, inhabitants of the Augsburg

region have contributed significantly to

scientific knowledge. Through regular

examinations and surveys, the partici-

pants’ health status can be described

over periods of up to more than 25 years.

Through the establishment of a myocar-

dial infarction registry and numerous

further studies, an extensive collection

of data and samples has been gener-

ated which continually give rise to new

scientific insights. This research results

in approximately 50 scientific publica-

tions every year.

Helmholtz Zentrum München has a cohort that is characterized by its particularly long ob-

servation period of more than 25 years and by the low attrition rate of the study’s partic-

ipants: KORA (Cooperative Health Research in the Augsburg Region) is a research plat-

form for population-based health surveys and follow-up studies on topics of epidemiology,

health economics and healthcare research. It is the continuation of the MONICA project,

which was started in 1984, and the myocardial infarction registry in Augsburg, and has con-

siderably broadened the spectrum of the different topics under investigation. The pool of

available study participants allows the realization of cohort and case-control studies.

The KORA database contains biological samples as well as phenotypic information from

approximately 18,000 adults from Augsburg and the surrounding area. The age of the par-

ticipants at the point of recruitment was between 25 and 74 years; in 2010 it was between

35 and 95 years. KORA can also be used by external partners for research on the cause of

diseases. The database of phenotypes and genotypes is available to all partners involved.

Scientific cooperation is an integral part of the KORA research project. Several institutes

of Helmholtz Zentrum München collaborate on KORA projects, and in addition, many exter-

nal partners jointly carry out fieldwork. Furthermore, KORA is used intensively nationally

and internationally and is involved in large research consortia on topics such as diabetes,

respiratory diseases, allergies and cardiovascular diseases. A new focus is the exploration

of the health situation and co-morbidity of elderly people.

31

The experience Helmholtz Zentrum München has gained within the framework of the KORA

cohort makes it a valuable partner in establishing the National Cohort. The preparation of

this new cohort is being coordinated by the Helmholtz Association together with university

partners. With over 200,000 participants it will be the largest German population study so

far. Over a period of twenty to thirty years, the participants shall undergo medical examina-

tions regularly and shall answer questions regarding their lifestyle and health status. The

examinations shall provide new insights into the causes of common chronic diseases such

as diabetes, cancer, cardiovascular diseases or dementia, as well as infectious diseases. Un-

der the aegis of Helmholtz Zentrum München and the German Cancer Research Center, the

process of setting up of the study was begun in 2009. Since then virtually all German uni-

versities with epidemiological expertise have joined the study. An important success factor

in setting up this cohort is the broad participation of basic researchers and clinicians in the

conception and determination of thematic priorities of the cohort, which will be accessible

to all interested biomedical researchers in Germany.

The KORA research platform is available

for use by additional external partners.

Information on the available data and

terms of use at

www.helmholtz-muenchen.de/KORA


German Diabetes Center DüsseldorfCentral Institute of Mental Health, Mannheim

University of Applied Sciences, AugsburgUniversity Hospital Schleswig-Holstein

Augsburg Health Authority University of Innsbruck

Augsburg HospitalUniversity of Ulm

Ludwig-Maximilians-Universität Munich

University of Münster

Technische Universität München

University of Lübeck

University of DüsseldorfUniversity of Greifswald

University of AugsburgUniversity of Leipzig

KORA

Cooperative Health Research in the Augsburg Region


32

International CooperationCountry City Institution1 Algeria 1.1 Béjaïa 1.1.1 University of Béjaïa

2 Belgium 2.1 Gent 2.1.1 Gent University

2.2 Louvain 2.2.1 Catholic University of Louvain

2.3 Mol 2.3.1 Flemish Institute for Technological Research

3 China 3.1 Beijing 3.1.1 National Analysis Center for Iron and Steel (NACIS)

3.2 Shanghai 3.2.1 Center for Bioinformation Technology

4 Denmark 4.1 Copenhagen 4.1.1 Geological Survey of Denmark and Greenland

4.1.2 Technical University of Denmark

4.1.3 University of Copenhagen

5 Germany 5.1 Aachen 5.1.1 RWTH Aachen University

5.2 Berlin 5.2.1 Charité University Medical Center Berlin

5.2.2 Max Delbrück Center for Molecular Medicine

5.3 Bonn 5.3.1 University of Bonn

5.4 Braunschweig 5.4.1 Helmholtz Centre for Infection Research

5.5 Düsseldorf 5.5.1 University of Düsseldorf

5.6 Dresden 5.6.1 Technical University of Dresden

5.7 Frankfurt 5.7.1 Goethe University Frankfurt

5.8 Heidelberg 5.8.1 German Cancer Research Center

5.8.2 University Hospital

5.9 Jena 5.9.1 Leibniz Institute for Age Research – Fritz Lipmann Institute

5.10 Marburg 5.10.1 University of Marburg

5.11 Munich5.11.1 Asklepios Pulmonary Hospital,

Gauting

5.11.2 Ludwig-Maximilians-Universität (LMU) Munich

5.11.3 Max Planck Institute of Biochemistry

5.11.4 Max Planck Institute of Psychiatry

5.11.5 Technische Universität München (TUM)

5.12 Tübingen 5.12.1 University of Tübingen

6 Finland 6.1 Oulu 6.1.1 University of Oulu

6.2 Helsinki 6.2.1 University of Helsinki

7 France 7.1 Grenoble 7.1.1 Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA)

7.2 Orleans 7.2.1 Centre National de la Recherche Scientifique (CNRS)

7.3 Paris 7.3.1 Institut National de la Santé et de la Recherche Médicale (INSERM)

7.4 Strasbourg 7.4.1 Institut Clinique de la Souris

8 Greece 8.1 Athens 8.1.1 Alexander Fleming – Biomedical Sciences Research Center

8.2 Heraklion 8.2.1 Foundation for Research and Technology – Hellas

Country City Institution9 Great Britain 9.1 Hinxton 9.1.1 EMBL – European Bioinformatics

Institute

9.1.2 The Wellcome Trust Sanger Institute

9.2 London 9.2.1 Medical Research Council (MRC)

9.2.2 University College London

9.3 Oxford 9.3.1 Medical University of Oxford

10 Italy 10.1 Milan 10.1.1 Università degli Studi di Milano

10.2 Monterotondo 10.2.1 Consiglio Nazionale delle Ricerche

10.2.2 European Molecular Biology Laboratory (EMBL)

11 Japan 11.1 Kobe 11.1.1 RIKEN Center for Developmental Biology

12 Canada 12.1 Toronto 12.1.1 Toronto Centre for Phenogenomics

12.2 Ottawa 12.2.1 International Commission on Radiological Protection (ICRP)

13 Austria 13.1 Vienna 13.1.1 University of Veterinary Medicine

13.1.2 International Atomic Energy Agency (IAEA)

14 Portugal 14.1 Oeiras 14.1.1 Instituto Gulbenkian de Ciência

15 Sweden 15.1 Lund 15.1.1 Lund University

15.2 Stockholm 15.2.1 Karolinska Institutet

15.3 Uppsala 15.3.1 Uppsala University

16 Switzerland 16.1 Bern 16.1.1 Vétérinaire Swiss

16.2 Zurich 16.2.1 Swiss Federal Institute of Technology (ETH)

16.2.2 University of Zurich

17 Slovenia 17.1 Ljubljana 17.1.1 Jožef Stefan Institute

18 Spain 18.1 Barcelona 18.1.1 Universitat Autònoma de Barcelona

18.2 Madrid 18.2.1 Centro Nacional de Biotecnología

18.2.2 Fundación para la Investigación Biomedica del Hospital Gregorio Maranon

19 Czech Republic

19.1 Prague 19.1.1 Czech Centre for Phenogenomics

20 USA 20.1 Ann Arbor 20.1.1 University of Michigan

20.2 Bar Harbour 20.2.1 The Jackson Laboratories

20.3 Berkeley 20.3.1 Lawrence Berkeley National Laboratory

20.4 Boston 20.4.1 Massachusetts General Hospital

20.5 La Jolla 20.5.1 Scripps Research Institute

20.6 Research Triangle Park

20.6.1 National Institute of Environmental Health Sciences (NIEHS)

20.7 Salt Lake City 20.7.1 University of Utah

20.8 Walnut Creek 20.8.1 Joint Genome Institute

20.9 Chapel Hill 20.9.1 US Environmental Protection Agency (EPA)

20.10 Pittsburgh 20.10.1University of Pittsburg Medical Center (UPMC)

20.11 San Antonio 20.11.1 Improvement Science Research Network (ISRN)

20.12 Rochester 20.12.1University of Rochester


33

1

2

3

4

5

6

7

8

9

10

11

12

1314

1516 17 18

19

20

1.1

2.1

2.2

2.3

3.1

4.1

5.1

5.1.1

5.3.15.4.1

5.5.15.6.15.7.15.9.15.10.1

5.12.1

6.1.1

6.2.1

7.1.1

7.2.1

7.3.1

7.4.1

8.1.1

8.2.1

5.2

5.35.4

5.55.65.75.85.95.10

5.11

5.12

6.16.2

7.1

7.2

7.3

8.1

8.2

9.1

9.2

9.3

10.1

10.2

11.1

12.1

12.2

13.1

14.1

15.115.2 15.3

16.1 17.1 18.1

18.1.1

19.1.1

20.1.120.2.1

20.3.1

20.4.1

20.5.1

20.6.1

20.8.1

20.7.1

20.9.1

20.10.1

20.11.1

20.12.1

18.219.1

20.120.2

20.320.4

20.5

20.6

20.7

20.8

20.10

20.11

20.12

20.9

17.1.1

16.214.1.1

15.1.115.2.1

15.3.116.1.1

12.1.1

12.2.1

11.1.1

10.1.1

7.4

4.1.1 – 4.1.3

5.11.1 – 5.11.55.8.1 – 5.8.2

5.2.1 – 5.2.2

9.1.1 – 9.1.2

9.2.1 – 9.2.2

9.3.1

10.1.1 – 10.1.2

13.1.1 – 13.1.2

16.2.1 – 16.2.218.2.1 – 18.2.2

3.2 3.1.1

3.2.1

2.2.1

2.3.1

2.1.1

1.1.1

Helmholtz Zentrum München cooperates closely with leading scientists across the

globe. Over 400 cooperation agreements exist between the Center and interna-

tional research institutions, university institutes, scientific organizations and public

authorities.

Bohle RM

Regele H

Siegel NJ

Königshoff M

Rose F

Block LH

Arbeiter KM

Perruchoud AP

Solèr M

Kouri FM

Thulin G

Bulau P

Nejman B

Kwapiszewska G

Bidmon B

Zakrzewcz D

Günther A

Ghofrani HA

Grimminger F

Bihl MP

Amarie OV

Kashgarian MJ

Centrella M

Aufricht C

Vicencio IV A

Endemann M

Mueller T

Morty RE

Hecker M

Seeger W

Ji C

Haddad GG

Zakrzewicz A

Ruffingshofer D

Fink L

Kitowska KE

Weissmann N

McCarthy TL

Markart P

Schermuly RT

Tamm M

Roth M

In the Comprehensive Pneumology Center, researchers and clinicians develop innovative

approaches for the early detection, diagnostics and therapy of chronic lung disease. The trans-

lational research center was founded together with Ludwig-Maximilians-Universität (LMU)

Munich and Asklepios Pulmonary Hospital in Munich-Gauting.

The graph describes a publication-based social network.Source: www.biomedexperts.com

Lung Diseases

“ Together with our partners at the Comprehen-

sive Pneumology Center, we can directly trans-

fer our research findings into medical applica-

tions. Our day-to-day contact with patients is

an important source of motivation for us not to

lose any time.”

Prof. Dr. Oliver Eickelberg

is the director of the Institute of Lung Biology at Helmholtz Zentrum München and holds the chair of

Experimental Pneumology at Ludwig-Maximilians-Universität Munich. As head of the Comprehen-

sive Pneumology Center (CPC) he is responsible for ensuring that the research of lung diseases is

carried out in excellent scientific networks.

36

Prof. Dr. Oliver EickelbergHelmholtz Zentrum München and Ludwig-Maximilians-Universität Munich

Since 2008 Director of the Institute of Lung Biology and Disease, Helmholtz Zentrum München and the Institute of Experimental Pneumology, Ludwig-Maximilians-Universität Munich; Chairman of the Comprehensive Pneumology Center2002 – 2008 Head of the Humboldt Research Group Molecular Mechanisms of Lung Fibrosis, University of Giessen2002 Sofja Kovalevskaja Award of the Alexander von Humboldt Foundation1998 – 2002 Feodor Lynen Fellow of the Alexander von Humboldt Foundation at the Yale School of Medicine, New Haven, CT, USA1997 MD, University of Basel

A new therapeutic approach has been found for treating fibrotic lung diseases: Injured

lung epithelium secretes increased levels of the signaling protein WISP1. If the levels of

WISP1 are decreased, the progression of the disease can be reduced in an experimental

model.

A research team headed by Oliver Eickelberg was able to show that injured lung epithelium

secretes increased levels of WISP1 protein from the WNT/β-catenin signaling pathway. In

the experimental model, reduced levels of the signaling protein WISP1 led to an attenua-

tion of the lung fibrosis. In fibrosis the lung loses its plasticity and gas exchange function

through increased production of extracellular matrix and connective tissue.

The WNT/β-catenin signaling pathway is involved in lung development in the healthy

organism and is reactivated during the development of lung fibrosis. WISP1 indirectly in-

duces the expression of connective tissue cells via profibrotic marker genes and leads to the

increased production of collagen.

If WISP1 is reduced, the growth of connective tissue is hampered due to the decreased

collagen deposition. This improvement of lung architecture attenuates lung fibrosis and

improves lung function. As a next step, the researchers want to utilize WISP1 reduction

therapeutically, in collaboration with pharmacological and medical technology companies,

in order to give patients with fibrotic lung diseases new perspectives for treatment in the

future.

Novel Approach for the Treatment of Lung Fibrosis

Helmholtz Zentrum München• Melanie Königshoff• Oana Veronica Amarie

University of Giessen• Monika Kramer• Nisha Balsara• Jochen Wilhelm• Andreas Jahn • Ludger Fink• Werner Seeger• Andreas Günther

University of Marburg • Frank Rose

Goethe University of Frankfurt am Main • Liliana Schaefer

Cooperation Partners / Authors

37

Original publication Melanie Königshoff et al.: WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosisJ. Clin. Invest. 119(4): 772-787 (2009) doi: 10.1172 / JCI33950.

The strongly increased formation of

connective tissue leads to destruction

of the lung architecture in fibrotic lung

diseases. Lung plasticity and lung

function are subsequently impaired, so

that adequate gas exchange is no longer

possible. The affected individuals suffer

from shortness of breath, recurring infec-

tions and feelings of suffocation.

The researchers are currently focusing on idiopathic pulmonary fibrosis (IPF), which is

characterized by an especially aggressive and rapid course of disease progression. At pres-

ent there is no effective medical treatment for this disease. Ultimately, lung transplantation

is the only available causal treatment option, but it is not feasible for all IPF patients. Aver-

age life expectancy after diagnosis of IPF is only two to three years. What triggers this dis-

ease and the underlying molecular mechanisms remains enigmatic.

The original injury to the lung tissue leads to in-

creased secretion of the signaling protein WISP1.

Further signaling pathways are thus activated

and stimulate the connective tissue cells to massive

collagen production.

Fibrosis

paracrine WISP1 autocrine WISP1

collagen deposition

epithelial- mesenchymal transition (EMT)

hyperplasia

apoptosis

Model for the Role of the Signaling Protein WISP1

in Fibrotic Lung Disease

Injury

WISP1

WISP1

WISP1

Research Highlights Lung Diseases

38


Francesca Alessandrini, PhD Helmholtz Zentrum München and Technische Universität München

Since 1997 Scientific staff member of the clinical coop-eration group Environmental Dermatology and Allergy, Helmholtz Zentrum München and Technische Universität München2007 habilitation, Technische Universität München1994 – 1997 research fellowship, Harvard School of Public Health, Boston, MA, USA1995 Young researcher scholarship of the Superfund Research Program of the U.S. National Institute of Environmental Health1994 PhD degree, Università degli Studi di Modena, Italy1991 – 1994 Pre-doctoral research fellowship, University of Illinois, Chicago, IL, University of North Carolina, Chapel Hill,NC and Harvard Medical School, Boston, MA, USA 1989 – 1993 Fulbright scholarship towards a PhDUntil 1989 Bachelor of Science, Faculty of Biological Sciences, Università degli Studi di Modena, Italy

Prof. Dr. Heidrun Behrendt Technische Universität München

Until March 2010 Head of the clinical cooperation group Environmental Dermatology and Allergy, Helmholtz Zentrum München and Technische Universität München and the ZAUM Center for Allergy and Environment, Technische Universität MünchenSince 1999 Assistant professor and C-3 professor, Technische Universität München1993 – 1998 Professor and director of the Dept. of Experi-mental Dermatology, University of Hamburg 1978 – 1993 Head of the Dept. of Electron Microscopy, Medical Institute for Environmental Hygiene, University of DüsseldorfUntil 1978 Medical studies and post-doc at the Universities of Freiburg and Hamburg, Habilitation at RWTH Aachen

Elemental carbon ultrafine particles (EC-UFPs) from anthropogenic environmental pollu-

tion induce oxidative stress and thus exacerbate allergic lung inflammation. This is the

finding of an interdisciplinary study, the results of which can lead to the development

of new approaches for treating allergic asthma and to a better understanding of innate

immune response.

Exposure to EC-UFPs is adversely associated with allergic diseases. The research group

led by Francesca Alessandrini and Heidrun Behrendt studied these effects in relation to

allergic lung diseases and discovered that ultrafine carbon particles exacerbated allergen-

induced allergic inflammation. By administering the antioxidant N-acetylcysteine (NAC),

this effect can be significantly reduced.

The experiments were carried out in four groups of ovalbumin-sensitized mice: expo-

sure to ultrafine carbon particles was compared to exposure to filtered air. Furthermore,

half of both groups were administered the antioxidant NAC with the aim of reducing the

oxidative stress caused by the ultrafine particles. Allergic inflammation was measured up

to one week after allergen challenge by means of bronchoalveolar lavage, cytokine assays,

measurement of lung function and histology. Isoprostane levels in the lung tissue served

as measure for oxidative stress.

In fact, NAC significantly reduced the effects of ultrafine particulate. Without the radi-

cal scavenger, inhalation of the ultrafine carbon particles led to increased allergen-induced

lung lipid peroxidation and to activation of the transcription factor NF-ΚB. Both effects oc-


• Ingrid Beck-Speier• Daniel Krappmann• Shinji Takenaka• Erwin Karg• Bernhard Kloo• Holger Schulz

Helmholtz Zentrum München and Technische Universität München

• Ingrid Weichenmeier• Martin Mempel

University Medical Center Freiburg

• Thilo Jakob

Elemental Carbon Ultrafine Particles Exacerbate Allergic Lung Diseases

39

Original publicationFrancesca Alessandrini et al.: Role of oxidative stress in ultrafine particle-induced exacerbation of allergic lung inflammation. Am. J. Respir. Crit. Care Med. 179(11): 984-91 (2009) doi: 10.1164 / rccm.200807-1061OC

Asthma is an inflammatory disease of the

airways characterized by an overreaction

to stimuli: Exposure to traffic-induced

particulate matter correlates with the

occurrence of asthma in non-smokers.

Smokers have an increased risk for asth-

ma in the first place due to the pollutants

in cigarette smoke. Asthma is the most

common chronic disease in children.

curred in addition to lung inflammation, cytokine release and airway hyperresponsiveness,

which augmented significantly in comparison to the group exposed to filtered air. Using

transmission electron microscopy and immunohistochemical analysis, the researchers

showed that NF-ΚB activation was always increased in those cells where EC-UFPs were

detected in the cytoplasm, i. e. endothelial cells, pneumocytes type I and type II, alveolar

macrophages and the bronchial / bronchiolar epithelium. In non-sensitized or non-chal-

lenged mice, the inhalation of particulate led to a brief, moderate NF-ΚB activation with a

simultaneous increase in isoprostanes. Other inflammation-relevant lung parameters and

lung function were not altered.

Asthma patients are more susceptible to the effects of oxidative stress than healthy

people. Scientists hope that improved understanding of the underlying processes will open

routes to new approaches for treating asthmatic lung diseases caused by anthropogenic air

pollution.

Inhaled elemental ultrafine carbon particles

(EF-UCPs) lead to increased oxidative stress in the

bronchial epithelium and exacerbate inflammatory

reactions. Dendritic cells are also involved in the im-

mune reactions at the site; TH1 production decreases,

and TH2 production increases.

ultrafine particles

dendritic cells in the tissue take up antigens and present them to the T lymphocytes

bronchial epithelium

small aggregates of particles

Effect of ultrafine particles


40


Dr. Joachim HeinrichHelmholtz Zentrum München

Since 1997 Deputy director of the Institute of EpidemiologySince 1992 Head of the research group Environmental Epidemiology1990 – 1992 Epidemiology, University of Wuppertal1974 – 1989 Scientific assistant and head of the research group Biostatistics, Medical School of Erfurt, PhD

Prof. Dr. Dr. H.-Erich WichmannHelmholtz Zentrum München and Ludwig-Maximilians-Universität Munich

Since 1990 Director of the Institute of Epidemiology and (since 1995) chair of Epidemiology, Ludwig-Maximilians-Universität Munich1988 – 1995 Head of the Dept. of Occupational Safety and Environmental Medicine, University of Wuppertal 1983 – 1988 Head of the Dept. of Biostatistics, Medical Institute of Environmental Hygiene, Düsseldorf1983 Habilitation

Prof. Dr. Holger SchulzHelmholtz Zentrum München

Since 2009 Head of the research group Applied Respiratory Physiology, Comprehensive Pneumology Center (CPC), Institute of Lung Biology and Disease2004 – 2008 Acting director, Institute of Inhalation Biology1992 – 2004 Research group leader and (from 1996) deputy director of the Institute of Inhalation Biology1990 – 1992 Scientist, Inhalation Project1988 – 1989 Anesthesiologist, University of Cologne1984 – 1988 Post-doc, Max Planck Institute of Experimental Medicine, Göttingen

(Principal Investigators at Helmholtz Zentrum München)

In a meta-analysis involving 14 international studies, scientists discovered five new loci

that have a significant influence on lung function. Reduced lung capacity is a key symptom

of many chronic lung diseases such as chronic obstructive pulmonary disease (COPD).

Scientists of the SpiroMeta consortium have identified five genetic variants which influ-

ence lung size and the FEV1 / FVC ratio (the ratio of forced expiratory volume in the first

second to forced vital capacity). To achieve this, they tested 2.5 million SNPs (single-nucle-

otide polymorphisms) of more than 20,000 people for their association with measures of

lung function. The effects were then confirmed in a further group of more than 33,000 indi-

viduals. The SpiroMeta consortium consists of 14 international studies with genome-wide

data and is coordinated at the University of Leicester in England. At Helmholtz Zentrum

München the research was carried out within the scope of the KORA study (Cooperative

Health Research in the Region of Augsburg) under the supervision of Joachim Heinrich,

H.-Erich Wichmann and Holger Schulz.

In the evaluated studies, lung function was measured by spirometry. After maximal

inspiration, the volume of air that can be exhaled in one second (FEV1) and the total vol-

ume of air that can be exhaled (FVC) are determined. Measurements enable an easy and

non-invasive detection of reduced lung size or airway narrowing, as detectable in COPD.

Limited Lung Function Has Genetic Background

University of Leicester • Emmanouela Repapi • Louise V. Wain • Paul R. Burton • Martin D. Tobin • Ian D. Pavord University of Nottingham • Ian Sayers, Ma’en Obeidat • John D. Blakey • Ian P. Hall • Tricia M McKeever • John R. Britton University of London • Toby Johnson Medical Research Council (MRC) Cam-bridge • Jing Hua Zhao • Ruth J. F. Loos • Nicholas J. Wareham

Imperial College London, The NSHD Respiratory Study Team • Adaikalavan Ramasamy • Seif Shaheen • Marjo-Riitta Jarvelin • Paul Elliott King’s College London • Guangju Zhai • Massimo Mangino • Nicole Soranzo • Tim D. Spector MRC Human Genetics Unit, Edinburgh • Veronique Vitart • Jennifer E. Huffman • Alan F. Wright • Caroline Hayward Uppsala University • Wilmar Igl • Ulf Gyllensten • Åsa Johansson • Ghazal Zaboli Helmholtz Zentrum München • Eva Albrecht • Eva Schnabel • Harald Grallert • Stefan Karrasch Wellcome Trust Sanger Institute, Cambridge • Panos Deloukas • Inês Barroso • Leena Peltonen • Nicole Soranzo University of Bristol • John Henderson • Raquel Granell • Wendy L. McArdle St. George’s University of London • Alicja R. Rudnicka • Peter H. Whincup • David P. Strachan

University of Helsinki, Helsinki • Linda Mustelin • Jaakko Kaprio, Ida Surakka • Leena Peltonen • Samuli Ripatti & Jaakko Kaprio

University of Jyväskylä • Taina Rantanen National Institute for Health and Welfare, Helsinki • Ida Surakka • Leena Peltonen • Mark-ku Heliövaara • Samuli Ripatti • Jaakko Kaprio University of Zürich • Medea Imboden • Nicole M. Probst-Hensch The University of Split Medical School •Ivica Grkovic • Stipan Jankovic •Igor Rudan

University of Zagreb •Lina Zgaga • Ozren Polašek University

of Oulu • Anna-Liisa Hartikainen • Fredrik Nyberg • Marjo-Riitta Jarvelin University of Edinburgh • Harry Campbell • Sarah H. Wild • James F. Wilson • Igor Rudan • Andrew K MacLeod • David J. Porteous University of Greifswald • Sven Gläser, Beate Koch• Georg Homuth • Henry Völzke Gen-Info, Zagreb • Ozren Polašek• Igor Rudan National Institute for Health and Welfare, Oulu • Anneli Pouta • Marjo-Riitta Jarvelin University of Gothenburg • Åsa Torinsson Naluai • Anna-Carin Olin • Kjell Torén, Fredrik Nybe

University of Western Australia • Matthew N. Cooper • Lyle J. Palm-er West Australian Sleep Disorders Research Institute • Alan L. James Sir Charles Gairdner Hospital, Western Australia • Alan L. James • Lyle J. Palmer • Jennie Hui University College London •Aroon D. Hingorani • S. Goya Wannamethee • Richard W. Morris MRC Centre for Causal Analyses in Translational Epidemiology • George Davey Smith • Debbie A. Lawlor • David M. Evans London School of Hygiene and Tropical Medicine • Shah Ebrahim University of Dundee • Andrew D. Morris MRC Epidemiology Resource Centre Southampton • Cyrus Cooper • Elaine Dennison National Institute for Health Research (NIHR) Oxford • Cyrus Cooper Pasteur Institute Lille • Nabila Bouatia-Naji • Jérôme Delplanque • Philippe Froguel Imperial College London • Philippe Froguel University of Southampton and PathWest Laboratory Medicine Western Austra-lia • John W. Holloway AstraZeneca Research and Development, Mölndal • Jennie Hui University of St. Andrews • Cathy Jackson

University of Tampere • Mika Kähönen University of Basel Nicole M. Probst-Hensch

41

Patients with COPD suffer first and fore-

most from cough, increased phlegm and

shortness of breath when under physical

strain. Respiratory flow rate and lung

volume are increasingly reduced. At pres-

ent it is only possible to treat the symp-

toms. Worldwide, COPD has meanwhile

become the fourth leading cause of death.

In Germany about 10 percent of the over

forty-year-olds are affected by the disease.

COPD has probably one of the lowest

levels of public awareness of any wide-

spread disease.

Original publicationEmmanouela Repapi et. al.: Genome-wide association study identifies five new loci associated with lung function. Nat. Genet. 42: 36-44 (2010) doi: 0.1038 / ng.501 (2009)

According to the insights gained from the study, lung function is influenced by genes whose

products play a key role in detoxification, inflammation and in wound healing process-

es. The effect of each single genetic variant on lung function is rather modest. Neverthe-

less, the identified associations offer new insights into the mechanisms regulating lung

function. They substantiate once again that physiological mechanisms can result due to

the combined impact of many single minor effects. To gain a deeper understanding of this

phenomenon, further research shall investigate which specific molecular alterations in the

lung result from these genetic variants and to what extent these can serve as potential tar-

gets for pharmacotherapy.

Lung Function

Lung Development

InflammationDetoxification

Genetic Variants

Tissue Repair

The genetic variants associated with lung function

are also involved in detoxification, inflammation and

wound healing processes.

Genetic Variants and Lung Function


42


Dr. Tobias StoegerHelmholtz Zentrum München

Since 2009 Head of the research group Dynamics of Pulmonary Inflammation, Comprehensive Pneumology Center, Institute of Lung Biology and Disease2003 – 2008 Research group leader, Institute of Inhalation Biology, Helmholtz Zentrum München1999 – 2002 Post-doc at Ingenium Pharmaceuticals, MartinsriedUntil 1999 Undergraduate and graduate studies, PhD, Technische Universität München1995 – 1996 Visiting researcher at The Jackson Laboratory, Bar Harbor, ME, USA

Dr. Otmar SchmidHelmholtz Zentrum München

Since 2009 Head of the research group Pulmonary Drug Delivery, Comprehensive Pneumology Center, Institute of Lung Biology and DiseaseSince 2006 Adjunct Assistant Professor of Physics, Missouri University of Science and Technology, USA2005 – 2008 Scientist, Institute of Inhalation Biology, Helmholtz Zentrum München2004 – 2005 Acting research group leader of Aerosols, Max Planck Institute of Chemistry, Mainz2000 – 2004 Post-docs at the University of Denver, the University of Missouri, USA, and the Max Planck Institute of Chemistry, MainzUntil 2000 Study of physics and PhD candidate, Ludwig-Maximilians-Universität Munich and the University of Missouri, USA

Helmholtz Zentrum München• Shinji Takenaka• Birgit Frankenberger• Baerbel Ritter• Erwin Karg• Daniela Dittberner• Konrad Maier• Holger Schulz

A simple but quantitative model can determine the effect of larger quantities of inhaled

soot nanoparticles on lung health and thus their toxicological risk. Using this empirical

toxicity model, routine experiments with mice to determine inflammatory reactions of

lung tissue due to soot nanoparticles could be replaced.

Tobias Stöger, Otmar Schmid and their colleagues have developed a toxicological method

which could help to avoid animal experiments in the future. Until now the toxicity of par-

ticles could only be determined by measuring the inflammatory reaction in experimental

animals. The novel nanotoxicological model determines the effect of inhaled soot nanopar-

ticles on lung health. It functions on the basis of two parameters – the oxidative potency

of the nanoparticles (OxPot) and the expression of the Cyp1a1 gene (GECyp1a1) . The latter is

stimulated by secondary organic matter associated with soot, and the de novo-expressed

CYP1A1 protein facilitates the inflammatory reaction (IEf).

The scientists first investigated the oxidative potency of nanoparticles by incubating

six physicochemically very different kinds of soot nanoparticles in an antioxidant test solu-

tion containing ascorbic acid. The antioxidative capacity of the test solution remaining after

incubation was determined by measuring the photochemical luminescence and from that,

the OxPot was derived which describes the surface reactivity of the respective nanoparticle.

Computer Model of Soot Particles Can Lead to Fewer Experiments on Animals

43

Original publicationTobias Stoeger et al.: Deducing in vivo toxicity of combus-tion-derived nanoparticles from a cell-free oxidative potency assay and metabolic activation of organic compounds. Environ. Health Perspect, 117: 54-60 (2009) doi: 10.1289 / ehp.11370.

Oxygen radicals elicit oxidative stress

and as a consequence pulmonary or

even systemic inflammation. These

processes can contribute adversely to the

progression of atherosclerosis and have

a negative effect on the cardiovascular

system. Soot nanoparticles can thus lead

to hypertension and even myocardial

infarction.

If the content of organic material in the particle is small, OxPot correlates well with its in-

flammatory potential in the lung. However, if the particles contain e. g. polycyclic aromatic

hydrocarbons (PAH), OxPot alone is not sufficient for the characterization of the biological

effect. For particles with high organic content, the inflammatory potential is increased ad-

ditionally by the enzyme CYP1a1, whose activation is measurable in the animal (in vivo) or

in a cell culture system (in vitro).

The combination of the OxPot and CYP1A1 test methods, both of which can be carried

out in vitro and make animal experiments superfluous, therefore represent a simple and

reliable alternative to experiments using animals. The method is cost-effective and is suit-

able for high throughput.

The oxidative potency (OxPot) of nanoparticles in test

solutions (in vitro) correlates well with their biologi-

cal inflammatory potential for the lung tissue. If the

particles contain organic compounds, in particular

polycyclic aromatic hydrocarbons (PAH), a bioactiva-

tion of the Cyp1a1 gene also takes place, which is like-

wise easily measurable in vitro.

Effect Pathways of Inflammatory Reactions Induced by Soot Particles

Effect Pathway-1: surface activity Effect pathway-2: Cyp1a1

PAH Detoxification Pathway

OC-poor CNP OC-rich CNP

surface reactivity

innate oxidative potency

oxidative stress

inflammatory response

redox-sensitive signaling cascades

ROS

ROS

organic compounds

phase III

conjugation

elimination

phase I

detoxification

bioactivation / transformation

NFkB AP1

IEf = OxPot + GECyp1a1

CNP: carbonaceous nanoparticleROS: reactive oxygen speciesOC: mass percentage of organic compoundsROS

Cyp1a1

Gst, Nqolphase II

R

RO•

RO•

RO-Conj

RO-Conj

Cyp1a1

Cyp1a1

Radicals induce oxidative stress

phase 1

phase 2

phase 2

R

phase 1


44


Helmholtz Zentrum München• Koustav Ganguly• Martina Schreiber

Ludwig-Maximilians-Universität Munich• Martin Depner• Erika von Mutius

Medical School of Hannover (MHH)• Michael Kabesch

University of Pittsburgh• Cheryl Fattman • Kiflai Bein• George D. Leikauf• Fei Gao• Tim D. Oury

University of Cincinnati• Scott C. Wesselkamper• Michael T. Borchers

Prof. Dr. Holger Schulz Helmholtz Zentrum München

Since 2009 Head of the research group Applied Respiratory Physiology, Comprehensive Pneumology Center (CPC), Institute of Lung Biology and Disease2004 – 2008 Acting director, Institute of Inhalation Biology1992 – 2004 Research group leader and (from 1996) deputy director of the Institute of Inhalation Biology1990 – 1992 Scientist, Inhalation Project1988 – 1989 Anesthesiologist, University of Cologne1984 – 1988 Post-doc, Max Planck Institute of Experimental Medicine, Göttingen

An international research team jointly led by Helmholtz Zentrum München and the Uni-

versity of Pittsburgh has succeeded in elucidating the biological function of the enzyme

superoxide dismutase 3 (SOD3) during postnatal development of the lung. The identified

gene variants enable scientists for the first time to understand the epidemiologically ob-

served association between poor lung function and increased susceptibility to environ-

mentally related lung diseases.

In a study on lung development in two mouse strains with most divergent lung function

Holger Schulz and his colleagues showed that gene variants of superoxide dismutase 3 im-

pact lung function. The gene coding for the enzyme was already identified in earlier studies

of Helmholtz Zentrum München and various national and international partners as a can-

didate gene for reduced lung function and capacity. The enzyme is significantly involved in

the defense against oxidative stress – last but not least in the lung.

The gene variants see to it that less superoxide dismutase 3 is secreted during lung

development in the mouse strain with the “small lung”. The reduced enzyme concentra-

tion adversely affects in particular the bronchial epithelium and the alveolar parenchyma,

which is crucial for gas exchange.

The research team was able to confirm these results in children as well: The human

lung, like in the mouse, does not develop its full capacity until long after birth – in the

Gene Mutations Adversely Affect Lung Development

45

Original publicationKoustav Ganguly et al.: Superoxide dismutase 3, extracellular (SOD3) variants and lung function. Physiol. Genomics 37: 260-267 (2009) doi: 10.1152 / physiolgenomics.90363.2008

Like all enzymes of the group, superoxide

dismutase 3 converts superoxide anions

into hydrogen peroxide, which is degrad-

ed via catalase into water and oxygen.

The enzyme thus protects against oxida-

tive stress in the lung for example caused

by inhaled chemicals or cigarette smoke.

course of childhood and early adolescence. Using data of the international asthma and al-

lergy study ISAAC, the gene coding for superoxide dismutase 3 was studied in more than

1500 nine- to eleven-year-old children from Munich and Dresden and gene variants associ-

ated with lung function measured by spirometry. Children with poor lung function showed

gene variations comparable to the studied mice.

These studies are an important step towards translating the findings of basic research

into medical applications. They serve to transfer the insights on the genetics of lung func-

tion gained in the laboratory to humans. In addition, they improve understanding of the

molecular biological mechanisms underlying the epidemiologically observed association

of poor lung function and increased disposition for lung diseases. The aim is to provide

starting points for developing new therapeutic or preventive measures.

Tissue damage due to environmental stressors / air pollution

Adaption to environmental stress

Common gene variant

Lung growth

Epidemiological association

Susceptibility to lung diseases

Gene variant SOD3

Impaired repair, tissue remodelingComplete tissue repair

Association of SOD3 Gene Variants, Lung Function and Susceptibility to Lung Diseases

The gene variant SOD3 adversely affects lung growth

during the developmental phase and increases suscep-

tibility to environmental stress.


46

Type of Cooperation Name of the Cooperation Partner

1 Important EU Projects

1.1 EMMAservice 1.1.1 Centre Européen de Recherche en Biologie et Médecine Illkirch

1.1.2 CNR Istituto di Biologia Cellulare Monterotondo

1.1.3 CNRS Institut de Transgénose Orléans-Villejuif

1.1.4 CSIC Centro Nacional de Biotecnología Madrid

1.1.5 EMBL European Bioinformatics Institute Hinxton

1.1.6 Fundação Calouste Gulbenkian Lisboa

1.1.7 Genome Research Ltd. London

1.1.8 Karolinska Institutet Stockholm

1.1.9 MRC Mammalian Genetics Unit Harwell

1.2 EUCOMM: The European Conditional Mouse Mutagenesis Program

1.2.1 Charité Berlin




1.2.5 Goethe University Hospital Frankfurt


1.2.7 Technical University of Dresden

1.2.8 Academisch Ziekenhuis Leiden

1.3 EvA: Markers for emphysema versus airway disease in COPD

1.3.1 CEA Centre National Génotypage Paris

1.3.2 Diagnostics Development Uppsala

1.3.3 European Respiratory Society Lausanne

1.3.4 Hannover Medical School

1.3.5 National Koranyi Institute for TB and Pulmonology Budapest

1.3.6 National Research Institute of Tuberculosis and Lung Diseases Warschau

1.3.7 University of Marburg

1.3.8 Università degli Studi di Ferrara

1.3.9 University Medical Center, Freiburg

1.3.10 University Hospitals of Coventry and Warwickshire

1.3.11 University of Leicester

1.3.12 University of Manchester

1.4 FMT-XCT: Development of new tomographic methods for imaging physiological and molecular functions

1.4.1 Commissariat a L’Energy Atomique Paris Grenoble

1.4.2 Computed Tomographic Imaging GmbH Erlangen

1.4.3 Foundation for Research and Technology Hellas

1.4.4 Hospital General Universitario Gregorio Maranon

1.4.5 University of Zurich

1.4.6 University of London

1.5 Goodwater: Research training for good European groundwater resources

1.5.1 Danish Technical University Lyngby

1.5.2 Flemish Institute for Technological Investigations Mol

1.5.3 Gent University

1.5.4 Geological Survey of Denmark and Greenland Copenhagen

1.5.5 Katolieke Universiteit Leuven

1.5.6 Université Catholique de Louvain

1.6 ECO: Research training in chemoinformatics

1.6.1 Stichting Katolieke Universiteit Nijmegen

1.6.2 Hochschule Fresenius Idstein

1.6.3 Universiteit Leiden

1.6.4 Instituto Nacional de Investigacion y Technologia Agraria Madrid

1.6.5 Hoegskolar i Kalmar

1.6.6 Università degli Studi di Milano-Bicocca

1.7 Infrafrontier: Infra-structure for the use of mouse models in biomedical research

1.7.1 Biomedical Sciences Research Center Alexander Fleming Athen

1.7.2 Centre Européen de Recherche en Biologie et en Médecine Illkirch


1.7.4 CNRS France Paris

1.7.5 CSIC Centro Nacional de Biotecnología Madrid

1.7.6 Czech Centre for Phenogenomics Praha


1.7.8 Fundação Calouste Gulbenkian Lisboa


1.7.10 Helmholtz Centre for Infection Research Braunschweig

1.7.11 Karolinska Institutet Stockholm


1.7.13 Toronto Centre for Phenogenomics

1.7.14 Universidad Autònoma de Barcelona

1.7.15 University of Copenhagen

1.7.16 University of Oulu

1.7.17 Veterinärmedizinische Universität Wien

Type of Cooperation Name of the Cooperation Partner

1.8 Madeira: Minimizing activity and dose with enhanced image quali-ty by radiopharmaceu-tical administrations

1.8.1 CSIC-IFIC Valencia1.8.2 Jozef Stefan Institute Ljubljana

1.8.3 SCIVIS GmbH Göttingen

1.8.4 Università degli Studi di Milano

1.8.5 University Lund1.8.6 University of Michigan, Ann Arbor

2 Large National Centers

2.1 German Center for Diabetes Research (DZD)

2.1.1 German Institute of Human Nutrition (DIfE)2.1.2 German Diabetes Center (DDZ)

2.1.3 University of Tübingen

2.1.4 Dresden University Hospital

2.1.5 Helmholtz Association of German Research Centres2.1.6 Leibniz Association

2.2 German Center for Neurodegenerative Diseases (DZNE)

2.2.1 Helmholtz Association of German Research Centres2.2.2 Leibniz Association

2.2.3 Core Center Bonn (DZNE)

2.2.4 Cooperation Partner Dresden

2.2.5 Partner Location Göttingen

2.2.6 Partner Location Magdeburg

2.2.7 Partner Location München

2.2.8 Partner Location Rostock / Greifswald

2.2.9 Partner Location Tübingen

2.2.10 Partner Location Witten – Herdecke

3 International Associations

3.1 International Gene Trap Consortium IGTC

3.1.1 BayGenomics3.1.2 Centre for Modelling Human Disease Toronto

3.1.3 Embryonic Stem Cell Database University of Manitoba

3.1.4 European Conditional Mouse Mutagenesis (EUCOMM)

3.1.5 Exchangeable Gene Trap Clones

3.1.6 German Gene Trap Consortium

3.1.7 Sanger Institute Gene Trap Resource

3.1.8 Soriano Lab Gene Trap Database, Mount Sinai School of Medicine New York

3.1.9 Texas Institute for Genomic Medicine Houston

3.1.10 TIGEM-IRBM Gene Trap Neapel

3.2 NorCOMM 3.2.1 Canadian Mouse Consortium

3.2.2 European Conditional Mouse Mutagenesis (EUCOMM)

3.2.3 Federation of International Mouse Resources

3.2.4 Manitoba Institute of Cell Biology

3.2.5 Mount Sinai Hospital Toronto

3.2.6 Mutant Mouse Regional Resource Center at Davis

3.2.7 NIH Knockout Mouse Project (KOMP)

3.2.8 University of Alberta

3.2.9 University of Calgary

3.2.10 University of Manitoba

3.2.11 University of Toronto

3.2.12 Australian Phenomics Network

3.3 International Knockout Mouse Consortium (IKMC)

3.3.1 Knockout Mouse Project (KOMP)

3.3.2 European Conditional Mouse Mutagenesis Program (EUCOMM)

3.3.3 North American Conditional Mouse Mutagenesis Project (NorCOMM)

3.3.4 Texas A&M Institut for Genomic Medicine (TIGM)

4 National Associations

4.1 Bavarian Research Cooperation for Adult Neuronal Stem Cells

4.1.1 University of Erlangen-Nürnberg4.1.2 University of Würzburg

4.1.3 Ludwig-Maximilians-Universität Munich

4.1.4 Technische Universität München

4.1.5 University of Regensburg

4.2 German Gene Trap Consortium

4.2.1 Max Planck Institute for Molecular Genetics Berlin

4.2.2 Goethe University of Frankfurt Medical School

4.3 German Mouse Clinic 4.3.1 University of Bonn



4.3.4 Technische Universität München4.3.5 University of Heidelberg4.3.6 Helmholtz Centre for Infection Research

4.4 Munich Center for Integrated Protein Research


4.4.2 Max Planck Institute of Biochemistry Munich

4.4.3 Max Planck Institute of Neurobiology Munich

4.4.4 Technische Universität München


Cooperation in Centers and Associations

47

1

1.7

1.8

1.61.7.1 – 1.7.17

2.2.1 –2.2.10

3.1.1 – 3.1.10

3.2.1 – 3.2.12

3.3.1 – 3.3.4

2.1.1 –2.1.6

1.8.1 – 1.8.6

1.5

22.1

2.2

3.1

3.2

3.3

4.1

4.2

4.3

4.4

3

4

1.1.1 – 1.1.9

1.2.1 – 1.2.8

1.3.1 – 1.3.12

1.4.1 – 1.4.6

1.5.1 – 1.5.6

1.6.1 – 1.6.6

4.2.1 – 4.2.2

4.3.1 – 4.3.6

4.4.1 – 4.4.4

4.1.1 – 4.1.6

1.1

1.2

1.3

1.4

Helmholtz Zentrum München belongs to a network of large national research centers

and also participates in international consortia. It cooperates with leading scientific

partners in all areas of the life sciences on a national level, in Europe and around the

world. Within the EU Framework Programs, Helmholtz Zentrum München is involved

in 70 projects; in seven of these projects the Center functions as coordinator. Helm-

holtz Zentrum München participates in the Munich partner location of the German

Center for Neurodegenerative Diseases (DZNE) and is a partner of the German Center

for Diabetes Research (DZD).

Busch DH

Pretsch W

Runkel F

Klempt M

Przemack GK

Behrendt H

Aigner B

Pargent W

Schneider MR

Kalaydjiev SK

Soewarto D

Dahlhoff M

Neuhäuser-Klaus A

Klaften M

Balling R

Gossler A

Fuchs H

Gailus-Durner V

Beckers J

Adamski J

Horsch M

Favor JB

Alessandrini F

Wanke R

Fella C

Marshall S Löster J

Heffner S

Rubio-Aliaga I

Herbach N

Graw J

Reis A

Franz T

Jakob T

Klopp N

Ring J

Renner-Müller I

Sinowatz F

Rathkolb B

With the platforms for metabolomics, genomics and proteomics based at the Genome Analy-

sis Center, the Institute of Experimental Genetics makes important biomedical technologies

available in order to develop biomarkers for the early detection of diabetes and new strate-

gies for prevention and therapy.


Metabolic Diseases

“ At the German Center for Diabetes Research,

we team up with leading institutions in an

integrative approach. For me, this means

obtaining new perspectives and accelerating

research results to better understand diabetes

and fight the disease successfully.”

is the director of the Institute of Experimental Genetics at Helmholtz Zentrum München and holds

the chair of Experimental Genetics at Technische Universität München. He is one of the leading re-

searchers internationally in the field of functional genetics and is spokesperson of the Helmholtz POF

program “Systemic Analysis of Multifactorial Diseases”. With his research network he significantly

contributes to the further development of diabetes research at Helmholtz Zentrum München.


50



• Peter Achenbach

Helmholtz Zentrum München• Kerstin Koczwara• Christiane Winkler• Maren Pflüger• Thomas Illig• Harald Grallert

San Raffaele Scientific Institute, Mailand• Vito Lampasona

Technische Universität München• Ulrike Landherr• Steffi Krause

Technical University of Dresden• Ezio Bonifacio

Prof. Dr. med. Anette-Gabriele ZieglerHelmholtz Zentrum München and Technische Universität München

Since 2010 Director of the Institute of Diabetes Research Type 1, Helmholtz Zentrum MünchenSince 2003 Member of the board of directors of the Munich Diabetes Research Group1998 Ernst Friedrich Pfeiffer Award of the German DiabetesAssociation Since 1996 Senior physician of the 3rd Medical Department of the Municipal Hospital Munich-Schwabing, head of theClinical-Experimental Department at the Institute ofDiabetes Research, Munich1994 Dr. Bürger-Büsing Award of the German Diabetes Union1993 – 1996 Heisenberg Fellow of the German Research FoundationUntil 1993 State medical examination and MD degree,Research fellowship of the German Research Foundation, Joslin Diabetes Center, Harvard Medical School, habilitation

New markers enable early diagnosis and prognosis of the onset of childhood type 1 dia-

betes. These are autoantibodies to a zinc transporter shown to be present in children who

have an increased risk for type 1 diabetes already before disease onset.

Scientists in the Diabetes Research Group at Helmholtz Zentrum München and Technische

Universität München led by Anette-Gabriele Ziegler studied the development of antibodies

to a zinc transporter in children who have an increased risk for type 1 diabetes. The study

indicated an early onset of the disease if specific antibodies are present in the blood and

if at the same time specific genetic variants of the corresponding zinc transporter gene are

also present in the genome. These at-risk individuals require special monitoring.

For the study, the data of 1633 children with at least one parent with type 1 diabetes

were analyzed. Genetic factors play an important role in the pathogenesis of the disease.

That is why the disease risk is high for these children in comparison to children without

diabetes in the family.

In the study, autoantibodies to ZnT8 in combination with a specific genetic variant of

the zinc transporter gene were correlated with an increased diabetes risk. Eighty-one per-

cent of children with ZnT8 antibodies developed diabetes mellitus. It has been known for a

long time that the islet autoantibodies, which include the autoantibodies to insulin and to

the enzyme glutamate decarboxylase as well as to two tyrosine phosphatase autoantibod-

ies, indicate an increased risk for diabetes.

Early Detection of Type 1 Diabetes with New Markers

51

Original publicationPeter Achenbach et al.: Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk. Diabetologia 52 (9): 1888 (2009) doi: 10.1007 / s00125-009-1438-0

The incidence of type 1 diabetes among

children is on the rise throughout the

world. In Germany about 11,000 chil-

dren are affected. At the time of diagno-

sis children are on average about eight-

and-a-half years old. Already at this age,

many children have severe metabolic

imbalances, which successful prevention

strategies and detailed screening can

prevent.

The SLC30A8 gene encodes the ZnT8 protein, which influences zinc transport in the beta

cells of the islets of Langerhans. This is important for the maturation of the beta cells and

insulin secretion. The beta cells of the pancreas secrete the hormone insulin, which is es-

sential for survival. Already before the onset of type 1 diabetes the body’s own immune

system destroys the beta cells. If this destruction exceeds a specific threshold, the disease

breaks out: The lack of insulin leads to various disturbances of the metabolism, including

an increase in blood glucose levels.

The autoantibodies that have now been identified against ZnT8 provide an addition-

al important marker for the progression of diabetes – especially in children, who are al-

ready forming islet autoantibodies. A differentiated analysis of all autoantibodies enables

an assessment of how soon the disease will break out. The higher the number of different

autoantibodies, the higher the diabetes risk, and the younger the child is with autoantibod-

ies, the sooner the disease will break out.

About 8 –10 percent of children with family-relat-

ed T1D risk develop autoantibodies in childhood

to insulin (IAA), glutamate decarboxylase (GADA),

tyrosine phosphatase IA-2 (IA-2A) and/or zinc

transporter 8(ZnT8A).

Development of islet autoantibodies in 1633 children with family-related T1D risk

Children who develop ZnT8A have a signifi-

cantly higher diabetes risk (P<0.0001) in com-

parison to ZnT8A-negative but islet autoan-

tibody (IAA, GADA and/or IA-2A)-positive

children.

Diabetes development in autoantibody-positive children

In ZnT8A-positive children the diabetes risk

continues to be stratified by the SLC30A8

SNP rs13266634 genotype. Homozygous car-

riers of R325- or W325-encoding alleles show

the highest diabetes risk, while a heterozy-

gous genotype is associated with relative pro-

tection (P=0.01).

Diabetes development in ZnT8A-positive children

Islet Autoimmunity and Diabetes Risk in Children in the BABYDIAB Study

with at Least One Type 1 Diabetes (T1D) Parent

12

10

8

6

4

2

0

100

80

60

40

20

0

100

80

60

40

20

0

Isle

t aut

oant

ibod

y pr

eval

ence

(%)

age (years)

GADA

IAA

IA-2A

ZnT8A

ZnT8A positive

ZnT8A negative

SLC30A8R325W-homozygous

SLC30A8R325W-heterozygous

Years since appearance of islet autoimmunity Years since appearance of ZnT8 autoimmunity0 2 5 8 11 14 0 2 4 8 10 12 0 2 4 8 10 12

Dia

bete

s ri

sk (%

)

Dia

bete

s ri

sk (%

)

Research Highlights Metabolic Diseases

52


Helmholtz Zentrum München, Institute of Health Economics and Health Care Management

• Renee Stark• Michaela Schunk• Reiner Leidl• Rolf Holle

Helmholtz Zentrum München, KORA Study Group and Institute of Epidemiology

• Christa Meisinger

Prof. Dr. Rolf Holle Helmholtz Zentrum München

Since 2005 Adjunct professor at the medical faculty ofLudwig-Maximilians-Universität Munich, teaching in the field of Public HealthSince 1996 Head of the research group Economic Evaluation, Institute of Health Economics and Health Care Management, Helmholtz Zentrum München1990 PhD, University of Giessen 1980 – 1995 Scientific assistant at the Universities of Giessen and HeidelbergUntil 1979 Study of mathematics and psychology

The disease management programs (DMPs) of the statutory health insurance com-

panies have improved the health care of patients with type 2 diabetes. This is the re-

sult of an evaluation of data from participants of the population-based KORA study.

The aim of the disease management programs (DMPs) of the health insurance companies

is to improve health care: Patients enrolled in the program are to be examined more regu-

larly, given advice more frequently regarding their health behavior and shall receive better

therapy. In the case of the health care quality for diabetics, this objective is being fulfilled,

as the analysis of data from the representative population-based KORA study carried out

at Helmholtz Zentrum München shows. In this study diabetics enrolled in DMPs were com-

pared with those who were not enrolled.

DMP patients receive better health care in multiple respects:

– They take antidiabetic medication and medication to treat hypertension more frequently.

– Their lab values such as the long-term blood glucose value, the HbA1c, blood pressure,

cholesterol or protein in urine are checked more regularly.

– Screening and preventive check-ups for secondary diseases are carried out in the DMP

more consistently: Nearly 83 percent of the surveyed DMP participants answered that

they had had an eye examination in the last 12 months. Among the non-participants

only 59 percent had had an eye examination. Foot examinations were carried out in

67 percent of the patients in the DMPs in contrast to only 38 percent of the non-par-

ticipants.

Disease Management Programs Improve Health Care Quality for Diabetic Patients

53

Original publication Renee Stark et al.: Prozessevaluation von Disease Manage-ment Programmen bei Typ 2 Diabetes auf Basis einer bevölkerungsrepräsentativen Studie in der Region Augsburg (KORA). Betriebswirtschaftliche Forschung und Praxis 61: 283-301 (2009)

Disease management programs are

systematic treatment programs for

chronically ill patients. Continual

support and health education in the

form of training courses shall help to

prevent secondary illnesses. The pro-

grams apply the insights of evidence-

based medicine: Therapy decisions must

always be based on the proven effective-

ness of the treatment.

– 63 percent of the DMP diabetics have attended training courses in diabetes manage-

ment and health care, in contrast to only 39 percent of the non-participants. These

training courses are an integral part of the Diabetes Management Program.

– DMP participants also pay more attention to their health status: Nearly 61 percent of

the surveyed DMP patients responded that they measure blood pressure at least once a

week, in contrast to 43 percent of the non-participants.

Self-examinations of feet, and measurements of weight and blood glucose levels were also

conducted more frequently in the DMP group. On average, the DMP patients had worse re-

sults with respect to waist circumference and body mass index (BMI). However, they were

more overweight before enrolling in the DMP program than the non-participants. One strik-

ing result was that the non-participants exercised more regularly than those enrolled in the

DMP program. The worse risk profile for overweight does not seem to be specifically influ-

enced by the Disease Management Program.

Further studies shall determine whether and how the structured treatment of the Dis-

ease Management Program will affect the medical values of type 2 diabetics over the long

term.

Within the framework of the KORA Study of Helmholtz

Zentrum München, the medical data of participants

of the Diabetes Management Program were compared

to the data of non-participants. One result: The DMP

participants were examined to detect secondary condi-

tions caused by diabetes and received medical advice as

to lifestyle on a more regular basis.

0 20 40 60 80 100

Eye examination

Examination of feet

Nutrition advice

Exercise advice

More Medical Advice and Monitoring for DMP Participants

DMP participants Non-participants


54


Helmholtz Zentrum München• Thomas Illig• Christian Gieger• Rui Wang-Sattler• Werner Römisch-Margl• Gabriele Kastenmüller• Cornelia Prehn

Helmholtz Zentrum München and Ludwig-Maximilians-Universität Munich

• H.-Erich Wichmman• Elisabeth Altmaier


• Hans-Werner Mewes• Thomas Meitinger• Martin Hrabe de Angelis• Jerzy Adamski

King’s College London• Guangju Zhai• Bernet S. Kato• Nicole Soranzo• Tim D. Spector

Innsbruck Medical University• Florian Kronenberg

The Wellcome Trust Sanger Institute Hinxton• Nicole Soranzo

Prof. Dr. Karsten Suhre Helmholtz Zentrum München and Ludwig-Maximilians-Universität Munich

Since 2006 Head of the research group Metabolomics at the Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Professor of Bioinformatics, Ludwig-Maximilians-Universität Munich1994 – 2006 Research at the Centre National de laRecherche Scientifique (CNRS) in Toulouse and Marseilleand in the automobile industry (Karmann 2000 – 2001)

By applying a metabolomics approach, gene variants were discovered which are claimed

to be responsible for lipid metabolic disorders. Some of these gene variants occurring

often in humans are known to be risk factors for diabetes mellitus.

A team of scientists from various institutes of Helmholtz Zentrum München and both Mu-

nich universities led by Karsten Suhre has confirmed the association of some gene variants

and changes in lipid metabolism. Some of the gene variants are known to be risk factors for

various metabolic disorders, among them diabetes.

The research team first determined the concentrations of 163 metabolic products in

blood samples of 1800 participants in the KORA study, a population-based study coordi-

nated by H.-Erich Wichmann at Helmholtz Zentrum München. As next step, they studied

the metabolite profiles in a genome-wide association study for possible associations with

common gene variants, the SNPs. In collaboration with the Sanger Institute, Hinxton and

King’s College London a second, independent study was carried out using data of the British

population-based study TwinsUK, which confirmed the identified associations.

Markers for Lipid Metabolic Disorders

55

Original publication Thomas Illig, Christian Gieger et al.: A genomwide pers pective of genetic variation in human metabolism.Nat. Genet. 42 (2) 137-144 ( 2010) doi: 10.1038 / ng.507, December 2009

The term metabolome denotes all of the

characteristic metabolism properties of

cells or organisms. The study of their

interactions, their identification and

quantification takes place with the aid

of metabolomics, which combines highly

sensitive analysis methods for its inves-

tigations. The combination of variants of

a specific gene and the thus influenced

metabolite concentration is termed the ge-

netically determined metabotype. Different

metabotypes can react differently to exter-

nal environmental influences and to other

living conditions.

Patients at risk for metabolic disorders can be identified earlier than previously by means

of metabolome analysis, which determines the concentrations of as many metabolic prod-

ucts – metabolites – as possible. In individuals with different gene variants the affected

enzymes are active to a varied extent and as a consequence, their metabolic products have

different concentrations. The study could thus detect genetically-caused metabolic process-

es, which play a key role in the pathogenesis, diagnosis and therapy of serious metabolic

diseases such as diabetes.

ACADLC9

ACADMC6

ACADSC4

ETFDHC10

Acyl-CoA

energy

acyl-carnitine

palmitoyl-CoA + serine

β-oxidation

SLC16A9C0

SLC22A4C5

transport

phosphatidylcholine

sphingomyelin

urea

fatty acid synthesis

SCDlyso-PC a

C16:1

poly-unsaturated fatty acids

ELOVL2PC aaC42:4

FADS1lyso-PC a

C20:4

amino acid metabolism

PHGDH serine

SPTLC3SM (OH)

C24:1

PLEKHH1PC aeC36:5

Kennedy pathway

SYNE2PC aaC28:1

CPS1Glycine

12 of the 14 identified genetic variants (SNPs) are

located in enzyme and transporter genes of impor-

tant metabolic pathways of the human organism. The

relevant metabotype exactly matches the function of

the respective gene. For example, the enzyme PHGDH

catalyzes the rate-limiting reaction step of serine bio-

synthesis.


A Genome-Wide Look at Genetic Variance in the Human Metabolism

56

Type of Cooperation Partner Name of the Cooperation1 Research Centers 1.1 Ludwig-Maximilians-

Universität (LMU) Munich

1.1.1 German Center for Diabetes Research (DZD)

1.1.2 German Center for Neurodegenerative Diseases / Partner Location Munich

1.1.3 Munich Center for Integrated Protein Science (CiPSm)

1.1.4 Bavarian Research Association Adult Neural Stem Cells

1.2 Max Planck Institute of Biochemistry


1.3 Max Planck Institute of Neurobiology


1.4 Max Planck Institute of Psychiatry


1.5 Technische Universität München (TUM)

1.5.1 German Center for Diabetes Research (DZD)



1.5.4 Bavarian Research Association Adult Neural Stem Cells

2 Joint Appointments 2.1 Ludwig-Maximilians-Universität (LMU) Munich

2.1.1 Epidemiology

2.1.2 Experimental Pneumology

2.1.3 Health Economics

2.1.4 Physiological Genomics


2.2.1 Biochemical Plant Pathology

2.2.2 Biological Imaging

2.2.3 Biomathematics

2.2.4 Soil Ecology

2.2.5 Development Genetics

2.2.6 Experimental Genetics

2.2.7 Genome Oriented Bioinformatics

2.2.8 Groundwater Ecology

2.2.9 Human Genetics

2.2.10 NMR Spectroscopy

2.2.11 Pathology

2.2.12 Radiobiology

2.2.13 Toxicology / Environmental Hygiene

2.2.14 Virology

3 Graduate Schools / Research Schools

3.1 Bavarian Health and Food Safety Authority

3.1.1 Pettenkofer School of Public Health

3.2 Ludwig-Maximilians-Universität (LMU) Munich

3.2.1 Graduate College Oligonucleotides in Cell Biology and Therapy

3.2.2 Graduate College Principles and Applications of Adoptive T Cell Therapy

3.2.3 Graduate School of Systemic Neuroscience

3.2.4 Helmholtz Graduate School for Environmental Health

3.2.5 Helmholtz-Kolleg Biology and Diseases of the Lung

3.2.6 Pettenkofer School of Public Health


3.3.1 Helmholtz Graduate School for Environ-mental Health

3.3.2 International Graduate School of Informati-on Sciences in Health

3.3.3 International Graduate School of Science and Engineering

4 Clinical Cooperation Groups

4.1 Ludwig- Maximilians-Universität (LMU) Munich

4.1.1 Hematopoietic Cell Transplantation

4.1.2 Immune Regulation in Childhood

4.1.3 Molekulare Onkologie

4.1.4 Pathogenesis of Acute Myeloid Leukemia

4.1.5 Tumor Therapy through Hyperthermia

4.2 Max Planck Institute of Psychiatry

4.2.1 Molecular Neurogenetics


4.3.1 Innate Immunity in Tumor Biology

4.3.2 Antigen-specific Immunotherapy

4.3.3 Osteosarcoma

4.3.4 Pediatric Tumor Immunology

4.3.5 Environmental Dermatology and Allergology

Type of Cooperation Partner Name of the Cooperation5 Translational

Centers5.1 Asklepios

Pulmonary Hospital5.1.1 Comprehensive Pneumology Center

5.2 Ludwig-Maximilians-Universität (LMU) Munich

5.2.1 Comprehensive Pneumology Center

6 Excellence Clusters 6.1 m4 6.1.1 Ludwig-Maximilians-Universität (LMU) Munich


6.1.3 Max Planck Institute of Biochemistry

6.1.4 Max Planck Institute for Extraterrestrial Physics


6.1.6 Ascenion GmbH

6.1.7 KFT Contact Agency for Research and Technology Transfer

6.1.8 Max-Planck-Innovation

6.1.9 TUM ForTe – Office for Research & Innovation

6.1.10 Activaero GmbH

6.1.11 Affectis Pharmaceuticals AG

6.1.12 AM Silk GmbH

6.1.13 Apceth GmbH & Co KG

6.1.14 Asklepios Clinics GmbH

6.1.15. Biomax Informatics AG

6.1.16 Biosigna Medical Diagnostics GmbH

6.1.17 Blood Donation Service of Bavarian Red Cross

6.1.18 conoGenetix biosciences GmbH

6.1.19 Corimmun GmbH

6.1.20 CORIOLIS Pharma Service GmbH

6.1.21 DIREVO Industrial Biotechnology GmbH

6.1.22 FGK Clinical Research GmbH

6.1.23 GE Healthcare Europe GmbH

6.1.24 Geneart AG

6.1.25 Genomatix Software GmbH

6.1.26 INFAP GmbH

6.1.27 Intana Bioscience GmbH

6.1.28 IPT

6.1.29 IQ-mobil Solutions GmbH

6.1.30 Itm AG

6.1.31 Jerini Peptide Technologies

6.1.32 Kinaxo Biotechnologies GmbH

6.1.33 Micromet AG

6.1.34 MorphoSys AG

6.1.35 multimmune GmbH

6.1.36 MWM Biomodels GmbH

6.1.37 Novartis Pharma GmbH

6.1.38 Paktis GmbH

6.1.39 Philips GmbH

6.1.40 Proteros Biostructures GmbH

6.1.41 Proteros Fragments GmbH

6.1.42 Regulus Therapeutics

6.1.43 Roche Diagnostics

6.1.44 Roche Kulmbach GmbH

6.1.45 Siemens AG, Healthcare Sector

6.1.46 Spherotec GmbH

6.1.47 Suppremol GmbH

6.1.48 Stage Pharmaceuticals GmbH

6.1.49 Sylvia Lawry Centre for Multiple Sclerosis Research e. V.

6.1.50 Trion Research GmbH

6.1.51 Wacker Chemie AG

6.1.52 Wilex AG

6.1.53 Xiphos Pharmaceuticals Inc.

6.1.54 XL Protein i.Gr.

Cooperation in the Munich RegionHelmholtz Zentrum München

57

1

1.1

1.1.1 – 1.1.4

1.2.1

4.2.1

1.3.1

1.4.1

3.1.1

1.5.1 – 1.5.4

2.1.1 – 2.1.4

2.2.1 – 2.2.14

3.2.1 – 3.2.6

3.3.1 – 3.3.3

4.1.1 – 4.1.5

4.3.1 – 4.3.5

6.1.1 – 6.1.54

2.1

2.23.1

3.2

3.3

4.1

4.2

4.3

5.1

6.1

5.2

5.1.1

5.2.1

1.2

1.3

1.4

1.5

23

4

5

6

The Center is engaged in numerous networks within the scientific community in and

around Munich. The close cooperation between Helmholtz Zentrum München and

the two Munich universities is reflected in the joint appointments of institute di-

rector positions and university chairs, in the training of doctoral students as well as

in research schools and graduate schools. Together with clinical institutions at the

Munich location, in particular with the two universities, the Center has created new

models of scientific cooperation in order to shorten the path between basic research

discoveries and medical applications and to develop improved methods of diagno-

sis and therapy. Besides institutes and hospitals of the Munich universities, biotech-

nology and pharmaceutical companies are also partners of the Center in the excel-

lence cluster “m4 – Personalized Medicine and Targeted Therapies: A New Dimension

in Drug Development.” Furthermore, the Comprehensive Pneumology Center (CPC)

is also part of a network with Helmholtz Zentrum München and Munich partners:

Ludwig-Maximilians-Universität and its hospital and Asklepios Pulmonary Hospital

in München-Gauting.

Arenas E

Brown S

Paez-Pareda M

Rosenthal N

Martinez S

Partanen J

Brodski C

Vogt-Weisenhorn DM

Arzt E

Pääbo S

Rossant J

Mewes HW

von Melchner H

Stewart F

Schmidt MV

Wolf E

Bruestle O

Nikkah G

Martin G

Björklund A

Spanagel R

Hyman A

Holsboer F

Hrabe De Angelis M

Bradley A

Landgraf R

Gasser T

Bally-Cuif L

Sillaber IMV Götz M

Nagy A

Müller MB

Wojtak CT

Kahle P

Riess O

Klopstock T

Joyner A

Skarnes B

Puelles E Klein R

Zilles K

Haass C

Lutz B

Simeone A

Ueffing M

Meitinger T

Rein Jles E

Ruiz P

Prochiantz A

In the EUCOMM laboratory at the Institute of Developmental Genetics, cell clones are gener-

ated to study neurological and psychiatric diseases in the mouse model. EUCOMM, the Euro-

pean Conditional Mouse Mutagenesis program, is one of the largest platforms for the investi-

gation of gene functions in the world.


Neurological Diseases

“ With the network “European Conditional

Mouse Mutagenesis Program” (EUCOMM),

we are breaking new ground in establish-

ing animal models and disease models for

the functional definition of all genes in the

mammalian genome. The scientific discus-

sion with my partners is a concrete example

of active innovation. Time and again, it

gives new impulses to me and my research.”

is the director of the Institute of Developmental Genetics at Helmholtz Zentrum München and holds

the chair of Developmental Genetics at Technische Universität München. As one of the leading

experts on the functional analysis of genes in the mammalian model, he coordinates the “European

Conditional Mouse Mutagenesis Program” (EUCOMM) and the Helmholtz Alliance “Mental Health in

an Aging Society”, which investigates the mechanisms of neurodegenerative diseases.

Prof. Dr. Wolfgang Wurst

60


Helmholtz Zentrum München and University of Minho, Braga • Luisa Pinto


• Johannes Beckers

Helmholtz Zentrum München and National Institute for Medical Research London

• Daniela Drechsel


• Monika S. Brill

Helmholtz Zentrum München, Ludwig-Maximilians-Universität Munich and Munich Center for Integrated Protein Science (CISPM)

• Magdalena Götz

Helmholtz Zentrum München• Marie-Theres Schmid• Jovica Ninkovic• Martin Irmler

National Institute for Medical Research London• François Guillemot

Consiglio Nazionale delle Ricerche, Pisa• Laura Restani• Laura Gianfranceschi• Chiara Cerri• Matteo Caleo

University of Bonn• Susanne N. Weber• Hubert Schorle

Max Planck Institute for Experimental Medicine• Victor Tarabykin

Swansea University• Kristin Baer

University of Connecticut• Nada Zecevic

INSERM and Université de Lyon • Colette Dehay

Prof. Dr. Magdalena Götz Helmholtz Zentrum München and Ludwig-Maximilians-Universität Munich

2007 Gottfried Wilhelm Leibniz Prize of the German Research FoundationSince 2004 Director of the Institute of Stem Cell Research,Helmholtz Zentrum München and chair of thePhysiological Institute, Ludwig-Maximilians-UniversitätMunicUntil 2003 Scientist and research group leader at Max Planck Institutes in Göttingen and MunichUntil 1996 PhD, post-doc in Tübingen, London and Harlow

The transcription factor AP2γ regulates the generation of neurons in the upper layer of

the cerebral cortex. It influences how the cerebral cortex modulates its structure and

function in different areas and layers, and thereby acts as a key factor for visual function.

The brain as a whole, but also the cerebral cortex, is organized in regions which are spe-

cialized to perform distinct functions. However, it is still not well understood how this func-

tional specialization is achieved. A team of scientists of the Institute of Stem Cell Research

and the Institute of Experimental Genetics at Helmholtz Zentrum München led by Magda-

lena Götz discovered that differences between the cortex regions are influenced by when

and where the progenitor cells develop into mature neurons and discovered that the key

regulatory molecule is the transcription factor AP2γ. Transcription factors are proteins that

are involved in the regulation of gene activity in cells.

AP2γ is the molecular factor which regulates development of the part of the cerebral

cortex devoted to process visual information. Starting from the observation that AP2γ is ex-

clusively present in the cerebral cortex, mice in which AP2γ was selectively deleted in this

brain region were examined. In these animals there were fewer neurons in the upper cor-

tex layers of the occipital lobe – the region where the visual areas of the cerebral cortex are

located. Adult mice lacking AP2γ do in fact have problems with vision: The spatial resolu-

tion (visual acuity) of the visual center is greatly reduced and the ability of mice to see with

both eyes is impaired.

AP2γ – A Key Factor for Visual Function

61

Original publicationLuisa Pinto et al.: AP2γ regulates basal progenitor fate in a region- and layer-specific manner in the developing cortex. Nat. Neurosci. 12: 1229-1237 (2009) doi:10.1038 / nn.2399

The cortex is the most highly developed

part of the brain. In the different regions

which are differentiated in their cellular

constitution the impressions of the senses

are processed. The differences on the

cellular level are coupled to the different

capacities and tasks of the individual

cortex regions

However, the cause is not diminished cell division. Cell division occurs to the proper extent

even when AP2γ is absent, but what is disturbed is the maturation of the progenitor cells:

In AP2γ knockout mice the neurons partially retain the characteristics of progenitor cells

and die earlier. As a consequence fewer mature nerve cells are generated.

What is especially striking about these study findings is that the failure of neuron de-

velopment in the AP2γ knockout mice is restricted to the visual cortex – and that although

many other neurons are also regulated by AP2γ.

The transcription factor AP2γ also influences the

development of the visual area in the forebrain.

If the molecule is missing, fewer neurons are formed

in the upper layers of the visual cortex.

AP2γ-mutant

wild type

visual cortex

Influence of AP2γ on the Visual Center

Research Highlights Neurological Diseases

62


Max Planck Institute for Evolutionary Anthropology • Wolfgang Enard • Sabine Gehre • Torsten Blass • Mehmet Somel • Christiane Schreiweis • Victor Wiebe • Birgit Nickel • Thomas Giger • Svante Pääbo

German Primate Center • Kurt Hammerschmidt • Julia Fischer

Helmholtz Zentrum München • Sabine M. Hölter • Claudia Dalke • Nicole Ehrhardt • Wolfgang Hans • Gabriele Hölzlwimmer • Anahita Javaheri • Magdalena Kallnik • Thure Adler • Ines Bolle • Svetoslav Kalaydjiev • Jan Rozman • Eva Kling • Julia Calzada-Wack • Ilona Moßbrugger • Sandra Kunder • Antonio Aguilar • Anja Schrewe • Lore Becker • Beatrix Naton • Birgit Rathkolb • Jochen Graw • Leticia Quintanilla-Martinez • Holger Schulz • Jack Favor • Helmut Fuchs • Valérie Gailus-Durner• Wolfgang Wurst • Prof. Dr. Martin Hrabe de Angelis

University of Leipzig • Martina K. Brückner • Uwe Müller • Thomas Arendt • Johannes Schwarz

Charité University Medical Center Berlin • Christine Winter • Reinhard Sohr • Rudolf Morgenstern

Ludwig-Maximilians-Universität Munich • Lore Becker • Thomas Klopstock • Eva Kling • Eckhard Wolf • Birgit Rathkolb

University of Bonn • Ildikó Racz • Andreas Zimmer

University of Heidelberg • Anja Schrewe • Boris Ivandic

Wellcome Trust Centre for Human Genetics • Matthias Groszer • Simon E. Fisher

Technische Universität München • Svetoslav Kalaydjiev • Jan Rozman • Thure Adler • Martin Klingenspor • Markus Ollert • Dirk H. Busch • Wolfgang Wurst • Martin Hrabe de Angelis

California Institute of Technology • Johannes Schwarz

Prof. Dr. Martin Hrabe de Angelis Helmholtz Zentrum München and Technische Universität München

Since 2000 / 2003 Director of the Institutes of ExperimentalGenetics, Helmholtz Zentrum München and Technische Universität MünchenSince 2000 Director of the German Mouse Clinic and theEuropean Mouse Mutant Archive1997 – 2000 Head of the research group Functional Genetics1994 – 1997 Post-doc at The Jackson Laboratory, Bar Harbor, ME, USAUntil 1994 Studies and PhD at University of Marburg and at the Max Planck Institute of Immunobiology, Freiburg

Dr. Helmut Fuchs Helmholtz Zentrum München

Since 2001 Scientific-technical head of the German Mouse Clinic Since 1997 Scientist at Helmholtz Zentrum MünchenUntil 1997 Studies and PhD at Technische Universität München

Dr. Valérie Gailus-DurnerHelmholtz Zentrum München

Since 2001 Scientific-administrative head of the German Mouse Clinic1998 – 2000 Post-doc at the Institute of Mammalian Genetics1995 – 1998 German Research Foundation Fellow and Charles and Johanna Busch Fellow at the Waksman Institute, Rutgers University, NJ, USAUntil 1994 Studies and PhD at the University of Konstanz

In the brains of mice studied at the German Mouse Clinic at Helmholtz Zentrum München,

alterations were found that may be closely linked to speech and language development.

The analyses were carried out in collaboration with the Max Planck Institute for Evolu-

tionary Anthropology in Leipzig.

In a comprehensive screening program, scientists of the German Mouse Clinic studied a

mouse model in which parts of the human Foxp2 gene were introduced. Foxp2 is known

to be a key gene for human language ability. In humans with a defective copy of the gene,

the fine motor skills needed to produce sounds and the ability to understand language and

to find words are impaired. The gene has remained the same almost without any changes

throughout evolution. Although over 140 million years of evolution lie between mice and

chimpanzees, their protein sequences differ in only one amino acid, while in the six million

years of human evolution two further amino acids have changed.

The “humanized” Foxp2 mice went through all of the diagnostic tests of the German

Mouse Clinic: Over 550 parameters are checked here as standard practice, including the

ability to see and hear, bone density, important metabolism parameters as well as neuro-

logical functions. In most of the tests the Foxp2 mice showed no abnormalities, only the be-

havioral tests pointed to specifically altered brain functions, resulting from the new gene:

The animals are more hesitant about exploring a new environment.

In a second step the researchers studied the heterozygous knockout mouse model – in

which one of the normally two copies of the Foxp2 gene is missing. This loss leads to seri-

Human Language Development in the Mouse Model

63

Original publication Wolfgang Enard et al.: A humanized version of foxp2 affects cortico-basal ganglia circuits in mice. Cell, 137 (5): 961-971 (2009) doi: 10.1016 / j.cell.2009.03.041

The German Mouse Clinic is funded by

the National Genome Research Network

(NGFN), the European Commission

(EUMODIC) and the Helmholtz Zentrum

München. Here mutant (genetically

modified) mice are characterized under

standardized conditions, in order to find

model animals for genetically caused

human diseases and to better under-

stand these diseases.

ous consequences for the mice: The capacity of the mice to hear and learn is diminished in

comparison to their wild-type littermates, they have more fat and less muscle, and they eat

more and consume more energy. Several blood parameters are altered. Besides, they are

more active than the “humanized” mice. The Foxp2 gene therefore has significant impact

on different organ systems.

The neurons in the brain were examined physiologically in both mouse lines. The neu-

rons of the “humanized” Foxp2 mice showed a higher synaptic plasticity – a neurophys-

iological reaction of nerve cells, which are important for learning and memory. Further

studies showed that this characteristic is significantly weakened if the mice carry only one

functional copy of Foxp2. These findings support the hypothesis of the Leipzig researchers

that the alteration of the sequence and function of the Foxp2 gene was an important evolu-

tionary step that gave humans the advantage of speech and language.

Normal language development

polyQ

polyQ

FOX

FOX

polyQ

polyQ

FOX

FOX

Impaired language development

Mouse model for FOXP2 function

polyQ

polyQ

FOX

FOX

polyQ

polyQ

FOX

FOX

Mouse model for language evolution

polyQ

polyQ

FOX

FOX

polyQ

polyQ

FOX

FOX

N S

N S

150 – 200 million years

D=>E

T=>N; N=>SA

C D

B

A: FOXP2 is necessary for normal language capability

in humans; if only one functional copy exists, language

development is disturbed.

B: The FOXP2 protein of rodents and primates differs

in only one amino acid, while in the course of human

evolution two additional amino acids were altered.

C: If one mutates a copy of the FOXP2 gene in the

mouse genome, one can study the function of FOXP2

in the mouse.

D: If the two amino acids which differentiate humans

from chimpanzees are exchanged, the role of FOXP2 in

human evolution can be studied.


64


Helmholtz Zentrum München • Ravi Jagasia• Kathrin Steib• Elisabeth Englberger• Sabine Herold• Theresa Faus-Kessler

The Salk Institute for Biological Studies • Michael Saxe• Fred H. Gage

John Hopkins University School of Medicine• Hongjun Song

Dr. Dieter Chichung LieHelmholtz Zentrum München

2009 ENI-Young Investigator of the network European Neuroscience Institute (ENI)2006 European Young Investigator AwardSince 2005 Head of the junior research group Adult Neurogenesis and Neural Stem Cells at the Institute of Developmental Genetics1999 – 2005 Post-doc at the Salk Institute, La Jolla, CA, USAUntil 1998 Medical studies and MD degree RWTH Aachen

How the generation of new neurons in the hippocampus of the adult brain is regulated

is still an open research question. Now CREB signaling has been identified as a central

pathway in adult hippocampal neurogenesis.

New neurons in the adult hippocampus develop from neural stem and progenitor cells. The

survival and maturation of these newly generated neurons and their integration into the

existing neuronal network are regulated by molecular signaling pathways which are still

not completely understood.

The research group led by Dieter Chichung Lie has now shown that the CREB signaling

pathway is essential for new hippocampal neurons during a distinct developmental phase.

Without CREB the maturation of the newly generated neurons is severely impaired and the

new neurons eventually die off. The researchers also showed that the CREB signaling path-

way is controlled by GABA-mediated excitation, thereby identifying for the first time a sig-

naling pathway which translates neurotransmitter signaling into a specific developmental

program in adult neurogenesis.

CREB Regulates Maturation and Survival of New Stem Cell derived Neurons

65

Original publicationRavi Jagasia et al: GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J Neurosci. 29 (25), 7966-7977 (2009) doi: 10.1523 / JNeurosci.1054-09.2009

The hippocampal dentate gyrus is one

of two regions in the brain of all mam-

mals – including humans – in which new

neurons are generated from neural stem

cells throughout adulthood. This adult

neurogenesis most likely plays a role in

learning, in memory functions and also

in emotional behavior.

These findings provide a basis for understanding how the adult brain preserves its ability to

learn and to adapt throughout life: According to current research evidence, the generation

of new neurons in the hippocampal dentate gyrus (adult hippocampal neurogenesis) sup-

ports not only learning and memory, but influences also anxiety behavior. The effect of an-

tidepressants may be partially based on the modulation of adult neurogenesis. Research-

ers hope that a better understanding of the signaling pathways will contribute to finding

new strategies for the modulation of adult neurogenesis. This may have consequences for

the design of novel stem cell-based therapies for age-associated cognitive impairment,

Alzheimer’s disease, and depression.

The GABA/CREB signaling pathway regulates the

maturation and survival of newly generated neurons

in the adult hippocampus. It is a possible entry point

for the development of new therapies for cognitive

impairment as well as for depression.

stem cellmature neuron

differentiation and survival lacking differentiation and cell death

CREB active CREB inactive

GABA GABA

stem cell

+ + + + + - - -- - - -

Role of GABA / CREB Signaling Pathway in the Generation of New Neurons in the Adult Hippocampus


66



• Matthias Elstner • H.-Erich Wichmann

Helmholtz Zentrum München and Technische Universität München • Thomas Meitinger • Holger Prokisch

Helmholtz Zentrum München • Katharina Heim • Peter Lichtner • Divya Mehta

Ludwig-Maximilians-Universität Munich • Andreas Bender • Thomas Klopstock

Newcastle University • Christopher M. Morris • Gavin Hudson • Ian G. McKeith • Robert H. Perry • E. Jaros •Douglass M. Turnbull • David J. Burn • Patrick F. Chinnery

Universität Tübingen • Claudia Schulte • Manu Sharma • Rejko Krüger • Thomas Gasser

Istituti Clinici di Perfezionamento, Milan • Stefano Goldwurm

IRCCS Foundation Neurological Institute C. Besta, Milan • Alessandro Giovanetti • Massimo Zeviani

University of Kiel • Stefan Schreiber

University of Edinburgh • Harry Campbell • James F. Wilson

MRC Human Genetics Unit, Edinburgh • Alan F. Wright

University of Edinburgh and MRC Human Genetics Unit, Edinburgh

• Malcolm Dunlop

San Raffaele Scientific Institute, Milan, und Consiglio Nazionale delle Ricerche, Pavia

• Giorgio Pistis • Daniela Toniolo

Dr. Holger ProkischHelmholtz Zentrum München andTechnische Universität München

Since 2003 Head of the research group Mitochondrial Diseases at the Institute of Human Genetics, Helmholtz Zentrum München and Technische Universität München1999 – 2003 Head of the research group Biogenesis of the Mitochondria at the Institute of Physiological Chemistry, Ludwig-Maximilians-Universität Munich (LMU) 1998 – 1999 Post-doc at the Institute of Physiological Chemistry, LMUUntil 1997 PhD, Institute of Applied Genetics and study of biology, University of Hannover

Whole-genome expression profiling in combination with association analysis revealed a

possible interaction of genetic and environmental factors such as dietary habits in the

pathogenesis of Parkinson’s disease. The study also confirmed that vitamin B6 status and

metabolism have an impact on disease risk and treatment of the disease.

Researchers of Helmholtz Zentrum München and the two Munich universities led by Holger

Prokisch investigated neurons in the brain to determine which genes modify their activity

in Parkinson’s disease. Among other findings, the research group detected altered activity of

the pyridoxal kinase gene. In a subsequent international cooperation project, the research-

ers compared this gene in over 1,200 Parkinson patients with the genetic data of more than

2,800 healthy test subjects. In doing so, they discovered a gene variant which increases the

risk for Parkinson’s disease and which may lead to a modified quantity or activity of the en-

zyme pyridoxal kinase (PDXK) in the brain.

PDXK converts Vitamin B6 from food sources into its physiologically active form, which

is the prerequisite for the production of the neurotransmitter dopamine. Parkinson’s dis-

ease is linked to the accelerated aging and dying off of neurons that produce dopamine, and

the decreased synthesis of this neurotransmitter explains most of the disease symptoms.

Genetic Risk Factor Identified for Parkinson’s Disease

67

Original publication Matthias Elstner et al.: Single cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson’s disease gene. An-nals of Neurology 66 (6) 792-798 (2009) doi: 10.1002 / ana.21780

Parkinson’s disease is a slowly progressing

neurodegenerative disease. It is character-

ized by the loss of neurons in the brain

which produce the messenger substance

dopamine. The disease is accompanied by

muscle rigor and tremor and a slowing of

movement (bradykinesia).

The identified gene variant represents only a small contribution to the total risk of Parkin-

son’s disease, but brings the vitamin B6 metabolism into the focus of therapeutic consid-

erations. In combination with genetic association analysis, the innovative method used

here – single cell expression profiling of dopaminergic neurons – opens up new possibili-

ties for analyzing genetic risk factors.

In Parkinson’s disease the neurons located in the sub-

stantia nigra of the midbrain slowly die off. The pro-

duction of the messenger substance dopamine de-

creases, and the necessary information for automatic

movement no longer reaches the basal ganglia of the

cerebrum.

horizontal cut through the midbrain, which makes the sub-stantia nigra visible

damaged substantia nigra – typical for Parkinson’s disease

substantia nigra

Neuropathology of Parkinson’s Disease


68

Cooperation with Hospitals

Type of Cooperation Group Name Partner1 Clinical Cooperation Groups 1.1 Innate Immunity in Tumor Biology 1.1.1 Institute of Pathology, Helmholtz Zentrum München

1.1.2 Clinic and Polyclinic of Radiotherapy and Radiological Oncology, University Hospital rechts der Isar, Technische Universität München

1.2 Antigen-specific Immunotherapy 1.2.1 Institute of Molecular Virology, Helmholtz Zentrum München

1.2.2 Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München

1.3 Hematopoietic Cell Transplantation 1.3.1 Institute of Molecular Immunology, Helmholtz Zentrum München

1.3.2 Medical Clinic and Polyclinic III Campus Grosshadern, University Hospital Munich

1.4 Immune Regulation in Childhood 1.4.1 Institute of Molecular Immunology, Helmholtz Zentrum München

1.4.2 Children‘s University Hospital Munich / Dr. von Haunersches Kinderspital

1.5 Molecular Neurogenetics 1.5.1 Institute of Developmental Genetics, Helmholtz Zentrum München


1.6 Molecular Oncology 1.6.1 Department of Gene Vectors, Helmholtz Zentrum München

1.6.2 Department for Otorhinolaryngology, University Hospital Munich, Campus Grosshadern

1.7 Osteosarcoma 1.7.1 Institute of Pathology, Helmholtz Zentrum München

1.7.2 Department of Pediatrics, Munich Municipal Hospital and Klinikum rechts der Isar, Technische Universität München

1.8 Pediatric Tumor Immunology 1.8.1 Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München

1.8.2 Department of Pediatrics, Munich Municipal Hospital and Klinikum rechts der Isar, Technische Universität München

1.9 Pathogenesis of Acute Myeloid Leukemia 1.9.1 Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München

1.9.2 University Hospital Munich, Department of Medicine III, Campus Grosshadern

1.10 Tumor Therapy through Hyperthermia 1.10.1 Institute of Molecular Immunology, Helmholtz Zentrum München

1.10.2 University Hospital Munich, Department of Medicine III, Campus Grosshadern

1.11 Environmental Dermatology and Allergology 1.11.1 Institute of Epidemiology, Helmholtz Zentrum München

1.11.2 Center for Allergy and Environment (ZAUM), Department of Dermatology and Allergology, Technische Universität München

2 Translational Centers 2.1 Comprehensive Pneumology Center (CPC) 2.1.1 Institute of Lung Biology, Helmholtz Zentrum München

2.1.2 Asklepios Hospital Gauting


2.1.4 University Hospital Munich


69

1

1.31.4

1.5

1.6

1.7

1.8

1.9

1.9.2

1.9.1

1.8.2

1.8.1

1.7.2

1.7.1

1.6.1

1.5.2

1.5.1

1.4.21.4.1

1.6.2

1.10

2

2.1

1.11

1.11.1

1.11.2

1.10.21.10.1

2.1.1

2.1.2

2.1.4

2.1.3

1.1

1.3.21.3.1

1.2.2

1.2.1

1.1.1

1.1.2

1.2

Translational research is an integral component of research at Helmholtz Zentrum

München. Due to the continual exchange between the clinic and basic research, pa-

tients can rapidly benefit from improved methods of diagnosis and therapy. To develop

medical progress on the basis of knowledge transfer, Helmholtz Zentrum München

cooperates with the Munich university hospitals in the translational center for lung

research and in (as of now) eleven clinical cooperation groups. Furthermore, new

clinical cooperation groups will be created in connection with the focus on diabetes

research.

Gerber IB

Schulze-Lefert P

Schmitt-Kopplin P

Michel C

Shah J

Foissner I

Bors W

Pugin A

von Rad U

Livaja M

Guy A

Pontier D

Loeffler C

Dubery IA

Lam E

Klessing DF

Kolanczyk M

Durand T

Bahnweg G

Lindermayr C

Hartung T

Dobrev PI

Hutzler P

Panstruga R

Navarre DA

Lebrun-Garcia A

Zemojtel T

Lecourieux D

Lamotte O

Wanker EE

Kachroo P

Lipka V

Mueller MJ

Wyrwicz LS

Wendehenne D

Stettmaier K

In the biochemical laboratory of the Institute of Biochemical Plant Pathology researchers are

studying the mechanisms of the plant’s innate immune system and the role of environmen-

tal factors in the fitness of plants. The main focus is on the preservation of the foundations of

human life and the prevention of environmentally caused diseases.


Health and the Foundations of Life

“ Networking is the basis of a successful future:

formulating shared goals, collaborating in

a focused way, each party contributing its

expertise. Through networking, I am able to

optimally connect research on the foundations

of life with health aspects.”

is the director of the Institute of Biochemical Plant Pathology and holds the chair of Biochemical Plant

Pathology at Technische Universität München. As spokesperson of the POF Terrestrial Environment

Program at Helmholtz Zentrum München, he coordinates research activities on soil, water and plants,

which constitute the basis for life, and the interfaces of this research with health research.

Prof. Dr. Jörg Durner

72


Helmholtz Zentrum München • Heike Brielmann• Susanne I. Schmidt

Texas Instruments Deutschland GmbH• Rainer Michel

The use of groundwater as a carrier of thermal energy influences the diversity of microor-

ganisms and small organisms living there, according to a study led by Tillmann Lüders and

Christian Griebler. It was the world’s first study on how the increasingly important use of

groundwater for heating and cooling purposes affects subsurface ecosystems. However,

the effects observed in the pilot study were too minor to impair the quality of the ground-

water at the study site and its potential use as a source of drinking water.

In a one-year field study, scientists of the Institute of Groundwater Ecology at Helmholtz

Zentrum München systematically monitored the effects of groundwater use for industrial

cooling purposes in a shallow aquifer. In collaboration with the Water Resources Authority

and a facility operator, groundwater was regularly sampled from the monitored wells of a

facility located to the north of Munich. The biological effects in the aquifer revealed in the

study were significant: The changes in temperature influenced biodiversity in the ecosys-

tem. While the diversity of microorganisms increased with rising temperatures, the diversi-

ty of aquifer fauna decreased. However, a threat to ecosystem status or to potential drinking

water use could not be determined at the study site, because of its uncontaminated ground-

water quality and the minor temperature fluctuations caused by the facility.

Thermal Use Alters Biodiversity in Groundwater

Dr. Tillmann LüdersHelmholtz Zentrum München

Since 2004 Head of the research group Molecular Ecology, Institute of Groundwater Ecology2002 – 2004 Junior scientist, Dept. of Biogeochemistry, Max Planck Institute for Terrestrial Microbiology, MarburgUntil 2001 Study of biology, University of Hohenheim,and PhD, Max Planck Institute for Terrestrial Microbiology, Marburg

Dr. Christian GrieblerHelmholtz Zentrum München

seit 2004 Head of the research group Microbial Ecology, Institute of Groundwater Ecology2001 – 2003 Post-doc, Center for Applied Geosciences,University of Tübingen1996 – 2000 PhD, then scientific staff member at theInstitute for Limnology of the Austrian Academy of Sciencesand at the Institute of Zoology and Limnology, University of InnsbruckUntil 1996 Study of biology, University of Vienna

73

Original publicationHeike Brielmann et al.: Effects of thermal energy discharge on shallow groundwater ecosystems. FEMS Microbiol Ecol. 68(3): 273-86 (2009) doi: 10.1111 / j.1574-6941.2009.00674.x

Ground source heat pumps use energy

stored underground for the heating or

cooling of buildings. In Germany ap-

proximately 45,000 geothermal facilities

in shallow groundwater are in operation.

The facilities are subject to authorization,

and the changes in temperature caused

by their operation are restricted to only a

few degrees.

The scientists expect a different scenario for groundwater with higher levels of contamina-

tion. This is usually the case in areas with intensive agricultural use or in urban regions:

Here, a growth of meso- and thermophilic microoganisms could cause an additional impact

on groundwater quality. Ecosystem-friendly guidelines for the thermal use of groundwater

are currently being developed in ongoing studies. These investigations are an important

prerequisite for a sustainable use of groundwater for heating and cooling purposes and for

the protection of our most important drinking water resource.

Extent of the temperature plume in monitoring wells

around an industrial facility to the north of Munich in

August 2007. The facility is cooled with groundwater.

U Unaffected wells

T Temporarily affected wells

C Continuously affected wells

C5

U2

C3 C6

C7T8

RiverDike

T1

16 °C

17 °C

15 °C

14 °C

13 °C11 °C 12 °C

500 m

U4

Research Highlights Health and Foundations of Life

74


Dr. Martin ElsnerHelmholtz Zentrum München

Since 2006 Head of the Helmholtz junior research group Environmental Isotope Chemistry at the Institute of Groundwater Ecology2004 – 2005 German Research Foundation Postdoctoral Fellow, Dept of Geology, University of Toronto2003 Post-doc at the Swiss Federal Institute of Technology (ETH) Zurich and Swiss Federal Institute of Aquatic Science and Technology (EAWAG)Until 2002 Study of Chemistry and PhD in Environmental Sciences, ETH Zürich and EAWG

Helmholtz Zentrum München• Armin H. Meyer• Holger Penning

While investigating the natural degradation of the pesticide atrazine to hydroxyatrazine,

a research team led by Martin Elsner at the Institute of Groundwater Ecology observed

a characteristic change in the stable isotope ratios of carbon (C) and nitrogen (N). This

observation led to the development of a new approach to track this degradation pathway,

which is often overlooked in risk assessments. Atrazine is ubiquitous in the environment.

It is highly persistent, and is therefore repeatedly found in groundwater even though its

use in Germany was discontinued years ago.

In their experiments, the research group at the Institute of Groundwater Ecology focused

on the hydrolysis of atrazine to hydroxyatrazine. In contrast to desethyl- and desisopro-

pylatrazine, which are formed by dealkylation of the herbicide, the hydrolysis product hy-

droxyatrazine is seldom detected in groundwater. The metabolite may possibly become

immobilized by sorption in the pedosphere. Until now, the ratio of desethylatrazine to at-

razine, or desisopropylatrazine to atrazine, has therefore been used as indicator for the

degradation and mobility of atrazine in the environment. In contrast, the transformation

pathway to hydroxyatrazine has frequently been neglected.

This study on isotope fractionation represents a new approach for detecting the biolog-

ical degradation of atrazine to hydroxyatrazine. The researchers observed significant and

characteristic C and N isotope fractionation in atrazine when this pesticide was microbially

degraded to hydroxytarazine: The relative content of 13C increased, that of 15N decreased.

Isotope Fractionation Characterizes Biodegradation of Atrazine

75

Original publication Armin H. Meyer et al.: C and N isotope fractionation suggests similar mechanisms of microbial atrazine transformation despite involvement of different enzymes (AtzA and TrzN). Environ. Sci. Technol. 43: 8079-8085 (2009)

The use of atrazine has been prohibited

in the EU for several years. Nonetheless,

atrazine itself and its metabolites – most

prominently desethyl- and desisopropyla-

trazine, which preserve some herbicidal

character – persist for a long time in the

environment. That is why – even today –

they represent a risk to the groundwater.

The pattern of the isotope shift was identical for the degrading bacteria Chelatobacter heint-

zii and Arthrobacter aurescens TC1. This observation suggests that the biochemical trans-

formation mechanism through both bacteria is the same despite involvement of different

bacterial enzymes, AtzA and TrzN. This is remarkable because the amino acid sequences of

AtzA and TrzN have a similarity of only 27 percent, indicating that the evolution of the two

enzymes probably occurred largely independently of each other.

Further experiments revealed first clues about the underlying biochemical degradation

mechanism. Abiotic reference experiments reproduced the pattern of biotic transformation

for pH 3, but showed a clearly different trend (increase of 13C and 15N) for pH 12. This sug-

gests that the bacteria in a first step activate atrazine via an acid catalyst, which precedes

the nucleophilic aromatic substitution. The biotransformation of atrazine to the non-toxic

hydroxyatrazine can possibly be regulated in a targeted manner by bacterial enzymes.

The characteristic changes in the isotope abundanc-es of 15N and 13C in atrazine during bacterial deg-radation to hydroxyatrazine opens new avenues to quantifying the degradation pathway in nature and to elucidating the degradation mechanism.

Characteristic Isotope Changes in the Isotope Abundances of 15N and 13C

in Atrazine during Bacterial Degradation to Hydroxyatrazine

atrazine

CI

NN

NN

N

desethylatrazine

often detected

start of the degradation

chan

ges

of 15

N / 14

N [i

n ‰

]

0

-2

-4

-6

-8

-10

-120 2 4 6 8 10 12 14

changes of 13C / 12C [in ‰]

end of the degradation

overlooked in nature?

hydroxyatrazine

Chelatobacter heintzii Arthrobacter aurescens TC1 Pseudomonas sp. ADP

OH

NN

NN

N

CI

NNH2

NN

N

Research Highlights Health and the Foundations of Life

76

The Role of Functionally Redundant Microorganisms in Land Use

An international team of microbiologists, soil and agricultural scientists has demonstrat-

ed the importance of functionally similar microorganisms for the stability of nitrogen

turnover processes in agriculturally used and charged soils. Under the influence of anti-

biotic residues, ammonia-oxidizing archaea (AOA) maintained the microbial formation of

nitrate in the soil, while ammonia-oxidizing bacteria (AOB) were inhibited in their activ-

ity due to changed environmental conditions.

Scientists led by Michael Schloter at Helmholtz Zentrum München and Christa Schleper at

the University of Bergen investigated ammonia-oxidizing archaea (AOA) and their bacteri-

al counterparts (AOB) to learn more about the role of the functional redundancy of microbi-

al communities. AOA and AOB are both involved in ammonia oxidation in the nitrogen cycle

and perform the same transformation step. They belong to phylogenetically quite distinct

groups: Archaea differentiated from classical bacteria very early in evolution.

The dynamics and function of these special microbial communities were tested on two

different agriculturally used soils that were fertilized with pig manure containing sulfadia-

zine in different concentrations. Sulfadiazine is an antibiotic frequently used in veterinary

medicine which reaches soil and water through the fertilization of manure. In the experi-

ments, pig manure stimulated the growth of AOB and – at least in one of the tested soils –

also the growth of AOA. The addition of the antibiotic significantly weakened the stimu-

lating effect of the manure on AOB, whereas AOA were less impacted. On the basis of the

experimental data the researchers developed a mathematical model, which estimated the

Prof. Dr. Michael SchloterHelmholtz Zentrum München and Technische Universität München

Since 2010 Professor of Soil Microbiology, Technische Universität MünchenSince 2008 Head of the Dept. of Terrestrial Ecogenetics,Helmholtz Zentrum München2001 – 2007 Head of the research group Functional Microbial Ecology, Institute of Soil Ecology, GSF2000 Visiting Scientist Environmental Protection Agency,Corvallis, OR, USA1991 – 2000 Post-doc and scientific staff member at the GSF (today Helmholtz Zentrum München) and at EMBRAPA, Rio de Janeiro, Brazil (1995) Until 1991 Study of biology, Ludwig-Maximilians-Universität Munich, and PhD, University of Bayreuth

Dr. Kristina Kleineidam (formerly Schauss)Helmholtz Zentrum München

Since 2009 Research group leader and deputy head of the Dept. of Terrestrial Ecogenetics, Helmholtz Zentrum MünchenSince 2006 Post-doc and scientific staff member, Helmholtz Zentrum MünchenUntil 2006 Study of agricultural sciences and PhD, University of Giessen

Helmholtz Zentrum München • Kristina Schauss • Shilpi Sharma


• Jean-Charles Munch

University of Osnabrück • Andreas Focks • Michael Matthies

University of Bergen • Sven Leininger

University of Bergen and University of Vienna • Christa Schleper

Technical University of Berlin • Anja Kotzerke • Berndt-Michael Wilke • Martin Kaupenjohann

Julius Kühn-Institute – Federal Research Institute for Cultivated Plants

•Holger Heuer • Kornelia Smalla

University of Trier • Sören Thiele-Brun

University of Bonn • Wulf Amelung


77 Research Highlights Health and the Foundations of Life

percentages of AOA and AOB in the ammonia oxidation. The results showed that the contri-

bution of AOA to this key step of nitrate formation in the soil increased under the influence

of the antibiotic. This finding suggests a functional redundancy of both microbial commu-

nities and at the same time corroborates their importance for the stability of turnover pro-

cesses in charged soils.

The results help to elucidate the role of microbial communities in the soil ecosystem

functioning under changing environmental conditions and contribute to the development

of strategies adapted to a sustainable use.

Original publication Kristina Schauss et al.: Dynamics and functional relevance of ammonia-oxidizing archaea in two agricultural soils. Env. Microbiol. 11: 446-456 (2009) doi:10.1111 / j.1462-2929.2008.01783.x

In ammonia oxidation, ammonium,

e. g., being released from dead organic

matter by microbial activity is oxidized

via nitrite to nitrate. Nitrate is one of

the most important nutrients for plants.

The transformation from ammonium to

nitrate takes place through nitrifying

bacteria and archaea, the latter of which

have not been investigated thoroughly

until now. The role of Archaea (Crenar-

chaeota) in ammonia oxidation in soils

has just recently been discovered (2006)

by an international research group in

which the Helmholtz Zentrum München

is participating.

Situation 1 (soil + pig manure)

Situation 2(soil + pig manure + antibiotic)

ammonia oxidation

AOB

AOB

NH4+ mobile

NH3

NH4+ immobile

NO2−

Under the influence of antibiotic residues from veter-

inary medicine in pig manure, the ratio of ammo-

nia-oxidizing microorganisms in the soil changes.

The proportion of ammonia-oxidizing bacteria (AOB)

decreases, while the proportion of functionally re-

dundant organisms from the Archaea domain (AOA)

increases.

Stable Turnover Rates Due to Functional Redundancy

AOB

AOA

AOB AOAAOB AOA

organismsAOB AOA

78

Type of Infrastructure Name Partner1 Core Facilities 1.1 Core Facility Proteomics 1.1.1. Department of Protein Science, Helmholtz Zentrum München

1.2 Genome Analysis Centre (GAC) 1.2.1 Institute of Experimental Genetics, Helmholtz Zentrum München

1.3 Animal Keeping 1.3.1 Department of Comparative Medicine, Helmholtz Zentrum München

2 Platforms / Technology 2.1 Immune Monitoring Platform 2.1.1 Institute of Molecular Immunology, Helmholtz Zentrum München

2.1.2 University Hospital Grosshadern, Ludwig-Maximilians-Universität Munich

2.1.3 University Hospital rechts der Isar, Technische Universität München

2.2 Central Service Platform Monoclonal Antibodies 2.2.1 Institute of Molecular Immunology, Helmholtz Zentrum München

2.3 Cooperative Health Research in the Augsburg Region (KORA)

2.3.1 German Diabetes Center, Düsseldorf

2.3.2 University of Applied Sciences, Augsburg

2.3.3 Public Health Department Augsburg

2.3.4 Institute of Epidemiology, Helmholtz Zentrum München

2.3.5 Medical Center / Augsburg Hospital



2.3.8 University of Augsburg

2.3.9 University of Düsseldorf

2.3.10 University of Greifswald

2.3.11 University of Innsbruck

2.3.12 University of Leipzig

2.3.13 University of Münster

2.3.14 University of Ulm

2.3.15 University Medical Center Schleswig Holstein

2.3.16 Central Institute of Mental Health, Mannheim

2.4 Protein Expression & Purification Facility (PEPF) 2.4.1 Institute of Structural Biology, Helmholtz Zentrum München

2.5 Screening and Assay Development Plattform 2.5.1 Institute of Structural Biology, Helmholtz Zentrum München

2.6 Central Inorganic Analysis Service 2.6.1 Institute of Ecological Chemistry, Helmholtz Zentrum München

2.7 Experimental Environmental Simulation (EUS) 2.7.1 Department Experimental Environmental Simulation, Helmholtz Zentrum München

2.8 Scheyern Experimental Farm 2.8.1 Institute of Soil Ecology, Helmholtz Zentrum München

3 Associations 3.1 Bavarian NMR Center (BNMRZ) 3.1.1 Department of Chemistry, Technische Universität München (TUM)

3.1.2 Institute of Structural Biology, Helmholtz Zentrum München

3.2 The European Mouse Mutant Archive – EMMA 3.2.1 Consiglio Nazionale delle Ricerche, Istituto di Biologia Cellulare, Monterotondo

3.2.2 CNRS – Centre de Distribution, de Typage et d’Archivage animal, Orleans

3.2.3 MRC – Mammalian Genetics Unit, Harwell

3.2.4 Karolinska Institutet, Stockholm

3.2.5 CG – Instituto Gulbenkian de Ciência, Oeiras

3.2.6 Institute of Experimental Genetics, Helmholtz Zentrum München

3.2.7 EMBL – European Bioinformatics Institute, Hinxton

3.2.8 Institut Clinique de la Souris, Illkirch / Strasbourg

3.2.9 Wellcome Trust Sanger Institute, Hinxton

3.2.10 Centro Nacional de Biotecnología, Madrid

3.2.11 Alexander Fleming Biomedical Sciences Research Center, Vari /Athens

3.3 German Mouse Clinic (GMC) 3.3.1 Institute of Experimental Genetics, Helmholtz Zentrum München



3.3.4 University of Bonn


3.3.6 University of Heidelberg

3.4 Mass Spectrometry Center 3.4.1 Institute of Ecological Chemistry, Helmholtz Zentrum München

3.4.2 University of Rostock

Cooperation through Platforms and Service Facilities


79

Helmholtz Zentrum München provides excellent research platforms which serve as

important instruments for the creation of science networks in Germany and in Europe.

Our biomedical research infrastructure is leading in the fields of mouse models, epide-

miology and structural biology. As central providers, the platforms and infrastructure

facilities provide services on the highest scientific level. They contribute to elucidating

the causes and courses of diseases in order to develop new therapeutic approaches

and drugs. Furthermore, they aid in the research on the interactions between environ-

ment and health.

1

2

3

2.1.1 – 2.1.3

3.1.1 – 3.1.2

3.4.1 – 3.4.2

3.2.1 – 3.2.11

3.3.1 – 3.3.6

2.3.1 – 2.3.16

2.1

3.1

3.2

3.3

3.4

2.3 2.2

2.4

2.5

2.6

2.7

2.8

1.3

1.2

1.1 1.1.1

1.2.1

1.3.1

2.2.1

2.4.1

2.5.1

2.6.1

2.7.1

2.8.1

Botzler C

Ntziachristos V

Mocikat R

Landthaler M

Schmetzer HM

Bickeböller H

Andreesen R

Kremmer E

Steinem C

Krause SW

Dressel R

Radons J

Kunz-Schughart LA

Asea AA

Gross C

Debets R

DeMaio A

Bausero Maria

Cordes N

Issels R

Eissner G

Arispe NJ

Ellwart JW

Pockley AG

Pfister K

Molls M

Hiddemann WD

Atkinson M

Holler E

Garrido CGaipl U

Vigh L

Feldmann HJ

Kolb HJ

Konings G

Wagner B

Jäättelä M

Walch A

Ortega E

The clinical cooperation group “Innate Immunity in Tumor Biology” investigates innovative

immunotherapeutic strategies based on heat shock proteins (HSP). The new strategies serve

as complement to radiochemotherapeutic and hyperthermic treatments now in standard use.

The direct connection to industry ensures smooth knowledge transfer from basic research into

the clinic and subsequently into applications.


Clinical Networks for Cancer Research

“ Networks are an important basis for the success-

ful transfer of knowledge. This applies both to

partnerships in all projects with public funding

as well as to cooperations with the industry.”

is the head of the clinical cooperation group “Innate Immunity in Tumor Biology”, a joint project with

Technische Universität München. Professor Multhoff has been Associate Professor of Experimental

Radio Oncology and Radiation Biology at University Hospital Rechts der Isar of Technische Univer-

sität München since 2007. She successfully links basic research on the mechanisms of tumor genesis

and of the immune system’s reaction with clinical applications in radiation therapy. She also is the

chief executive officer of multimune GmbH, a biotechnology company.

Prof. Dr. Gabriele Multhoff

Further Research Highlights

84



• Arne Pfeufer • Zasie Schäfer • Hanna Prucha • Christian Johannes Glöckner •Marius Üffing • Thomas Meitinger


• Martina Müller • H.-Erich Wichmann

Helmholtz Zentrum München • Christian Gieger • Siegfried Perz

Ludwig-Maximilians-Universität Munich • Moritz F. Sinner • Britt M. Beckmann • Gerhard Steinbeck • Stefan Kääb

CNR, Monserrato • Serena Sanna • Marco Orrú • Gianluca Usala • Mariano Dei • Laura Crisponi • Silvia Naitza • Manuela Uda

John Hopkins University, Baltimore • Dan E Arking • Georg B Ehret • Anna Köttgen • Man Li • W H Linda Kao • Josef Coresh • Aravinda Chakravarti

University of Michigan, Ann Arbor • Vesela Gateva • Gonçalo R. Abecasis

EURAC European Academy, Bolzano • Andrew A. Hicks • Christian Fuchsberger • Cristian Pattaro • Fabio Marroni • Peter P Pramstaller

University of Texas Health Science Center, Houston • Maja Barbalic • Eric Boerwinkle

Max-Planck-Institute of Psychiatry • Bertram Müller-Myhsok • Benno Pütz

Istituto Ricovero e Cura per Anziani, Rome • Angelo Scuteri

Wake Forest University School of Medicine, Winston-Salem

• Ronald J. Prineas

National Institute on Aging, Baltimore • Samer S. Najjar • Edward Lakatta • David Schlessinger

University of Bonn • Thomas W. Mühleisen • Markus Nöthen

University Hospital of Essen • Stefan Möhlenkamp • Susanne Möbus • Raimund Erbel • Karl-Heinz Jöckel

Dr. Arne PfeuferHelmholtz Zentrum München andTechnische Universität München

Since 2006 Head of the research group Complex Characte-ristics of the Cardiovascular System, Helmholtz Zentrum München and Technische Universität MünchenSince 2001 Scientific staff member, Institute of Human Genetics, Helmholtz Zentrum München and Technische Universität München 2000 Resident physician, Kerckhoff Hospital of the Max Planck Society, Bad Nauheim1998 – 1999 Humboldt University Berlin, MD1991 – 1997 Study of medicine, Hannover andHumboldt University Berlin1986 – 1992 Study of biochemistry, University of Hannover

An international team of scientists led by Arne Pfeufer has identified common gene vari-

ants in the human genome which influence the electrical activity of the heart muscle in

humans. They can be directly associated with cardiac arrhythmia and sudden cardiac

death and can thus facilitate early risk detection.

The scientists analyzed the electrocardiograms of more than 15,000 test persons from the

population-based cohorts KORA, ARIC, SardiNIA, GenNOVA and Heinz Nixdorf Recall

(HNR) with respect to the QT interval. This interval is a measure of cardiac repolarization

and a risk marker often used by physicians for ventricular arrhythmias and sudden cardiac

death.

The ten gene variants that have now been identified can influence the length of the QT

interval in each individual and thus influence the risk for cardiac arrhythmia. Four of them

are localized close to the known disease genes for the heritable long QT syndrome. They do

not have any effect as single genes, but rather in their respective constellation and along

with other risk factors such as drugs or ischemia.

Genetic Risk Factors Identified for Sudden Cardiac Death

85

Original publicationArne Pfeufer et al: Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat. Genet. 41 (4): 407-414 (2009) doi: 10.1038 / ng.362

The QT interval describes the time span

needed to send the electrical impulse to

the heart chambers and then to recharge

(repolarization). A prolonged QT inter-

val can – depending on the underlying

disease – increase the risk of cardiac

arrhythmia and sudden cardiac death

five-fold.

In interaction with other, not previously discovered factors, these gene variants can influ-

ence the repolarization of the heart beat and thus also the risk for cardiac arrhythmia. Next,

further studies shall confirm the association between the new gene variants and sudden

cardiac death. The researchers intend to collect and evaluate further data from a larger

number of patients on the respective individual genetic risk for cardiac arrhythmia. They

want to gain additional insights into the pathogenic mechanisms and thus perspectives for

improved risk recognition and more successful treatments.

RNF2

07

ATP1

B1 SCN

5A

SLC3

5F1

/ PLN

/ C6o

rf20

4

KCN

H2

KCN

Q1

LITA

F

KCN

J2G

INS3

/ ND

RG4

/ SET

D6

/ CN

OT1

NO

S1AP

-log10

(p-v

alue

)

22211 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Chromosome

10

20

25

30

35

15

5

0

The so-called Manhattan Plot from the publication of

the QTSCD consortium shows the individual associ-

ation signals of the ten QT interval-associated genes

and/or gene regions against the background of the hu-

man genome (chromosomes 1-22).


86


Helmholtz Zentrum München• Hanna M. Eilken

RIKEN Center for Developmental Biology, Kobe • Shin-Ichi Nishikawa

Dr. Timm SchroederHelmholtz Zentrum München

Since 2006 Deputy director, Institute of Stem Cell ResearchSince 2004 Head of independent research group Hemato-poiesis, Institute of Stem Cell Research (tenure since 2009)2002 – 2004 Visiting scientist, RIKEN Center for Develop-mental Biology, Kobe, Japan 2000 – 2002 Post-doc, Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München2001 T. Ray Bradley New Investigator Award of the Inter national Society for Experimental Hematology (ISEH)Until 2000 Study of biology and PhD, University ofErlangen and Helmholtz Zentrum München

The first blood cells in the embryo arise from hemogenic endothelial cells. Within the

scope of an international cooperation a research group of Helmholtz Zentrum München

tracked the transformation of endothelial cells into blood cells, using new bio-imaging

techniques. In the future, blood cells can be generated in the laboratory in a targeted

manner.

A question scientists have puzzled over for decades has now been solved: How are the first

blood cells generated in the embryo? Timm Schroeder and his colleagues at the Institute of

Stem Cell Research identified a special kind of endothelial cells which can transform into

blood cells. Endothelial cells line the inside walls of blood vessels.

The first blood cells come into being within a very short time span during embryonic

development in the uterus. In order to study this generation process, the scientists first had

to create the technical means to observe the transformation of endothelial cells into blood

cells over a long period on the single-cell level. They developed new methods for imaging

and tracking a multitude of single cells. This bio-imaging approach combines microscopic,

incubation and imaging techniques as well as newly developed computer programs to track

single cells in time-lapse films with complex methods of cell purification and cell culture. It

allows the scientists to continually observe the differentiating mesodermal cells for up to

one week. After careful analysis of tens of thousands of cells and the molecules expressed

by them, the researchers detected some rare endothelial cells which transformed them-

selves into blood cells. This clarifies the last differentiation step in blood cell generation.

How Blood Cells Are Generated

87

Original publication Hanna M. Eilken et al.: Continuous single-cell imaging of blood generation from haemogenic endothelium. Nat. 457: 896 – 900 (2009) doi: 10.1038 / nature07760

The endothelium is the innermost wall

layer of lymph and blood vessels. It is

integrated into a series of physiological

processes and plays a crucial role in

inflammatory processes. The sprouting

of new vessels also takes place via endo-

thelial cells.

Besides enabling a better understanding of the mechanisms of hematopoiesis, the study

findings are important for improving the production of blood cells in the laboratory for clin-

ical therapies. The ability to generate unlimited quantities of blood cells from embryonic

stem cells in the laboratory is a promising basis for new approaches to cell therapy.

Using novel bio-imaging methods, the research group

tracked the fate of differentiating mesodermal cells on

the single-cell level over a period of several days. They

were indeed able to detect hematopoietic endothelial

cells giving rise to blood cells.

blood vessel

endothelial cell

mature blood cells

developing blood cells

blood-generating endothelial cells

Generation of Blood from the Endothelium


88


PD Dr. Michaela AubeleHelmholtz Zentrum München andTechnische Universität München

Since 2007 Deputy director of the Institute ofPathology2004 habilitation, Technische Universität München1995 – 2007 Head scientist, Institute of Pathology1986 – 1995 Post-doc in Biomedical Image Analysis,Helmholtz Zentrum MünchenUntil 1995 Graduate studies and doctorate, Ludwig-Maximilians-Universität Munich

Dr. Daniela SchulzHelmholtz Zentrum München

Since 2007 Scientific staff member, Helmholtz Zentrum München2002 – 2006 Scientific staff member, University ofLeipzig, PhD, University of Halle-Wittenberg Until 2002 Study of agricultural science, focus on agricultural biology, Technische Universität München-Weihenstephan

Helmholtz Zentrum München• Claudia Böllner

Imperial College London• Gerry Thomas

Helmholtz Zentrum München and Technische Universität München• Mike Atkinson• Heinz Höfler• Irene Esposito• Michaela Aubele

In triple-negative (TN) breast cancer, the receptors for the growth factor HER2 and those

of the female sex hormones estrogen and / or progesterone are absent in the cells or only

present in very small concentrations. Since drugs available today target an elevated con-

centration of these receptors, they are ineffective against TN breast cancer. Researchers

at Helmholtz Zentrum München have now developed a potential approach to treat this

form of breast cancer.

In triple-receptor-negative or triple-negative (TN) breast cancer there is little or no expres-

sion of estrogen and progesterone receptors nor of HER2 receptors, which are the targets

of drug therapy for breast cancer. The research team led by Michaela Aubele has now inves-

tigated TN tumors more closely and has discovered significant differences in the concen-

tration of around 30 proteins in contrast to the HER2-positive / hormone receptor-negative

cancer types. Of these, 13 proteins are found in higher concentrations in TN breast cancer,

and over 20 proteins are found in lower concentrations than in HER2-positive / hormone

receptor-negative breast cancers.

The researchers examined 34 samples of frozen breast cancer tissue (15 of triple-nega-

tive and 19 HER-2 positive / hormone-receptor-negative tumors). Among the identified pro-

teins are e. g. annexins A1 and A2, lactoferrin, NME1-NME2 protein, fibronectin and L-Plas-

tin. The physiological role of some of these marker proteins is known: They are involved in

signaling chains which are relevant for the growth and invasion of tumors in the surround-

ing tissue.

Basis for New Approach to Treating Triple-Negative Breast Cancer

89

Original publication Daniela Schulz et al.: Identification of differentially ex-pressed proteins in triple-negative breast carcinomas using DIGE and mass spectrometry. J. Proteome Res. 8: 3430-3438 (2009) doi: 10.1021 / pr900071h

80 percent of all breast cancers are

hormone-dependent in their growth, and

in about 25 percent of these the HER2

receptors are overexpressed. Around 15

percent are characterized as triple-nega-

tive (TN) – that means neither estrogen,

progesterone nor HER2 receptors are

formed in the tumor in high concentra-

tions. HER2 receptors can be blocked with

the antibody drug trastuzumab (Her-

ceptin). Tumors with high concentrations

of hormone receptors can be treated with

tamoxifen or aromatase inhibitors.

Further studies shall characterize triple-negative breast cancer in more detail and con-

tribute to the development of new options for therapy. Over the long term, researchers are

striving to significantly improve the prognosis for TN breast cancer, for which there is at

present no targeted treatment.

lactiferous ducts

nodetriple-negative and / or receptor triple-negative breast cancer cell

cell nucleus

HER2 geneHER2 receptor

glandular lobules

A comparison of triple-negative (TN) breast cancer

with HER2-positive / hormone receptor-negative

breast cancer on the molecular level shows that more

than 30 proteins are expressed in different quantities.

Some of these downregulated or upregulated proteins

could serve as targets for drug therapy against TN

breast cancer.

HER2-Positive, Hormone-Receptor-Negative Breast Cancer Cell

TN

HER2

CK7 fibronectin NME1-2 annexin A1


90


Helmholtz Zentrum München and Ludwig-Maximilians-Universität

• Dorothea Maetzel• Sabine Denzel• Michael Benk

Ludwig-Maximilians-Universität Munich• Brigitte Mack• Martin Canis• Cuong Kieu

University of Zürich• Philip Went

Helmholtz Zentrum München• Peer Papior

Micromet Inc., Bethesda• Patrick A. Baeuerle• Markus Münz

PD Dr. Olivier GiresHelmholtz Zentrum München and Ludwig-Maximilians-Universität Munich

2007 habilitation in Otorhinolaryngology, Ludwig-Maximilians-Universität MunichSince 2001 Head of the clinical cooperation group Molecular Oncology, Helmholtz Zentrum München and the Dept. of Otorhinolaryngology, Grosshadern Medical Center, Ludwig-Maximilians-Universität2000 – 2001 Head of the research group Gene and Immuno-therapies of Tumors1999 – 2000 Junior researcher, Dept. of Otorhinolaryngology, Grosshadern Medical Center Ludwig-Maximilians-Univer-sität MunichUntil 1998 Study of biology and PhD

The transmembrane protein EpCAM promotes cell division and thus cancerous growth.

How this functions biochemically is shown in a current project led by Helmholtz Zentrum

München. The protein is already a target molecule for therapeutic antibody drugs in can-

cer therapy. New insights on EpCAM facilitate the development of therapeutics and help

prevent undesirable side effects.

The molecule EpCAM (epithelial cell adhesion molecule) is expressed by tumor cells with

high frequency and in very abundant numbers and thus plays an important role in cancer-

ous growth. Both the entire EpCAM protein and its shortened form (EpICD) promote the tu-

morigenic growth of cells when they are injected into immune-deficient mice.

The research team led by Olivier Gires was able to elucidate the molecular basis for this

effect: Upon activation, the transmembrane protein EpCAM is split into two parts. One part

(EpEX) remains outside the cell and detaches itself. The second part, EpICD, is released in-

side the cell and migrates in several steps into the cell nucleus. There it regulates the tran-

scription of c-myc and other genes, which leads to increased cell division.

EpCAM is already a target molecule for therapeutic antibody drugs in cancer therapy. Also

the trifunctional bispecific antibody Removab®, developed by Trion Pharma, a spin-off

of Helmholtz Zentrum München, and approved in May 2009 by the EU, attacks the tar-

get molecule EpCAM. The basic research for this development was conducted at Helmholtz

Zentrum München.

How a Tumor Factor Promotes Cancerous Growth

91

β-Catenin

α-Catenin

FHL2

EpICD

β-Catenin

lef

Original publication Dorothea Maetzel et al: Nuclear signalling by tumour- associated antigen EpCAM. Nat. Cell Biol. 11: 162-171 (2009) doi:10.1038 / ncb1824

The transmembrane protein EpCAM

(epithelial cell adhesion molecule) plays

an important role in cell adhesion in

healthy tissue. Excessive production

of EpCAM is typical for many types of

cancer, such as colon and breast cancer.

The new insights into the function of EpCAM will accelerate the development of further

therapeutic drugs and help prevent undesirable side effects. The fact that EpCAM, in com-

bination with other markers, is also overexpressed by embryonic stem cells and by cancer

stem cells makes the molecule highly promising as a therapeutic target. In cooperation with

the Micromet company and Dierk Niessing at the Institute of Structural Biology of Helm-

holtz Zentrum München, the research group led by Olivier Gires will utilize these findings

to develop preclinical trials. The group will receive funding for this from the excellence clus-

ter “m4” of the Federal Ministry of Education and Research (BMBF).

EpCAM is the transmembrane protein on the left with

the dark intracellular part. EpCAM is split by the two

proteases TACE and PS-2, so that the intracellular

part (EpICD) can translocate into the nucleus. In con-

junction with beta-catenin and Lef-1 it regulates the

expression of target genes, which are involved in the

regulation of the proliferation and migration of cells.

plasma membrane

cell nucleus

E-CadherinEpEX

CTF NTF

EpICD

EpCAM target genec-myc, cyclines

PS-2

TACE

EpCAM Activation through Proteolytic Cleavage


β-Cateninβ-Cateninβ-Catenin

FHL2

β-Catenin

92

Scientists of the Institute of Ecological Chemistry at Helmholtz Zentrum München have

identified new potential biomarkers for Crohn’s disease (CD), an inflammatory bowel dis-

ease. Relying solely on metabolic analyses, the researchers were able to diagnose Crohn’s

disease in patients non-invasively and, additionally, to distinguish between different

forms of the disease.

In their search for new biomarkers of Crohn’s disease, a team of researchers led by Philippe

Schmitt-Kopplin investigated metabolites produced by the intestinal microflora. These are

partly positively and partly negatively correlated with the disease phenotype. The metabolic

products of the intestinal flora could thus be used as non-invasive diagnostic biomarkers,

as progress monitoring tool or as potential targets for disease therapy and prevention.

The exact pathogenic mechanisms underlying Crohn’s disease are still unknown. How-

ever, it is certain that a combination of genetic and bacterial factors is involved. In order to

determine to what extent bacterial metabolites affect the status of the disease, researchers

performed non-targeted metabolite profiling. In doing so, thousands of metabolites from

diluted fecal samples of 17 pairs of identical twins were examined with using Fourier trans-

form ion cyclotron resonance mass spectrometry (ICR-FT / MS). Some of the test persons

were healthy, the others had fallen ill with Crohn’s disease. Also, all metabolites that are

present in connection with metabolism and / or the synthesis of amino acids, fatty acids,

bile acids and arachidonic acid were separated according to their mass. Thanks to the high

performance of the ICR-FT / MS, even the smallest mass differences could be measured.


Helmholtz Zentrum München• Ages Fekete

Lawrence Berkeley National Laboratory, USA • Janet Jansson

Swedish University of Agricultural Sciences, Sweden

• Janet Jansson• Ben Willing• Johan Dicksved

Örebro University, Sweden• Curt Tysk

PD Dr. Dr. Philippe Schmitt-Kopplin Helmholtz Zentrum München

Since 2009 Head of the Dept. of BioGeoChemistry andAnalytics at the Institute of Ecological Chemistry2002 habilitation, Technische Universität München1997 PhD, Institut National Polytechnique de Lorraine, Nancy, FranceSince 1996 Scientific staff member, Helmholtz Zentrum MünchenFrom 1995 bis 1996 Post-doc as National Research Council Fellow at USEPA in Athens, GA, USA 1993 – 1995 PhD, Technische Universität München

Dr. Marianna Lucio Helmholtz Zentrum München

Since 2008 Post-doc, Institute of Ecological Chemistry, Helmholtz Zentrum München2005 – 2008 Scientific staff member, Institute of Ecological Chemistry, PhD2000 – 2005 Development of production programs for the textile industryUntil 1999 Study of statistics and demography at Padua University

Biomarkers for Crohn’s Disease

Crohn’s disease is classified as an autoim-

mune disease of the intestinal mucosa.

For its diagnosis, an endoscopic examina-

tion is currently necessary. A non-invasive

diagnostic option with biomarkers would

be desirable for the patients.

93

At the same time, the profile of the bacteria present was created from the same fecal sam-

ples, thus establishing a correlation – negative or positive – between some metabolites and

bacteria such as F. prausnitzii and E. coli. This made it possible to determine masses that

allow a differentiation of healthy test persons and patients with Crohn’s disease either with

a distinct disease of the colon or the terminal ileum.

The study shows that in Crohn’s disease, metabolomics is able to differentiate between

different phenotypes of disease – colon or terminal ileum – and to provide new insights

about the causes. At the same time, the study underlines the importance of the intestinal

flora and its metabolic products for intestinal health.

Original publicationJanet Jansson et al.: Metabolomics reveals metabolic biomarkers of Crohn’s disease. PLoS ONE 4 (7): e6386. (2009) doi: 10.1371 / journal.pone.0006386

The multivariable statistical analysis of thousands of

signals and thus metabolic products made an ideal

separation of sick and healthy test persons possible.

In a second step, a correlation between meta-metabo-

lome and the known microbiome could be established.

To this end, structural identification of new metabo-

lites and profiling of the bacteria typical for Crohn’s

disease were combined.

Differentiation of the Phenotypes by Means of Spectrometric Data

healthy adults

healthy adolescents

Patients with Crohn’s disease of the ileum

Patients with Crohn’s disease of the colon and healthy discordant twins

ICD

80,000

0

0-80,000

-100,000 100,000


94

A study led by Michael Sattler has shed new light on the molecular mechanisms of Zellwe-

ger syndrome in patients with Pex14 mutations. The study elucidated the spatial structure

of an important binding domain of the peroxisomal membrane protein Pex 14.

The team of researchers led by Michael Sattler has elucidated the interaction mechanism of

three peroxisomal proteins. Peroxisomes are involved in fatty acid degradation and intra-

cellular detoxification. Disruption of the interactions between the three investigated pro-

teins interferes with the protein import into peroxisomes and is associated with peroxisom-

al diseases such as Zellweger syndrome.

Protein import into peroxisomes takes place via a complex and dynamic network of

protein-protein interactions. Pex14, a protein within the lipid membrane of the peroxisomes

plays a key role in these interactions. It binds the soluble receptor proteins Pex5 and Pex19,

which play crucial roles in the development of the peroxisomes.

The researchers showed that the exchange of amino acids in the N-terminal region of

the Pex14 protein interferes with the binding to Pex5 and / or Pex19. Using state-of-the art

NMR spectroscopy, the spatial structure of the domain in complex with regions from Pex5

and Pex19 was determined, and thus atomic details of the binding mechanism could be re-

solved. The molecular interactions of the N-terminal domain are essential for the intracel-

lular localization of Pex14. If these interactions are disturbed, e. g. by mutations in the Pex14

protein, this will result in mislocalization in the cell and lead to peroxisomal diseases such

as Zellweger syndrome.


European Molecular Biology Laboratories (EMBL)• Christian Neufeld• Fabian V. Filipp• Bernd Simon• Nicole Schüller• Matthias Wilmanns

Ruhr Universität Bochum• Alexander Neuhaus• Christine David• Ralf Erdmann• Wolfgang Schliebs


• Hamed Kooshapur• Tobias Madl• Michael Sattler

Prof. Dr. Michael SattlerHelmholtz Zentrum München and Technische Universität München

Since 2007 Director of the Institute of Structural Biology atHelmholtz Zentrum München and Professor of BiomolecularNMR Spectroscopy at Technische Universität München1997 – 2006 Group leader Biomolecular NMR Spectroscopy, European Molecular Biology Laboratory (EMBL)1995 – 1997 Post-doc Abbott Laboratories, Abbott Park, IL, USAUntil 1995 Study of Chemistry and PhD, Goethe University of Frankfurt

Novel Insights into the Molecular Mechanisms of Zellweger Syndrome

Zellweger syndrome is an inherited

metabolic disorder. It is associated with

the loss of function of the liver, kidney and

other organs and leads to death within

a few months after birth. This very rare

disease is brought about by mutations of

the genes that are essential for the forma-

tion of peroxisomes.

95

These findings are the starting point for further studies aimed at understanding the com-

plex biogenesis of peroxisomes and the molecular mechanisms of the Zellweger syndrome.

The insights gained from these studies may lead to the development of novel treatments for

peroxisomal diseases in the future.

Original publicationChristian Neufeld et al.: Structural basis for competitive interactions of Pex14 with the import receptors Pex5 and Pex19. The EMBO Journal 28: 745 - 754 (2009) doi: 10.1038 / emboj.2009.7

Pex5 is the receptor for the import of peroxisomal pro-

teins (peroxins) into the peroxisomal matrix. Pex5

recognizes a so-called peroxisomal transport signal

(PTS1). For the protein import, interactions with the

peroxins Pex14 and Pex19 are important. Pex19 is

also required for the import of peroxisomal membrane

proteins (PMPs) (such as e. g. Pex14). For the recogni-

tion of the so-called WxxxF motif in Pex5 (tryptophan

118 and phenylalanine 122) by Pex14, the amino ac-

ids phenylalanine 52 and lysine 56 in Pex14 are essen-

tial. In patients with Zellweger syndrome, these amino

acids are lacking or are replaced by others. The effect

caused thereby in the biogenesis of peroxisomes is the

molecular cause of the Zellweger syndrome in these

patients

Zellweger Syndrome Mutations

PTS1 cargo

cytosol

peroxisomal matrix

PMP

5

5

14

19

19

133

1914

14

145 5

Trp118

Phe122

Phe52

Lys56 Pex14

Pex5


Facts

98

Management in Networked Structures

Research at Helmholtz Zentrum München takes place in networked structures. The com-

plexity resulting from extensive networks requires effective management methods. Out-

moded management models based on hierarchical structures and micromanagement of

details have proven to be inadequate in meeting today’s research challenges. The same

applies to the cumbersome decision-making processes of scientific co-determination as it

has been practiced up to now.

Helmholtz Zentrum München has therefore streamlined its decision-making pro-

cesses and work structures and adapted them to the requirements of working in a global

network of scientific cooperations.

Strengthening the Ability to ReactIn networked structures, it is crucial to be able to react quickly and appropriately to chang-

ing requirements and unforeseen constellations.

– Fundamental decisions are made centrally by the Management Committee (MC): It har-

nesses the necessary expertise and competence and bears responsibility for the deci-

sions made. Scientists are directly involved.

– In making operational decisions in networked structures, the principle of familiarity

with the subject has proven to be of value. For this reason, Helmholtz Zentrum München

promotes decentralization of the administration. Thus, in many cases the different re-

search organizational units can make decisions quickly and directly.

Maintaining Unity in DiversityWorking in networked structures means allowing for diversity. Uniform paradigms hinder

initiative and the growth of networks. At the same time, it is important to preserve the iden-

tity of the Center. Here a clear-cut strategic orientation, communicated objectives and pri-

orities, performance evaluation and defined values in the interaction with each other serve

as guidelines and form the basis on which the Center develops its diversity.

99 Management in Networked Structures

Defining Core ProcessesThis also applies to the operative processes: Defined standard processes and an Enterprise

Resource Planning (ERP) system with the most important business processes are being

implemented on the basis of these guidelines. In this way, collaboration in the networks

can be developed as needed, and decisions can be made autonomously. Both scientific and

administrative units have gained freedom of action through the new governance.

Entrusting Responsibility to Staff Members Responsible, autonomous employees with excellent scientific expertise and management

skills are the prerequisite for successful networks. In recent years, the Center has there-

fore pursued a consistent strategy for staff development. Through the introduction of staff

appraisals and target agreements, management processes were improved as well. Junior

staff members take on supervisory and project responsibility at an early stage. The Center

thus systematically develops the managers of tomorrow who fulfill all the requirements for

a successful contribution within the network of scientific collaborations and for the benefit

of the Center.

100

In 2009, a total of 1792 people were employed at Helmholtz Zentrum München. 33 percent

of all staff positions were financed by third-party funding.

More than three quarters of the staff work in the scientific area, including 281 gradu-

ate students, 112 post-docs and 443 researchers from the fields of biology, chemistry / bio-

chemistry, physics / biophysics and medicine. Furthermore, Helmholtz Zentrum München

offers a wide array of trainee positions: As of the end of 2009, 40 young people were being

trained in commercial and technical professions as well as in animal keeping.

The staff of Helmholtz Zentrum München is made up of over 50 different nationalities.

The average age is 38 years.

Human Resources Development and Further Training

At Helmholtz Zentrum München we attach great importance to professional and personal

development. In 2009, 61 in-house further education events took place in which 787 em-

ployees participated. The course offering included modules on leadership and communica-

tion as well as training seminars on science topics and methodology. Moreover, 290 staff

members attended special courses held by external organizations. In 2009, the “blended-

learning” courses in “Effective Managing and Performing” (EMP) for junior management

staff and “Effective Performing” (EP) for all staff members were again offered. Among other

things, they provide methodical and systematic support and serve as preparation for future

tasks and responsibilities.

Equal Opportunity

Women make up more than 50 percent of the staff at Helmholtz Zentrum München. The

Center, which twice has received the Total-E-Quality certificate for equal opportunity,

attaches great importance to compatibility between work and family. In the period be-

tween 2002 and 2009, the proportion of women scientists – including post-docs and doc-

toral students – increased from 37 percent to 46.2 percent. For leadership positions the

increase was even more striking – from 17 percent to 28.4 percent.

Staff

Staff 101

As of: December 31, 2009

20% Animal Keeper

13% Office Administrator

5% IT Specialist

5% Agricultural Assistant

5% Radiation Protection Engineer

47% Biology Laboratory Assistant

5% Warehouse Specialist

9% Administrative staff

15% Technical staff incl. infrastructure

Scientists’ Disciplines

Vocational Training Disciplines

Distribution of Staff by Area of Work

76% Scientists

4% Epidemiology / Nutritional Sciences / Health Sciences

1% Geology / Geophysics / Geoecology

40% Biology / Biotechnology / Agricultural Biology

5% Engineering

5% Mathematics

7% Other Disciplines

7% Medicine

10% Physics / Biophysics

15% Chemistry / Biochemistry

2% Veterinary Medicine

4% Informatics

102

For the fiscal year 2009, the overall budget of Helmholtz Zentrum München amounted to

159.9 million euros, with 114.2 million euros coming from institutional funding provided

by the German Federal Government and the Bavarian State Government at a ratio of 90:10.

The remaining part of the budget consisted of third-party grants of national and interna-

tional origin which were acquired by the Center for specific projects.

Finances

Total funding according to the 2009 budgetTotal €159.86 m

€12.10 m Investments, construction < €2.5 m

€11.26 m Grants / subsidies

€47.12 m Material costs

€15.48 m Investments, construction > €2.5 m

€73.9 m Personnel costs

103 Finances

Institutional funding according to the 2009 budgetTotal €114.19 m

Third-party funding according to source 2009Total €41.5 mthereof special tasks €7.8 m and research tasks €33.7 m

Totals reflect values as of: June 6, 2010

€8.42 m Investments, construction < €2.5 m

€6.26 m Grants / subsidies

€28.13 m Material costs

€15.48 m Investments, construction > €2.5 m

€55.9 m Personnel costs

* does not contain the specially financed share (€1.95 m) of start-up funding for the German Diabetes Center (DDZ)

€3.1 m Other (national)

€1.3 m Industry (national)

€4.9 m German Research Foundation (DFG)

€0.3 m State government project funding

€12.8 m Federal government project funding *

€4.0 m Other (international)

€0.5 m Industry (international

€6.8 m European Union

104

Project Funding

Helmholtz Zentrum München successfully participates in grant competitions of the Fed-

eral Ministry of Education and Research, the European Research Framework Programme,

the German Research Foundation, the Helmholtz Association of German Research Centres

and other public and private institutions. In 2009, grant acquisition reached an all-time

high. Grants from the Federal Government were highest with 12.8 million euros, followed

by 6.8 million euros in grants from the European Union and 4.9 million euros from the

German Research Foundation (DFG).

In 2009 Helmholtz Zentrum München had more than 350 third-party grant contracts for re-

search projects amounting to a total of 33.7 million euros. This corresponds to approximate-

ly 30 percent of the institutional funding. For the founding phase of the German Center for

Diabetes Research (DZD), coordinated by Helmholtz Zentrum München, the German Fed-

eral Ministry of Research and Education is providing additional start-up financing totaling

1.95 million euros.

As of the end of the year 2009, Helmholtz Zentrum München has participated in more

than 210 grant applications in the 7th Framework Programme (FP7) of the European Com-

mission. To date, 56 projects with EU funding amounting to almost 30 million euros have

been approved for the Center. Along with GOODWATER, the Center meanwhile coordinates

an additional Initial Training Network on the topic of chemoinformatics (ECO). Dr. Heiko

Lickert of the Institute of Stem Cell Research received 1.5 million euros in funds from the

European Research Council (ERC). With the ERC Starting Grant, Lickert will establish a

research group to investigate the causes of ciliopathies. Helmholtz Zentrum München is

partner in two projects of the “Innovative Medicine Initiative (IMI)”, a joint technology ini-

tiative of the European Commission and industry (JTI). The question at issue here, among

other things, is the identification and epidemiological validation of biomarkers for second-

ary diseases of type 1 and type 2 diabetes mellitus.

A study conducted by the Center for European Economic Research (ZEW) substantiates

the strong position of the Center in the funding of the 6th Framework Program of the EU:

With 60 participations, Helmholtz Zentrum München takes first place among the Helmholtz

centers focused on health research and ranks 28th in the “top hundred” list of German part-

ners with the most project participations.

In addition, Helmholtz Zentrum München successfully takes part in various programs

of the Federal Ministry of Education and Research (BMBF), through which it was able to ac-

quire important collaborative research projects in 2009:

– In the program “Application-oriented Systems Biology SysTec”, histological and mass

spectrometry analyses of cells and tissues are performed (total funding 1.9 million

euros).

105 Project Funding

In 2009 the Center received 5.6 million euros from the

Initiative and Networking Fund (IVF) of the Helmholtz

Association of German Research Centres. After deduc-

tion of all funds forwarded to project partners, 3.24 mil-

lion euros remained at the Center. By far the largest

share of the money went to the three Helmholtz Allianc-

es. In addition, three Helmholtz junior research groups,

two virtual institutes, two endowed W2/W3 professor-

ships for excellent women scientists and two spin-off

companies were funded by the IVF in 2009.

– In the medical network “Systems Biology of Metabotypes” (SysMBO), research focus-

es on the characterization of metabolic profiles to gain information on health status

through analyses of serum and tissue samples (2.7 million euros).

– In the field of personalized medicine, new diagnostic and prognostic markers for medi-

cal diagnosis and therapy are identified in the network “GANI-MED” (0.6 million euros).

– With its technology platform “Bioinformatics and Sequencing”, the Center participates

on a large scale in the competence network in agricultural and nutrition research with-

in the network “SynBreed – Synergistic Plant and Animal Breeding” (3.1 million euros).

– The HOPE project focuses on the evaluation of an assay to determine the development

of hepatitis B virus resistance (0.9 million euros).

Through the coordinated programs of the German Research Foundation (DFG), Helmholtz

Zentrum München has established close regional networks in the health sector with the

two Munich universities and the Max Planck Institutes of Biochemistry and Neurobiology.

With a total of 31 individual projects, the Center – together with Ludwig-Maximilians-Uni-

versität Munich and Technische Universität München – is involved in nine collaborative

research centers (German abbreviation: SFB) and Transregional Collaborative Research

Centers (Transregio). Munich thus plays a leading role, along with Berlin, as a cluster loca-

tion for research in Germany.

Funding Programs (DFG) Projects

6 Collaborative Research Centers (SFB) and 3 Transregios 31

6 Priority Programs 10

5 Research groups 7

Leibniz Prize 1

Emmy Noether 1

EURYI Award 1

Individual funding 36

International Cooperations

In October 2009 an official ceremony took

place marking the tenth anniversary of

cooperation with the U.S. Environmental

Protection Agency (EPA) to investigate

the effects of fine and ultrafine particles.

The current focus of the cooperation is to

study the short-term effects of fine par-

ticulate on cardiac function in patients

with diabetes. In the course of the reorga-

nization of the Institute of Lung Biology

and Disease, research collaborations

in the area of “Immunology, Hematol-

ogy, Pneumology” were prepared with

the INSERM Institute in Paris and the

UPMC in Pittsburgh, PA USA.

€2.343 m Helmholtz Alliances

€0.236 m Helmholtz Junior Research Groups

€0.222 m Cooperation with Universities – Virtual Institutes

€0.170 m W2 / W3 professorships for female scientists

€0.167 m Spin-off companies

€0.104 m Funding of doctoral students

106

Helmholtz Zentrum München – German Research Center for Environmental Health is a

research institution of the Federal Republic of Germany and the Free State of Bavaria.

The partners of Helmholtz Zentrum München are the Federal Republic of Germany, repre-

sented by the Federal Minister of Education and Research, and the Free State of Bavaria,

represented by the Bavarian State Minister of Finance. The Center has existed since 1960

and since 1964 under the legal form of a GmbH (German limited liability company).

The bodies of Helmholtz Zentrum München are the Assembly of Partners, the

Supervisory Board, and the Board of Directors. On scientific questions, Helmholtz Zentrum

München is advised by the Scientific Advisory Board, which consists of external members.

Organization

As of: June 2010

As of: June 2010

Members of the Board of Directors

Prof. Dr. Günther WessCEO and President

Members of the Supervisory Board

MinDir’in Bärbel Brumme-Bothe– Chair – Federal Ministry of Education and Research – until May 13, 2010 MinDir Dr. Peter Lange (Federal Ministry of Education and Research)

Ltd. MinR Dr. Michael Mihatsch– Vice Chair – Bavarian State Ministry of Sciences, Research and the Arts – until May 11, 2010 MinDirig. Dr. Adalbert Weiß (Bavarian State Ministry of Sciences, Research and the Arts)

MinR Klaus HerzogBavarian State Ministry of Finance

Members of the Scientific Advisory Board

Prof. Dr. Hillel Koren – Chair since January 1, 2010 – UNC Institute for the Environment, Durham, North Carolina, USA

Prof. Dr. Steve BrownMRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, UK

Prof. Dr. Karl-Heinz JöckelInstitute of Medical Informatics, Biometry and Epidemi ology at the University Hospital of Essen

Prof. Geoffrey J. Laurent Centre for Respiratory Research, Department of Internal Medicine, Division of Medicine, Rayne Institute, University College London

MinDirig Dr. Karl Eugen HuthmacherFederal Ministry of Education and Research– until June 24, 2010

RD Ulrich Schäffler Federal Ministry of Education and Research– until February 23, 2010

MinR Dr. Axel VorwerkFederal Ministry of Education and Research – from June 24, 2010

Dr. Martin SchölkopfFederal Ministry of Health

Dr. Nikolaus BlumCFO

PD Dr. Arnd Kieser Gene Vectors Department (AGV), Helmholtz Zentrum München

Prof. Dr. Peter SchröderDepartment of Microbe-Plant Interactions (AMP), Helmholtz Zentrum München

Prof. Dr. Ruth Brack-WernerInstitute of Virology (VIRO), Helmholtz Zentrum München

Prof. Edward H. LeiterThe Jackson Laboratory, Bar Harbor, Maine, USA

Prof. Dr. Urban LendahlDepartment of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden

Prof. Stephanie J. LondonNational Institute of Environmental Health Sciences, Epidemiology, Genetics, Environment & Respiratory Disease Group, Research Triangle Park, North Carolina, USA

Prof. David B. PedenCenter for Environmental Medicine, Asthma Lung Biology, Department of Pediatrics, Medicine and Microbiology / Immunology, School of Medicine, University of North Carolina, Chapel Hill, USA

Prof. Dr.Ir. L.A. Peletier Emeritus, Institute of Mathematics, Leiden University, the Netherlands

Dr. Manfred RösnerSanofi-Aventis Deutschland GMBH, Frankfurt am Main

Prof. Sisko Salomaa STUK, Radiation and Nuclear Safety Authority, Research and Environmental Surveillance, Helsinki, Finland

Prof. Hans Thordal-ChristensenDepartment of Plant Biology and Biotechnology, Frederiksberg, Denmark

Prof. Bernhard WehrliETH Zurich, Institute for Biogeochemistry and Pollutant Dynamics, Zurich, Switzerland

The Helmholtz Association

The Helmholtz Association of German Research Centres is Germany’s

largest scientific organization. It consists of 16 scientific-technical and

medical-biological research centres which combine their resources to

investigate complex problems of social, scientific and technological

relevance.

The main objectives of the Helmholtz Association are:

– to make substantial contributions to basic scientific issues and,

through excellent research, to assume a leading position in all

research areas

– to investigate complex scientific, social and economic issues

with a holistic approach and to offer appropriate system solutions

– to identify and implement solution strategies from theory to

application

– to develop methods, technologies and services and to advise

decision-makers in politics and society

– to contribute significantly to the effectiveness and standing of the

entire scientific system in Germany

Research Institutes and Departments and joint appointments with Ludwig-Maximilians-Universität (LMU) Munich

and Technische Universität München (TUM)

Imprint

PROGRAM ENVIRONMENTAL HEALTH: Institute of Epi-

demiology (EPI) Director: Prof. Dr. Dr. H.-Erich Wichmann

Chair of Epidemiology, Ludwig-Maximilians-Universität

Munich [email protected] Institute of

Epidemiology 2 (EPI2) Prof. Dr. Annette Peters peters@

helmholtz-muenchen.de Dept. of Gene Vectors (AGV) Head:

Prof. Dr. Wolfgang Hammerschmidt hammerschmidt@

helmholtz-muenchen.de Institute of Health Economics and

Health Care Management (IGM) Director: Prof. Dr. Reiner

Leidl Chair of Health Economics and Health Care Manage-

ment, Ludwig-Maximilians-Universität Munich leidl@

helmholtz-muenchen.de Institute of Clinical Molecular

Biology and Tumor Genetics (KMOLBI) Director (acting):

Prof. Dr. Wolfgang Hammerschmidt hammerschmidt@

helmholtz-muenchen.de Institute of Lung Biology (iLBD)

Director: Prof. Dr. Oliver Eickelberg Chair of Experimen-

tal Pneumology, Ludwig-Maximilians-Universität Munich

[email protected] Institute of

Molecular Immunology (IMI) Director: Prof. Dr. Dolores

Schendel [email protected] Institute of

Pathology (PATH) Director: Prof. Dr. Heinz Höfler Chair of

General Pathology and Pathologic Anatomy, Technische

Universität München [email protected] In-

stitute of Radiation Biology (ISB) Director: Prof. Dr. Michael

Atkinson Chair of Radiation Biology, Technische Universi-

tät München [email protected] Institute

of Radiation Protection (ISS) Director (acting): Dr. Peter

Jacob [email protected] Dept. of Medical

Radiation Physics and Diagnostics Head: Prof. Dr. Chris-

toph Hoeschen christoph.hoeschen@helmholtz-muenchen.

de Dept. of Radiation Cytogenetics Head (acting): Prof. Dr.

Horst Zitzelsberger zitzelsberger@helmholtz-muenchen.

de Institute of Toxicology (TOXI) Director: Prof. Dr. Martin

Göttlicher Chair of Toxicology and Environmental Hygiene,

Technische Universität München martin.goettlicher@helm-

holtz-muenchen.de Institute of Toxicology | Dept. of Cellular

Signal Integration (AZS) Head: PD Dr. Daniel Krappmann

[email protected] Institute of

Virology (VIRO) Director: Prof. Dr. Ulrike Protzer Chair of

Virology, Technische Universität München protzer@helm-

holtz-muenchen.de PROGRAM SYSTEMIC ANALYSIS OF

MULTIFACTORIAL DISEASES: Institute of Bioinformatics

and Systems Biology (IBIS) Director: Prof. Dr. H.-Werner

Mewes Chair of Genome-Oriented Bioinformatics, Techni-

sche Universität München w.mewes@helmholtz-muenchen.

de Institute of Biological and Medical Imaging (IBMI) Di-

rector: Prof. Dr. Vasilis Ntziachristos Chair of Biological

Imaging, Technische Universität München v.ntziachristos@

helmholtz-muenchen.de Institute of Biomathematics and

Biometry (IBB) Director: Prof. Dr. Rupert Lasser Chair of

Biomathematics, Technische Universität München lasser@

helmholtz-muenchen.de Institute of Biomathematics and

Biometry | Dept. of Scientific Computing (ASC) Head: Dr.

Wolfgang Graf zu Castell- Rüdenhausen castell@helm-

holtz-muenchen.de Institute of Developmental Genetics

(IDG) Director: Prof. Dr. Wolfgang Wurst Chair of Develop-

mental Genetics, Technische Universität München wurst@

helmholtz-muenchen.de Dept. of Zebrafish Neurogenetics

(ZEN) Head (acting): Prof. Dr. Wolfgang Wurst wurst@

helmholtz-muenchen.de Institute of Experimental Gene-

tics (IEG) Director: Prof. Dr. Martin Hrabe de Angelis Chair

of Experimental Genetics, Technische Universität München

[email protected] Institute of Experimental

Genetics | Genome Analysis Center (GAC) Head: Prof. Dr.

Jerzy Adamski [email protected] Insti-

tute of Human Genetics (IHG) Director: Prof. Dr. Thomas

Meitinger [email protected] Chair of

Human Genetics, Technische Universität München Dept.

of Protein Science (PROT) Head: Prof. Dr. Marius Ueffing

[email protected] Institute of Stem

Cell Research (ISF) Director: Prof. Dr. Magdalena Götz Chair

of Physiological Genomics, Ludwig-Maximilians-Universi-

tät Munich [email protected] In-

stitute of Structural Biology (STB) Director: Prof. Dr. Michael

Sattler Chair of Biomolecular NMR Spectroscopy, Techni-

sche Universität München [email protected]

Dept. of Comparative Medicine (AVM) Head: Prof. Dr. Jörg

Schmidt [email protected] Institute

of Diabetes Research Type 1 Director: Prof. Dr. Anette-

Gabriele Ziegler anette-g. [email protected]

PROGRAM TERRESTRIAL ENVIRONMENT: Institute of Bio-

chemical Plant Pathology (BIOP) Director: Prof. Dr. Jörg

Durner Chair of Biochemical Plant Pathology, Technische

Universität München [email protected]

Institute of Biochemical Plant Pathology | Dept. of Expe-

rimental Environmental Simulation (EUS) Head (acting):

Dr. Jana Barbro Winkler bwinkler@helmholtz-muenchen.

de Institute of Soil Ecology (IBOE) Director: Prof. Dr.

Jean Charles Munch Chair of Soil Ecology, Technische

Universität München munch@helmholtz- muenchen.de

Institute of Soil Ecology | Dept. of Terrestrial Ecogenetics

(TEG) Head: Prof. Dr. Michael Schloter schloter@helm-

holtz-muenchen.de Institute of Groundwater Ecology

(IGOE) Director: Prof. Dr. Rainer Meckenstock Chair of

Groundwater Ecology, Technische Universität München

[email protected] Microbe-

Plant Interactions Dept. (AMP) Director: Prof. Dr. Anton

Hartmann [email protected] In-

stitute of Ecological Chemistry (IOEC) Director (acting): Dr.

Sigurd Schulte-Hostede [email protected]

Institute of Ecological Chemistry | Dept. of Biogeochemistry

and Analytics (BGCA) Head: PD Dr. Dr. Philippe Schmitt-

Kopplin [email protected] Insti-

tute of Ecological Chemistry | Cooperation Group Analysis

of Complex Molecular Systems (KMS) Head: Prof. Dr. Ralf

Zimmermann [email protected]

As of: June 2010

ISSN 0941-3847

Excerpts from the articles in this publication may be reproduced without further permission, provided that Helmholtz Zentrum München – German Research Center for Environmental Health is mentioned. All other rights are reserved.

© Helmholtz Zentrum München 2010

Published byHelmholtz Zentrum MünchenGerman Research Center for Environmental HealthIngolstädter Landstr. 185764 NeuherbergGermanyPhone: +49 (0)89 3187-0Fax: +49 (0)89 3187-3324www.helmholtz-muenchen.de

Editorial OfficeCommunications DepartmentSven Winkler, Cordula Klemm,Dr. Brigitte [email protected]

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Helmholtz Zentrum MünchenGerman Research Center for Environmental Health

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