Biotechnology in Bavaria by media mind GmbH & Co. KG

Biotechnology in Bavaria

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Editorial Bavaria’s biotechnology is world-renowned With its comprehensive research network and its award-winning leading-edge projects, Bavaria plays an important role in the area of bio technology. A whole host of significant awards can be documented such as the „Young Investigator Award“, the „Dr. Josef Steiner cancer research prize“, as well as sponsorship amounting to eight million US dollars for the development of a vaccine against AIDS. From there, synergies for research and development in the economy and industry have been derived. What conventional therapies are possible in the treatment of degenerative diseases? Who develops and markets biopharmaceutical therapeutic agents for oncology and transplant medicine?

Why is a centre for metastasis research so vitally important? What possibilities does EU research funding offer to scientists and entrepreneurs? A whole host of multisided, fascinating topics taking us to new levels of knowledge!

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What does the innovative RNA-seq service bring to life development and conservation? Which discoveries, based on human embryos, cannot be patented? Where is the meeting point for lab technology, analysis and biotechnology? What opportunities and risks does green gene technology pose?

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munich biotech CLUSTER m4 Editorial Advert

Bayern Innovativ GmbH Summary Prof. Dr. Horst Domdey CAMPUS MARTINSRIED

2. CP 3 6 7 8

Der Life Science Campus Martinsried – TOP site for life sciences Contact: Dr. Peter Hanns Zobel Table of contents: P. 12

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IMGM LABORATORIES BioRegio Regensburg

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Regensburg – at the head of the Danube Author: Dr. Thomas Diefenthal, CEO BioPark Regensburg GmbH

IGZ

Würzburg

Table of contents

IGZ Würzburg – where knowledge becomes business Contact: Klaus Walther, Dr. Christian Andersen, Dr. Gerhard Frank

Bavarian Research Cooperations

Bavarian Research Cooperations Contact: Anita Schneider Bavarian Research Alliance (BayFOR)

Biopharmaceuticals

Effektive antibody therapies Contact: Fresenius Biotech GmbH

EU research funding

EU research funding for biotechnology projects Author: Dr. rer. nat. Iana Parvanova Bavarian Research Alliance (BayFOR)

Bavarian Genome Research Network The Bavarian Genome Research Network: A special support program shows success Authors: Dr. U. Kaltenhauser, M. Sc. C. Szeibert, Bavarian Genome Research Network

Innovation

Where innovation is born Author: Prof. Dr. Peter Buckel, Geschäftsführer SuppreMol GmbH

Ribonucleic acid (RNA)

VERTIS innovative RNA-seq Service Contact: Dr. Fritz Thümmler, Vorstand vertis Biotechnologie AG

Messe

München

analytica 2012 Gathering for innovations Author: Susanne Grödl Messe München GmbH

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Bavarian Research Alliance

Patent Law

59 60

No patent protection for inventions that rely on human embryos Authors: Dr. Franz Josef Zimmer, Dr. Benjamin Quest Grünecker Kinkeldey Stockmair & Schwanhäusser

BioSysNet

The Bavarian Center for Molecular Biosystems Authors: Prof. Dr. Patrick Cramer, Dr. Ulrike Kaltenhauser Gene Center, LMU München

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Forschungsverbund

FORPLANTA

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FORPLANTA – harvest in times of climate change Authors: Prof. Dr. J. Soll, Bio Center, LMU München Dr. Ulrike Kaltenhauser, Gene Center, LMU München

Personalized

tumor therapy

Establishing a Centre for Metastasis Research in Bavaria Author: Prof. Dr. Christoph Klein, Lehrstuhl für Experimentelle Medizin und Therapieverfahren

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GRÜNECKER

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... encountering the future. Bayern Innovativ GmbH Gewerbemuseumsplatz 2 90403 Nuremberg Germany

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info@bayern-innovativ.de www.bayern-innovativ.de

Today ' s knowledge for tomorrow ' s innovations

Strong partners make for a strong network “Success through synergies” is the guiding principle behind

Federal Government, the Free State of Bavaria and industry,

the Bavarian Cluster Initiative, where companies belonging to

which is channelled into separate cooperative research pro-

one segment of an industry regard themselves, not as com-

jects, as well as into infrastructural measures, for example, the

petitors, but as mutual beneficiaries, for example through

new consortium of tissue banks, the Munich-Biobank-

trustful cooperation (open innovation), through a shared

Alliance.

market or through a pool of highly qualified personnel. Most of these effects are favoured by spatial proximity, so, as a rule,

Equally successful in the Leading-Edge Cluster Competition

a “single cluster” is delimited in terms of its location, for

was Nuremberg-Erlangen, a Centre of Excellence for Medical

example, to one city. Combining various clusters into a net-

Technology that is able to use to its advantage a tight network

work can be especially successful, as demonstrated by the

linking science, business, hospitals and care facilities along

Bavarian biotechnology industry, which received support

with the innovative strength of the SMEs.

from the Bavarian Ministry of Economic Affairs between the years 2006 and 2011 as part of the “Bavarian Biotechnology Cluster”.

Deserving a special mention in the field of medical technology is once again the Regensburg region, which is a particularly shining example, not only of interdisciplinary cooperati-

One of the initial successes of the “Bavarian Biotechnology

on between medical technology and the biotechnology

Cluster” was its function as a “catalyst” for white, i.e. industri-

companies in the Regensburg BioPark, but also of innovative

al, biotechnology. Bavaria’s strategically completely new

developments from seemingly remote fields such as the tex-

white biotechnology initiative was able to raise funding in the

tile and glass industries.

order of millions from the federal and state governments and this led to the foundation of a specific network of companies

Wurzburg has successfully established itself as a Centre of

and research institutes with their own network coordination.

Excellence for biomedical research and Bayreuth is strong in

At various locations, and especially in Straubing, there are

the field of materials research, as well as scoring highly with

deliberate efforts to promote a large variety of projects devo-

interesting discoveries in the biology of photosynthesis and

ted to industrial applications, for example, in the field of

its technical exploitation.

renewable raw materials. With the injection of funds from the Bavarian Ministry of Red pharmaceutical biotechnology is still networked within

Economic Affairs, a great deal has been achieved and a lot of

the “Bavarian Biotechnology Cluster” and headed by BioM

wheels have been set in motion. To make sure they continue

Biotech Cluster Development GmbH, which coordinates the

rolling, the “Bavarian Biotechnology Cluster” will go on being

well developed Bavarian BioRegions of Munich-Martinsried

promoted as a network in future. Each location contributes

and Regensburg as well as the up-and-coming locations of

its own individual strengths to this network and can profit

Nuremberg-Erlangen, Wurzburg and Bayreuth. In the last

from its combined efforts, with BioM GmbH serving as a cen-

few years, each of these locations has developed its own

tral point of exchange and contact. I am convinced that the

unique profile with specific on-site core competences.

success of each separate local player impacts positively on the entire network and that we are well positioned to continue

Munich has concentrated on drug development for many

down the road to success that we have taken together.

decades and in 2010 sharpened its profile in the field of “personalised medicine” even further by winning an award in the “Leading-Edge Cluster Competition“ held by the German Federal Ministry of Education and Research. Under the title “m4 – Personalised Medicine”, this major investment project attracts funding to a total of almost € 100 million from the

Prof. Dr. Horst Domdey Speaker of the „Bavarian Biotechnology Cluster“

Der Life Science Campus Martinsried – TOP Standort für Life Sciences The integration of science, economy and society is growing in importance, which is true especially in the area of biological basic research. In the long term this means for the field of biological sciences that only those sites will prosper, which can provide and effectively support the contacts and translation between basic research and application. This does not only require money, but above all short distances and the possibility of personal interaction - fast and uncomplicated. Today, the Life Science Campus Martinsried is one of the largest centers in Europe in which basic research, education, clinical research and technological innovation are combined in one campus. Located in close proximity are institutes of the Ludwig Maximilians University (LMU) Munich, the Max Planck Institute of Biochemistry, the Max Planck Institute of Neurobiology and the Innovation Center for Biotechnology (IZB). The campus provides exceptional conditions for students and scientists, as well as an economic benefit to the region through the regular establishment of spin-off companies from the basic research.

CAMPUS MARTINSRIED

Basic Research at the Highest Level In 1973, the creation of the Max Planck Institute of Biochemistry (MPIB) was the foundation stone for the Life Science Campus Martinsried which today has a worldwide reputation. With about 850 employees from approximately 45 different nations, the MPIB is one of the largest biomedical research institutions of the Max Planck Society. In currently eight large research departments and about 25 research groups, the MPIB basic scientists work in the fields of biochemistry, cell biology, structural biology, biophysics and molecular medicine. Living cells are highly complex formations in which a multitude of molecules work together to make our organism function. Without proteins, this would be inconceivable: They coordinate the mechanisms of the cell by implementing

Max-Planck-Institut für Biochemie Martinsried (Foto: Max Schreder / ©MPIB)

the information contained in the genes into cellular processes and structures. Proteins give cells their shape and they are the main protagonists in all cellular processes – whether they transport substances, convey messages or carry out vital processes in their role as molecular machines. What decides which genes are translated into proteins? How do proteins regulate highly complex cell processes and how do cells communicate with each other? Which control mechanisms are

effective in these processes and what happens when errors are made? All these are questions which the scientists of the MPIB are seeking to answer. To elucidate the rules of cell division and specialization and to understand how cells fulfil their tasks in the body, the scientists are investigating the structure and function of the involved molecules. The size of the “study subjects” ranges in scale from the individual molecule and the cell up to the entire tissue and the organism. Biomedical basic research is likewise an important aspect, because disturbances of cellular signal transduction or abnormal protein structures lead to diseases such as cancer, diabetes or Alzheimer’s. Deeper insights into the cellular mechanisms and structures also help to better understand the pathogenesis of these diseases and to develop new therapy strategies.

For their analyses, the researchers use a broad spectrum of ultramodern methods partly developed directly at the MPIB. The methodological expertise, which has increased over the years and which covers all of the research areas of the Institute, is a particular strength of the MPIB and is what makes the implementation of research projects possible at all. In particular, new methods in electron and light microscopy and mass spectrometry offer unimagined opportunities for gaining insights into cells. An example: scientists of the institute have recently identified the genetic switch that regulates the formation of flight muscles in fruit flies. (Nature, November 17th 2011).

vous system, and (4) the processes in the case of illness of the nervous system such as the multiple sclerosis. The scientists’ work thereby often borders directly on the limits of the known knowledge. To extend this knowledge is the aim of the approximately 250 employees of the institute. The mainstays of the institute are the four departments which are complemented by eight independent research groups with wideranging focal points. The departments and research groups work closely together in overlapping projects. Among others, the institute’s scientists are especially skilled in the development of optical methods for the investigation of neural activities.

Max Planck Institute of Neurobiology in Martinsried (Photo: R. Schomer/MPIN)

Flies are excellent flyers. However, without the gene spalt they stay on the ground and walk. Picture: Frank Schnorrer / Copyright: MPI of Biochemistry

Since 1984, the Max Planck Institute of Neurobiology (MPIN) has been situated in close proximity to the Max Planck Institute of Biochemistry. Acknowledged for a long time now as an international top institution in the field of neurobiology, the MPIN researchers investigate the development and the basic functions of the brain and the nervous system. The work focuses on the slightest changes of nerve cells as well as the formation and interconnection of complex neural networks. Special emphasis is laid on (1) the structural changes of the brain when it learns or forgets, (2) the processing of optical information, (3) the molecular mechanisms in the developing ner-

Accordingly, the development of genetically encoded indicators as well as the further development of microscopic techniques are an important part of the work. The MPIN scientists identified for instance aggressive cells of the immune system with the Green Fluorescent Protein (GFP) and thus observed for the first time the invasion of these cells into the brain “live” under the microscope. The knowledge gained from this investigation gives a completely new insight into the basic process of multiple sclerosis (Nature, October 14, 2009). Other scientists, such as those working in the emeritus group of the Nobel Prize winner Prof. Bert Sakmann, intend to portray each of the thousands of connections between nerve cells in three dimensions with the help of a revolutionary microscopic technology. The MPIN scientists are also very successful in other research areas. They were able

to show for instance that an essential process for the regeneration of mature nerve cells in the brain and the spinal cord remains available (Science, January 7, 2009). Another study showed that the brain only inactivates currently unused contacts between nerve cells and keeps them so to say “in reserve”, which clearly facilitates the recalling of forgotten memory contents (Nature, November 12, 2008). Although applied research is not a primary aim of the work, a series of discoveries made in the institute have been tested for their clinical relevance. In this way, the new knowledge has some influence on the development of new therapies, for instance with regard to damage of the nervous system due to paraplegia, multiple sclerosis or Parkinson’s disease. In addition, the scientific results can facilitate the development of analytical tests up to prostheses. And even robotics has profited from the institute’s research which has supplied important circuit diagrams based on simple but efficient circuits in the brain of the fly. As a guarantee for first-class basic research in life sciences, the two Martinsried Max Planck Institutes

Computer reconstruction of the life pictures showing how marked T-cells (green) leave a blood vessel (red) and enter the neural tissue (blue). (MPIN/Bartholomäus)

have provided the impetus for the establishment of further institutes over the last decades. Today, the Campus Martinsried stands for unique research cooperation between the local institutes, whose interdisciplinary approaches are an essential component of the site‘s innovation potential.

The Life Science Campus Martinsried/Großhadern (IZB mbH & Bertram aerial picture publishing house)

Research and teaching at the university of excellence Biology is the leading science of the 21st century and has central contact functions with other areas in the LMU such as medicine, physics and chemistry. Due to the rapid development in the biosciences during the last decade, it is now possible to examine the life processes in their complexity, from molecular details up to the general understanding of complex processes in their entirety. It was therefore just logical to establish the biology faculty of the Ludwig-Maximilians-Universität München (LMU) in a bio-center in Martinsried. Technologically, and with regard to research the Biology I and II Departments have taken an early lead position so that they can maintain their hold at a national and international competitive level and are able to consolidate this position in the future. They combine areas of science which provide for an overlapping, interdisciplinary research and a comprehensive and modern training of students. The emphasis in research ranges from the elucidation of molecular structures and performances of microorganisms (prokaryotes and

eukaryotes), the evolution and function of organelles, autotrophic organisms (plants) up to the vertebrates including man. The organismic biology concentrates on the structural

Das Biozentrum der LMU Martinsried (© LMU)

and ecological variety of all organisms as well as the speciation principles. A further central position is occupied by neurobiology which integrates systemic (organismic) and theoretical formulations. The areas with orientation toward ecological and evolutionary biology focus on the research of population genetics which is governed by theory and hypotheses, evolutionary and aquatic ecology as well as behavioral ecology. In the context of educational research, the didactics of biology refer to the different areas of biology. Finally, all Bavarian national scientific collections with biological

orientation and the Botanic Garden in Munich are in close contact with the faculty. High-ranking interdisciplinary institutions, special research areas as well as excellence institutions such as a graduate school in the Munich Center for Computational Neuroscience (MCN) or the Bernstein Center for Computational Neuroscience (BCCN*) show that today good integration is a sustainable factor for a site. In September 2011 the construction of a Biomedical Center (BMC) unique in Europe, has been started. Here, the LMU explains, a „starting point will be created for an overall identity for teaching and research of biomedicine at the University Munich“. Importance will be attached to largescale public areas with lots of green. This alignment is the best prerequisite for a new generation of qualified academics and new inventions. 500 people will work there on 18,000 sqm *

BCCN: a “national network for computational neuroscience” supported by the Federal Ministry of Education and Research; it consolidates and integrates the capacities available in Germany in the area of experimental and theoretical neuroscience to promote new research impulses.

Haupteingang IZB Martinsried

Turning research results into business results - an essential criterion for the economy Back in the 90s, the Bavarian State Government recognized early that the biosciences would play a key role in the 21st. century. By establishing the Innovation and Founding Center for Biotechnology (IZB) on the science campus between Martinsried and Grosshadern, a Munich neighborhood in 1995, as well as on the science campus of Freising-Weihenstephan, exceptional conditions for young entrepreneurs and company founders in the life-sciences sector have been developed. Excellent building infrastructures (high-standard laboratories) at reasonable rents are found in a lifescience competence cluster. For over 15 years, the turning of product and service ideas into viable businesses has been supported here. Scientists whose research results, on the one hand, no longer fall into the basic research category and, on the other hand, are not yet ripe for the market can begin their work here immediately while having access to great experience and networks. Communication lines on both spots are known to be short, which makes it especially

High-standard laboratory in IZB © IZB GmbH

attractive to all involved. Since 1995, the IZB GmbH (a limited liability company) has accompanied over one hundred company start-ups. Since the completion of West II in Martinsried, the IZBs at both locations have grown to approx. 75 square feet of office and lab space each. The Elhardt School of Chemistry, which is also located in West II, has been creating a new path of opportunity since 2010. Students here receive practice-oriented training in the technical assistant professions.

IZB Weihenstephan (Photo: Hr. Martin)

Together with the BioKids day-care center, the Freshmaker cafe and meeting place has already set another standard since 2002. A new flagship project, which will take the future of the IZB Campus in a new direction, is the approval of a boardinghouse. The seven-storey building containing 42 rooms and its own cuisine is designed to offer guest scientists from all over the world an attractive and comfortable place to stay, close to their workplace. This has become necessary since the growing number of institutions around the IZB has become more and more important. The Faculty Club on the top floor will form the heart of the building, where scientists, company managers and other

partners can meet regularly in a relaxed atmosphere to discuss research results, developments and possible projects. The goal is to promote cooperation as well as encourage turning research results into business results, which in turn leads to the creation of new jobs. Another piece of good news is that by 2017 the subway No.6, „Science Line“ will commute between the Martinsried Campus and the campus in Garching. Current developments at IZB firms show that bringing medical research to market needs time and money but also prove that a flexible infrastructure and programmes as the actual ‚m4 – Personalized Medicine and Targeted Therapies‘ programme promote medical progress and are having beneficial effects. Mehr zu allen Campuseinrichtungen unter: www.campusmartinsried.com

Contact: Dr. Peter Hanns Zobel

Fördergesellschaft IZB mbH

Am Klopferspitz 19 D-82152 Martinsried phone.: +49 (0)89 700 65 670 fax: +49 (0)89 700 65 677 E-mail: info@izb-online.de Internet: www.izb-online.de

Content Categories Biotechnology in Bavaria 2012/2013 Agro, Food, Environment aromaLAB AG Hans-Dieter-Belitz-Institut

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Bioinformatics gimbio mbH quattro research GmbH

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Biotech Consulting & Service Adriacell SpA ATRES Group BioM Biotech Cluster Development GmbH BioM WB GmbH DPC Pharma Consulting/ BioMedPartners Venture Partner FROST LIFESCIENCE Patentquadrat RSA Consulting GmbH that’s it gmbh THE WORKING GROUP VELUMETRIX GmbH

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Biotech Consulting & Training Chemieschule Dr. Erwin Elhardt

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Biotech Devices & Reagents Biontex Laboratories GmbH ibidi GmbH LEUKOCARE AG Menlo Systems GmbH SIRION Biotech GmbH

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Biotech Environment, Instruments Umwelt-Geräte-Technik GmbH

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Biotech Preclinical Services Coriolis Pharma PhaToCon Smart Move GmbH

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Biotech Therapeutics & Diognostics 4SC AG amYmed GmbH Bernina Plus GmbH conoGenetix biosciences GmbH DoNatur GmbH ELLA Biotech GmbH eticur) GmbH Euroderm GmbH Evotec Exosome Diagnostics GmbH GENidee Omegametrix GmbH origenis GmbH Pieris AG R&D-Biopharmaceuticals GmbH SiNatur GmbH SuppreMol GmbH XL-protein GmbH

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DNA/Protein Analytics ChromoTek GmbH TRION Research GmbH vertis Biotechnologie AG

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Drug Discovery Service CRELUX GmbH

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Tissue Engineering Bayerische Gewebebank GmbH

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Industrial Biotech AMSilk GmbH

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Medtech EKFS Herzchirurgie SMARTEC IngenieurB端ro GmbH

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Personalized Cancer Therapy SpheroTec GmbH

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Pharma & Chemical Industrie Fresenius Biotech GmbH NanoScape AG PhaToCon

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Venture Capital VC Vesalius Biocapital

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Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

14 Biotech Therapeutics & Diagnostics

Drug discovery and development focused on autoimmune and cancer indications 4SC (ISIN DE0005753818) discovers and develops targeted small-molecule drugs for the treatment of diseases with a high unmet medical need in various autoimmune and cancer indications. These drugs are intended to provide patients with innovative treatment options that are more tolerable and efficacious than existing therapies, and provide a better quality of life. The company's balanced pipeline comprises promising products in advanced stages of clinical development. 4SC's aim is to generate future growth and enhance its enterprise value

by entering into partnerships with leading pharmaceutical companies. Founded in 1997, 4SC currently has 94 employees and has been listed on the Prime Standard of the Frankfurt Stock Exchange since December 2005. Contact: 4SC AG, Am Klopferspitz 19a in IZB 82152 Planegg-Martinsried/Germany Jochen Orlowski, IR & PR FON: +49 (0)89 70 07 63 66 FAX: +49 (0)89 70 07 63 29 mailto: jochen.orlowski@4sc.com www.4sc.de

Biotech Consulting & Service

Disease-specific macromolecules for intracellular application Adriacell SpA is a biotech company based in Northern Italy and is specialized in the development of first in class oncology therapeutics and diagnostics. The proprietary CROMOC therapeutic platform allows for the selection of disease-specific macromolecules that exhibit intracellular active principles. The innovative diagnostics CERVIMAX program focuses on early detection and therapy follow-up for cervical cancer. This product will be launched on the German, Austrian and Swiss market from Martinsried. At the same time, Adriacell is conducting a Small

Molecule program in Martinsried. Given the high density of expertise in modern pharmaceutical chemistry in Munich, the IZB campus offers an ideal strategic center for these developments.

Contact: Adriacell SpA Dr. Christian Kuehne Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70 07 649-1 FAX: +49 (0)89 70 07 649-9 eMail: izb.business@adriacell.com www.adriacell.com

Industrial Biotech

AMSilk has developed a unique process to produce biopolymers like spider silk at an industrial scale The AMSilk®-Technology enables the production of tailor-made materials which are unrivaled by most common synthetic materials. AMSilk addresses many applications and industry sectors with new materials enabling new products with previously unachievable features.

Contact: AMSilk GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany Fon: +49 (0)89 38 156-44 30 Fax: +49 (0)89 38 156-38 59 eMail: info@amsilk.com www.amsilk.com

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

15 Biotech Therapeutics & Diagnostics

Classification of amyloidoses with respect to therapy Diagnostic Service for Amyloid Diseases in Man and Animals. The amYmed GmbH is developing immunoreagents for distinguishing precisely the 25 or so different and mostly life-threatening diseases such as Alzheimer‘s disease, hereditary amyloidoses and those derived from monoclonal gammopathies, with respect to an effective therapy. The amYmed also provides a service on demand for the precise classification of the various amyloidoses, including an evaluation, for both patients and physicians. Although the different amyloidoses can be clinically similar, they represent different diseases, every one of which requires a highly precise diagnosis for appropriate treatment. The amYmed also develops comparable reagents for

classifying amyloidoses in animals (mammals and birds) and provides a similar diagnostic service.

Contact: amYmed GmbH Referenzzentrum für Amyloidkrankheiten Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (o)89 52 01 26 38 FAX: +49 (o)89 52 38 90 13 eMail: linke@amymed.de www.amymed.net

Tissue Engineering

The establishment of a Bavarian Tissue Bank The Bayerische Gewebebank GmbH was founded in 2009 by the Medical Centre of the University Munich and the German Heart Centre Munich. The purpose of the Bavarian Tissue Bank is the processing and transmission of human tissue preparations with a production permission and license according to the tissue law. In future, it is planned to provide even further medical centers in and near Munich with tissue preparations, and not only to provide for the partners‘ needs. A network of extraction institutions, laboratories, tissue banks and institutions transplanting tissues is connected via the European Association of Tissue Banks – and the Bavarian Tissue Bank regards itself as a part of this association. The aim of this network is to ensure the high-qua-

lity, transparent and economical supply of the required tissue transplantations for patients. In the meantime, the structural requirements for the issuing of the production license have been created so that it will soon be possible to produce tissue preparations under aseptic conditions at the IZB.

Contact: Bayerische Gewebebank GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 55 89 84 50 FAX: +49 (0)89 90 55 89 84 52 eMail: bayerischegewebebank@arcor.de

Biotech Therapeutics & Diagnostics

Smart oral drug delivery Bernina Plus and HDS develop smart oral drug delivery systems for therapeutic peptides. The proprietary technology is based on artificial envelopes created by lipids. In addition, these nano-particulate natural and synthetic lipids are used in coating and surface protection.

Contact: Bernina Plus GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 52 38 87 40 FAX: +49 (0)89 52 38 83 33 eMail: gropp@berninaplus.de www.berninaplus.de

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

16 Biotech Consulting & Service Competence in Biotechnology

BioM Biotech Cluster Development GmbH serves as the coordinating agency of the Munich Biotech Cluster, and is the top address for all biotechnology companies and start-ups in the region – since more than 15 years. BioM provides support in marketing, communications, and public promotion, also maintaining an information portal at www.bio-m.org. The website offers an extensive company database, news updates and a job exchange. In addition to business advice and help in business development, BioM offers a wide range of seminars and events to biotech entrepreneurs and their employees. In the nationwide competition "Germany´s Leading-Edge Cluster" by German Ministry for Research and Education (BMBF) the “Munich Biotech Cluster m4” (coordinated by BioM) was announced in 2010 as one of 15 winners in such different branches like automotive, software or logistics with the new focus on “personalized medicine” now receiving a grant of about € 40 Mio which is paralleled by a commitment of the local industry by another € 40 Mio and basic financing by the Bavarian Ministry of Economics to a total of nearly € 100 Mio for the new strategic program “m4 – personalized and targeted therapies leading to drug development in a new dimension”. The legal unit BioM AG functions as seed investor in innovative start-ups having a managed portfolio of about 14 companies to date. www.bio-m.org www.m4.de

On behalf of the Bavarian Ministry of Economic Affairs, Infrastructure, Transport and Technology, BioM, with its 10 year experience in managing the Munich Biotech Cluster, was additionally mandated to manage the Cluster Biotechnology Bavaria as part of the governmental "Cluster Initiative Bavaria" (www.biotech-bavaria.de). The objective is to connect the different Biotech Regions of Bavaria within a large, statewide network. Central tasks are: Targeted scouting of research projects and Technology Transfer Network Organisation and International Representation As a Bavaria-wide network organisation the Bavarian Biotech Cluster develops synergy potentials and communicates a uniform public presence as shown in the annual publication “Report Biotech in Bavaria”.

Contact: BioM Biotech Cluster Development GmbH Am Klopferspitz 19a (IZB West II) 82152 Martinsried/Germany FON: +49 (0)89/89 96 79-0 FAX: +49 (0)89/89 96 79-79 eMail: info@bio-m.org www.bio-m.org

Biotech Consulting & Service

Networking for Industrial Biotechnology in Bavaria BioM WB GmbH was founded in June 2008 as the Bavarian management organization of an interdisciplinary competence network for Industrial Biotechnology. The BioM WB network emerged from the ‚IBP network‘, one of the winners of the nationwide competition ‚BioIndustrie 2021‘ of the Federal Ministry of Research and Education (BMBF). So far, the network grew to 80 members including large scale industry, SMEs and academia. BioM WB supports the network in all matters of technology transfer and public affairs, promotes the visibility of the network members and seeks dialogue with policy and decision makers. Basis of our work is cross linking partners between and beyond branches and sectors for the benefit of Industrial Biotechnology.

Steady progress in understanding biological processes and implementation of new knowledge in the Industrial Biotechnology area is providing the economy with even more of a tailwind. The ‚biologization‘ of industry is proceeding apace. BioM WB serves as catalyst for this process. Contact: BioM WB GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 54 04 54 70 FAX: +49 (0)89 54 04 54 715 eMail: info@BioM-WB.com www.BioM-WB.com

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

17 Biotech Devices & Reagents

High Level Transfection technology Biontex is a research-focused genetic engineering company offering a comprehensive range of products in the field of transfection technology, including long-established reagents such as METAFECTENE® and METAFECTENE® PRO. Our new development METAFECTENE® EASY+ is a GLOBAL INNOVATION in this product sector that eliminates the need for timeconsuming optimization, while METAFECTENE® SI is a reagent designed specifically for efficient siRNA transfection. A major alternative to nucleic acid transfection is the direct transport of proteins into cells–a purpose for which the new reagents in the PROTEOfectene® series were specifically developed. Our groundbreaking new Microfection product series enables outstanding optical properties in live cell imaging to enhance the versatility and efficiency of nucleic acid and

protein transfection applications. To complement these products, Biontex sells agaroses for efficient protein purification (Ni-NTA Agarose, Ni-IDA Agarose, Co-IDA Agarose, GST Agarose etc.) and cell culture products that are guaranteed mycoplasma-free–eliminating one of the foremost obstacles to successful transfection. The product portfolio is completed by mycoplasma detection (MycoSPY®) and removal (MycoRAZOR®) kits. Contact: Biontex Laboratories GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany Fon: +49 (0)89 32 47 99 50, Fax: +49 (0)89 32 47 99 52 eMail: s.koenig@biontex.com, www.biontex.com

Biotech Consulting & Training Starting in September 2010

Training center for chemistry, biology and environment The Dr. Erwin Elhardt School of Chemistry, located in the training center for chemistry, biology and environment, is the oldest private school in Munich with more than 120 years of experience in the area of scientific technological training. State-approved chemical-technical assistants (CTAs), biotechnical assistants (BTAs) and chemical techniciens are trained here. The vocational training of the BTAs is given in the new building of Innovation and Startup Center for Biotechnology (IZB) in Martinsried. Here, modern laboratories with state of the art equipment are available – tailor-made for this training. The practical and theoretical instruction is given in close proximity to the numerous life science companies.

Contact: Chemieschule Dr. Erwin Elhardt Staatlich anerkannte Berufsfachschule für Biologisch-Technische Assistenten Am Klopferspitz 19a in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 65 14 031 FAX: +49 (0)89 65 14 033 eMail: info@chemieschule-bayern.de www.chemieschule-bayern.de Gemeinnütziger Schulträger: Chemieschule Dr. Elhardt GmbH Ludmillastraße 30 81543 München

DNA/Protein Analytics

Authentic Chromobody® Technology ChromoTek GmbH, founded in 2008, is a biotech company focused on the discovery and development of novel nanoprobes and cell based assays for biomedical research and early drug development. During the last years ChromoTek has developed innovative research tools including the GFP-Trap® and RFP-Trap®, two versatile pull-down reagents for biochemical analysis of fluorescent fusion proteins. In April 2011 ChromoTek successfully introduced its first cell based assay for early drug development, the U2OS Cell Cycle Chromobody®. This real-time High-Content Analysis (HCA) screening assay enables to monitor the complete cell cycle in live cells for the first time. In addition ChromoTek developed

the Fluorescent 2-Hybrid (F2H)-Assay to analyze protein-protein interactions in vivo in real time.

Contact: ChromoTek GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 78 79 73 10 FAX: +49 (0)89 78 79 73 11 email: info@chromotek.com www.chromotek.com

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

18 Biotech Therapeutics & Diagnostics

Development of New Peptide Therapeutics for the Treatment of Autoimmune Diseases conoGenetix is a privately owned biopharmaceutical company focused on the development of new peptide therapeutics for the treatment of autoimmune diseases. conoGenetix was founded in 2002 by Dr. Andreas Klostermann and Dr. Jörg Stockhaus and is located in Martinsried, Germany. The company has developed an integrated technology platform that allows for the efficient discovery of drug leads that modulate ion channel targets causatively involved in the generation of autoimmune diseases. conoGenetix runs a program targeting severe autoimmune disorders like Multiple Sclerosis (MS), Rheumatoid Arthritis (RA) and Vasculitis. Several peptides called cgtx-peptides within this program are in preclinical development. The leading indi-

cation for the cgtx-peptides will be Vasculitis – a fatal disease strongly related to Rheumatoid Arthritis. Vasculitis is a rare disease and will be a market door opener for conoGenetix.

Contact: conoGenetix biosciences GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49(0)89 547269-50 FAX: +49(0)89 547269-59 eMail: info@conogenetix.de www.conogenetix.de

Biotech Preclinical Services

The outsourcing partner for individual and innovative analytical and formulation development of biopharmaceuticals Coriolis PharmaService is one of the worldwide leading, independent service providers in research and development of formulations, analytics as well as established and innovative drying-technologies for biopharmaceutical drugs. Within Coriolis an interdisciplinary team of highly qualified scientists with many years of experience develops individual and innovative solutions for questions concerning therapeutic proteins, peptides and vaccines. Innovative analytical technologies, long lasting experience in formulation development, a strong scientific background and the implementation of most recent scientific advances in the field of biopharmaceutical drug development are the unique characteristics of Coriolis‘ services. Formulation development ranging from early screening of excipients to the final marketed liquid or lyophilized

formulation is offered. Aggregate and particle characterization by innovative analytical methods, i.e. AF4, Nanosight® or Micro-flow imagingTM and stability / comparability studies according to the ICH guidelines or lyophilization process development, are just some examples illustrating the outstanding services provided by Coriolis. Contact: Coriolis Pharma Biopharmaceutical Research and Development Service Dr. Michael Wiggenhorn, Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49(0) 89 54 24 498-0, FAX: +49(0) 89 54 24 498-22 eMail: contact@coriolis-pharma.com www.coriolis-pharma.com

Drug Discovery Service

Premium Protein and Protein Crystallography Service CRELUX specializes in tailor made protein and protein crystallography drug discovery services. The company is privately owned and a professional and dedicated service provider for the global pharma and biotech industry. CRELUX is a client focused provider with a portfolio of premium drug discovery services based on a top level protein expertise. In our PRIME PROTEIN programs we are advancing innovations in protein expression to promote the availability of high quality proteins. Our XPRESS portfolio of readily available crystallographic targets grants turnaround times within a few weeks. Our XPERT crystallography services from concept to high resolution complex structure are provided under tailor made agreements. Based on our unique screening technology INTRACT we

are offering compound and fragment screening. And our i2c (idea to candidate) service includes target to hit and concept to early development candidate fee-for-service projects.

Contact: CRELUX GmbH Am Klopferspitz 19a in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70 07 60 170 FAX: +49 (0)89 70 07 60 222 eMail: schaeffer@crelux.com www.crelux.com

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

19 Biotech Therapeutics & Diagnostics

Therapeutics from herbal extracts for the therapy of rheumatic diseases DoNatur GmbH develops new therapeutics from herbal extracts with traditionally confirmed therapeutic efficiency. The comprehensive analysis of the genuine extracts, the isolation and structural characterization of the active substances and the test of their pharmacological activities constitutes the main competence of the company. Over the last years DoNatur has successfully developed a new immunomodulatory acting natural substance which has been proved highly efficacious for the therapy of rheumatic diseases.

Contact: DoNatur GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89/85 66 25 55 eMail: info@donatur.de www.donatur.de

Biotech Consulting & Service

Recognizing the bearing capacity of an idea: from the solid scientific result to the feasibility of the product DPC Pharma Consulting was founded in 2007 by Dr. Karl Deres with offices in the IZB Martinsried Biotech Centre and in Berlin City. DPC Pharma Consulting is an advisory company offering services in the pharmaceutical/ biotech industry, including interim management in the fields of business & strategic corporate development, clinical & regulatory aspects as well as R&D management. The main emphasis results from the core competence drug development in the area of chronic inflammatory diseases like auto-immune disorders and cancer. As a venture partner of the BiomedPartners, Dr. Karl Deres also supports their representation in Munich. The effectiveness of DPC Pharma Consulting lies in its ability to value and appreciate people and thereby to inspire

people: when performance is recognized, the willingness to perform increases; those who have the courage to find differences, help to make the difference. Contact: DPC Pharma Consulting | BioMedPartners Venture Partner Dr. Karl Deres Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 55 05 47 510 FAX: +49 (0)89 55 05 47 521 eMail: info@dpcpharma.de www.dpcpharma.de

Medtech

Laboratory for Interdisciplinary Stem Cell Research The Laboratory for Interdisciplinary Stem Cell Research (EKFS-Herzchirurgie; Head: Prof G Eißner PhD) belongs to the Department of Cardiac Surgery (Head: Prof Ch. Hagl, MD, PhD) at Munich University Medical Ctr, Munich, Germany, and is investigating novel preclinical approaches in regenerative and transplant medicine. Major research topics are (i) the use of mesenchymal stem cells (MSC) from umbilical cord tissue for the therapy of cardiomyo-degenerative disorders and their interaction with cardiac stem cells (CSC). (ii) the immunomodulatory potential of MSC in transplant settings and (iii) the pathophysiology of endothelial complications in the course of solid organ and hematopoetic stem cell transplantation (SCT).

Contact: EKFS Herzchirurgie Prof. Dr. G. Eißner Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70 06-5008 FAX: +49 (0)89 70 06-5065 eMail: guenther.eissner@med.uni-muenchen.de www.herzklinik-muenchen.de

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

20 Biotech Therapeutics & Diagnostics

Creative services for the production of high quality special oligonucleotides ELLA is an independent, privately owned company founded in October 2004. ELLA offers creative services for the production of high quality special oligonucleotides for selected projects in diagnostics, chip technologies and further topics - following quality standards which you would appreciate and expect in your own lab. ELLA´s vision is the closest cooperation with our customers, such that the external oligonucleotide synthesis unit at Ella Biotech operates like an outsourced in-house production of the particular company. The guidelines for the synthesis standards are defined by our customers themselves after intensive

consultation. Before production commences, we fully work up this list of requirements based on our customers production standards.

Contact: ELLA Biotech GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70 93 93 16 FAX: +49 (0)89 70 93 94 40 eMail: info@ellabiotech.com www.ellabiotech.com

Biotech Therapeutics & Diagnostics

Stem cells from the umbilical cord – a biological life assurance In cooperation with the stem cell bank of the University Hospital Erlangen, eticur) currently has the capability of collecting the stem cells from the umbilical cord of newborn children in approximately 600 hospitals nationwide. These are then processed and stored in a frozen condition. During this process, all currently valid regulations for therapeutic procedures are strictly adhered to. eticur) would like to inform future parents in an atmosphere of respect and integrity of the opportunities and benefits of the storage of umbilical cord blood stem cells. Furthermore, eticur) offers a safe storage and guarantees highest quality and comprehensive testing through highly qualified personnel.

For further information about the individual steps, from the contract up to the storage as well as the medical benefit of stem cells from the umbilical cord, we recommend visiting our internet site: www.eticur.de

Contact: eticur) GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 12 59 810 FAX: +49 (0)89 12 59 81 19 eMail: info@eticur.de www.eticur.de

Biotech Therapeutics & Diagnostics

Chemical proteomics and phosphoproteomics applications Evotec Munich is an affiliate of Evotec AG and based in Munich/Martinsried, Germany. Evotec Munich is a service company specializing in chemical proteomics and quantitative phosphoproteomics methods to support the successful development of small molecule drugs. Evotec Munich delivers a comprehensive analysis of a compound‚s mode of action in a cell. This significantly supports decision making at various stages of the drug discovery process, such as lead optimization or clinical trial candidate selection, reduces development times and predicts a drug‚s therapeutic outcome.

Contact: Evotec Am Klopferspitz 19a in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 4524465-0 FAX: +49 (0)89 4524465-220 eMail: proteomics@evotec.com www.evotec.com

Innovations- und Gr端nderzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a 揃 82152 Martinsried

21 Biotech Therapeutics & Diagnostics

Biofluid-based Molecular Diagnostics Exosome Diagnostics is a leading developer of biofluid-based molecular diagnostic tests for use in personalized medicine. Exosomes are shed into all biofluids, including blood, urine, and CSF, forming a stable source of intact, disease-specific nucleic acids. The Company's proprietary exosome technology makes use of this natural stability to achieve high sensitivity for rare gene transcripts and the expression of genes responsible for cancers and other diseases. The Company is commercializing in-vitro diagnostic tests for use in companion diagnostic applications and real-time monitoring of disease. The Company maintains facilities in New York, NY, St. Paul, MN and Munich/Martinsreid, Germany.

Contact: Exosome Diagnostics GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 89 416 17270, FAX: +49 89 416 17269 eMail: munich@exosomedx.com www.exosomedx.com

Pharma & Chemical Industrie

Bringing effective antibody therapies to patients Fresenius Biotech GmbH is a globally operating company dedicated to delivering targeted biopharmaceutical treatment options in oncology and transplantation medicine. The focus of our activites is the development and commercialization of immunologically active biopharmaceutical therapeutics based on innovative antibody technologies. Clinical and development activities as well as production are located in Germany with an additional development unit in the USA. The Commercialization of ATG-Fresenius速 S and Removab速 is performed by own marketing activities or by co-operation partners.

Contact: Fresenius Biotech GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 89 88 88 0 FAX: +49 (0)89 70 92 90 35 eMail: info@fresenius-biotech.com www.fresenius-biotech.com

Biotech Consulting & Service

Support in the areas of business development, marketing and sales FROST LIFESCIENCE offers support in the areas of business development, marketing and sales for life science and biotechnology start-up companies. It is particularly important for start-up companies to enter the market at the right time, and to successfully establish their innovative technologies and products with potential customers. Services: Business development Marketing Sales

FROST LIFESCIENCE is a specialist for human primary cells and stem cells, 3D in vitro test systems (skin, angiogenesis, tumor models), cell based assays and viral gene transfer. Contact: FROST LIFESCIENCE Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany Fon: +49 (0)89 51 77 71 40 Fax: +49 (0) 89 5177 71 60 eMail: info@frost-lifescience.com www.frost-lifescience.com

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

22 Biotech Devices & Reagents

Cells in focus ibidi is a system provider for microscopy based functional cell-based assays. ibidi develops, produces and distributes cell-culture biochips (µ-Slides) and complete solutions for functional cell-based assays. An extensive line of µ-Slides and µ-Dishes offers solutions for immunofluorescence and basic cell culture, plus the following complex assays: angiogenesis, chemotaxis, wound healing, shear stress and flow. The company also specializes in instruments such as heating and incubation units, and a unique perfusion system that provides continuous flow for the simulation of blood vessels. All of ibidi‘s products are designed with high end microscopy in mind. The high optical quality of the µ-Slides allows microsco-

pic cell investigations, using phase contrast or DIC, fluorescence and also confocal microscopy. The new F-actin marker LifeAct makes it possible to keep track of the development and movement of F-actin structures in living cells. More than 1000 publications document the successful use of ibidi‘s technologies. Contact: ibidi GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 52 04 61 70 FAX: +49 (0)89 52 04 61 759 eMail: info@ibidi.de, www.ibidi.de

Biotech Devices & Reagents

Leading Provider of Technologies for Biological Functionalization of Medical Devices LEUKOCARE is a leading provider of technologies for biological functionalization of medical devices, as well as the stabilization and protection of proteins and biological molecules in biopharmaceutical formulations in order to ensure safety, to extend shelflife and to enable terminal sterilization. As a product-focused biotechnology company, LEUKOCARE uses its proprietary Stabilizing and Protecting Solutions (SPS) to leverage its comprehensive expertise in industrial co-development partnerships. The company offers its know-how in formulation of biologics, biofunctional coatings of combination devices and product development.

LEUKOCARE was founded in 2003 and is headquartered in Martinsried near Munich, Germany.

Contact: LEUKOCARE AG Am Klopferspitz 19a in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 780 16 65- 0 FAX: +49 (0)89 780 16 65-11 eMail: info@leukocare.com www.leukocare.com

Biotech Devices & Reagents

Portable solutions for precision measurements The eye muscle is the fastest muscle in the human body, closing in milliseconds. One would think of it as quick as lightning. However, compared to the shortest time segments in modern daily life it is nearly an eternity. We are facing this challenge with our patented frequency comb technology. The technology - simply put - makes it possible for the first time ever to measure the entire spectrum of light in the visible and near infrared. Based on the technology we have developed a series of instruments over the last years that allow for finer and finer measurements. The pride and joy of Menlo Systems is the „optical frequency synthesizer“. With the portable instrument, light frequencies can be measured with a precision of up to 15 digits

beyond the decimal point. This allows our customers to measure time more precisely than ever - a thousand times more precisely than the Cesium atomic clock, until now regarded as the non-plus-ultra in capturing time. Contact: Menlo Systems GmbH Am Klopferspitz 19a in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 18 91 660 FAX: +49 (0)89 18 91 66 111 eMail: sales@menlosystems.com www.menlosystems.com

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

23 Pharma & Chemical Industrie

Encapsulation and Controlled-Release technology using porous nanoparticles NanoScape is a developer and producer of porous, nanoscale materials for the pharmaceutics, environment (e.g. water purification membranes) and electronics (e.g. chemical gas sensors; anti-reflection-coatings) sectors. Its NanoZeolite materials are cage-like structures with very high loading capacity which, through modification of the particle size and pore diameter, functionalisation of the surface chemistry or binding of ligands, can be adapted to the meet the requirements of the individual customer, allowing a wide range of pharmaceutical, biochemical, electrical and optical properties to be realised. Using such materials intelligent drug-delivery systems for active pharmaceutical ingredients (small molecules, biopharmaceuticals, vaccines)

and diagnostic sensors can be developed, and applications in the area of proteomics supported.

Contact: NanoScape AG Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 46 13 34 43 10 FAX: +49 (0)89 46 13 34 43 30 eMail: info@nanoscape.de www.nanoscape.de

Biotech Therapeutics & Diagnostics

Risk minimization for heart attacs A low omega-3 index is a significant risk factor towards heart attack (acute myocardial infarction). To know ones omega-3 index can help calculate this risk. The right alimentation/ fish oil supplementation can increase the index. Omegametrix GmbH, a international reference laboratory, measures the omega-3 index in a standardised way.

Contact: Omegametrix GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 55 06 30 07 FAX: +49 (0)89 55 06 30 08 eMail: info@omegametrix.eu www.omegametrix.eu

Biotech Therapeutics & Diagnostics

Creative Services for Design, synthesis and characterisation of targets Origenis (www.origenis.com) is a privately owned biotech-company providing creative services for drug design, synthesis, and characterisation based on its unique, patented technology platform – MOREsystem®. The company employs proprietary multiparametric design approaches for the directed target and indication optimised exploitation of billions of novel compounds. The unique process allows immediate realisation of designed molecules by parallel noncombinatorial synthesis, their automated MedChem optimization and biological characterisation of the products. Origenis generates and delivers rapidly patentable pre-clinical drug candidates with

a priori defined biological, physico-chemical, and pharmacological profiles.

Contact: origenis gmbh Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 78 01 67 60 FAX: +49 (0)89 78 01 67 67 77 eMail: info@origenis.de www.origenis.de

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

24 Biotech Consulting & Service

Your Partner for Intellectual Property Rights Patentquadrat is an internationally working patent law firm and offers services and consulting covering all topics related to industrial property (IP) rights – patents, utility models, designs and trademarks. Besides drafting and filing of new IP applications, Patentquadrat also attends their legal enforcements before the Offices and their prosecution before the courts. Further, we offer consulting in and execution of licensing negotiations. Particular attention is paid to the economic aspects of IP rights, e.g. to portfolio management, evaluation of property rights and patent clearance investigations. Basic questions from an economic point of view are for example: Is the technology protected in all IP and tech-

nical aspects? Is a third party able to circumvent the protected technology? How valuable is the IP right, particularly for sales? Is the IP an asset in negotiations? For an optimal result, Patentquadrat always considers all aspects of IP rights, i.e. technology, economy, legal aspects and innovation process aspects. Contact: Patentquadrat Am Klopferspitz 19a in IZB 82152 Planegg-Martinsried/Germany FON: +49 89 51777828, FAX: +49 89 51777829 eMail: seifert@patentquadrat.de www.patentquadrat.de

Biotech Preclinical Services

Individually Tailored Quality Management for the Life Science • scientific • economic • regulatory valid • PhaToCon (Pharm / Tox Concept) provides proven consulting and management services in all aspects of preclinical development and quality management. Product safety and risk assessment in pharmaceutical, biopharmaceutical and medical device development carry potentially significant risks already in early R&D stages. Also, the traceability of scientific and commercial decisions in the life sciences should remain accessible for years to come. To ensure this validity and reproducibility specific industrial and regulatory quality management systems (GxP, ISO, ...) as well as guidelines (OECD, ICH, ...) are used. Our support is customized based on these standards and we deliver resources and expertise both fast and flexible. We operate from a scientific point of view and with our

"hands-on" mentality we have strong execution skills. Thematic priorities and core competencies are: • Pharmacology and Toxicology in R & D • Preclinical Development • Lab Management • Validation • Qualification • Process optimization • Preclinical and bioanalytical methods expertise (in vitro / in vivo). Contact: PhaToCon Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON:+49 (0) 89 444 899 41, FAX:+49 (0) 89 444 899 43 eMail: info@phatocon.com www.phatocon.com

Bioinformatics

Software solutions for the management and analysis of chemical and biological data quattro research GmbH develops and markets software solutions for the management and analysis of chemical and biological data in drug discovery and development.

Contact: quattro research GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70 07 63-16 FAX: +49 (0)89 70 07 63-29 eMail: info@quattro-research.com www.quattro-research.com

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

25 Biotech Therapeutics & Diagnostics

Preclinical development of small molecules deriving from natural products R&D-Biopharmaceuticals is a biotechnology company focusing on the preclinical development of unique small molecules deriving from natural products for targeting approaches towards safer and more efficacious therapies. The Company is developing its own preclinical pipeline of natural compounds addressing a major disease area with unmet medical needs and is partnering its natural compound classes to Biotech and Pharma companies for a development towards specific applications.

Contact: R&D-Biopharmaceuticals GmbH Dr. Wolfgang Richter Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70 07 649-0 FAX: +49 (0)89 70 07 649-9 eMail: wolfgang.richter@rdbiopharma.de www.rdbiopharma.de

Biotech Consulting & Service

Branchenspezifische Personalberatung für den Biotech und Life Sciences Sektor RSA is a global leader in the provision of Executive Search and Interim Management to the life sciences industries With offices in the UK - our head office in Hertfordshire and premises in London - plus China, Germany in Frankfurt and Munich, Singapore, Switzerland, Turkey and the USA, RSA consultants talk to hundreds of industry leaders every day, and our network reaches every corner of the worldwide pharmaceutical, biotechnology and allied industries. Our unique blend of knowledge, teamwork and integrity has made us one of the world's largest specialist recruiters - but we've never lost sight of the values we started with: respect, integrity, quality and professionalism.

Contact: RSA Consulting GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70009907 FAX: +49 (0)89 70009947 eMail: RSAGermany@theRSAgroup.com www.theRSAgroup.com

Biotech Therapeutics & Diagnostics

Novel drugs to treat diabetes, hypertension and gastric hyperacidity SiNatur is focused on development of novel drug products to treat diabetes, hypertension and gastric Hyperacidity. For these purposes its recently discovered drug substance SNSA is applied which is actually the first biologically active Si compound. The proprietary drug-substance SNSA of SiNatur is a very potent nontoxic inhibitor of the P-type ATPases involved in several diseases. The discovery of SNSA is of deep scientific impact confirmed by

the lecture given by Dr. Franz Kerek (kerek@sinatur.net) at the „12-th World congress of ATPases“ in Aarhus, Denmark (5-9 August 2008)

Contact: SiNatur Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 85 662-555 FAX: +49 (0)89 85 662-556 eMail: info@donatur.de www.sinatur.net

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

26 Biotech Devices & Reagents

Genetically modified cells for target validation, drug discovery and screening SIRION BIOTECH is a technology leader in the field of functional gene analysis and cell models for basic research, drug and compound development. The company serves leading European, US and Japanese Drug and Biotech companies as a provider of latest technologies for them to advance identification of novel compounds and target validation. Given its founding in late 2006, SIRION BIOTECH is growing strongly as it is changing the paradigm of cell modelling with its key competencies in unmatched viral vector technologies for both RNAi and overexpression (Oex). Enjoy knockdown rates of about 90% with SIRION BIOTECH‘s in-house validation system screens for high-performance shRNA sequences

Benefit from pre-clinical study cycles shortened by 25% with advanced cell models Impress with inducible gene expression (“Tet-on” and “Tet-off”) in cell systems from a client‘s cDNA/shRNAsequence to a stable cell pool in less than 6 weeks Contact: SIRION Biotech GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70 09 61 999 FAX: +49 (0)89 70 09 61 998 eMail: info@sirion-biotech.de www.cellcompetence.de

Biotech Preclinical Services

Digital controllers for high speed servo motors Smart Move designs digital controllers for high speed servo motors. Thanks to our patented technology, highest precision is possible even at fastest speeds. Researching the physics of any device in order to achieve best performance is our business, as well as the development of all necessary hardware, software and communication interfaces.

Contact: Smart Move GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70 92 98 94 FAX: +49 (0)89 89 92 32 10 eMail: contact@smart-move.biz

Medtech

Individual system approaches and instrument development in the biological laboratory Smartec IngenieurBüro is your competent partner for individual system approaches and instrument development in the biological laboratory. Smartec IngenieurBüro convinces with know-how within the ranges biotechnology, analytics, genetic engineering, micro technology as well as micro fluidic. Smartec IngenieurBüro solves tasks of instrumentation for molecular and immunological process engineering. Smartec IngenieurBüro supports you from the idea to all stages of the product. Smartec IngenieurBüro offers complete solutions, consisting of mechanics, optics, electronics, as well as firm- and software of a hand.

Smartec IngenieurBüro consists of engineers and physicists which are predominantly settled in the ranges Research and Development (R&D) of bioanalytic systems.

Contact: SMARTEC IngenieurBüro GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 85 46 65 13 FAX: +49 (0)89 85 46 65 15 eMail: ulrichschubert@smartecbio.de www.smartecbio.de

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

27 Individualized Cancer Therapy

Spheroid Microtumor Diagnostics for Individualized Cancer Therapy Spherotec aims at the optimization of systemic therapy in oncology using the companies proprietary SpheroidMicrotumor-Technology in two different business areas. SpheroMed: In this area an innovative diagnostic test, combining Spheroid-Microtumor Technology and biomarker profiling, was developed. This test is used for identification of the individually optimal drug regimen in oncological patients before begin of systemic treatment. Thus, therapeutic agents can be chosen more specific and with less side effects for the individual patients. Testing can be performed with cytostatic drugs, antibodies and small molecules. Currently the test is under clinical validation in breast and colorectal cancer studies.

SpheroSelect: In this business area the patented Spheroid-Microtumor-Technology is applied for functional testing of drug candidates, new indications for established drugs and new drug combinations on behalf of Pharma and Biotech companies. Contact: SpheroTec GmbH Am Klopferspitz 19 82152 Planegg-Martinsried/Germany FON: +49 (0)89 540 41 34 - 0 FAX: +49 (0)89 540 41 34 - 20 eMail: info@spherotec.com, www.spherotec.com

Biotech Therapeutics & Diagnostics

Fc-Receptors to interfere with autoimmune diseases SuppreMol GmbH is leveraging the therapeutic potential of Fc receptors (FcRs) for the treatment of autoimmune diseases and allergies. Lead product of the company is a soluble FcR (SM101) that interfers with the underlying cause of the autoimmune diseases and therefore has the potential to cure the disease rather that only treating the symptoms in addition with fewer side effects as compared to the current standard therapies. The company has successfully completed a phase I study in healthy individuals with SM101 and is presently conducting two clinical phase II studies in the orphan disease Primary Immune Thrombocytopenia (ITP) and Systemic Lupus Erythematosus (SLE). Furthermore, three antibody candidates directed against FcRs and a cytokine

are in early preclinical development to treat autoimmune diseases and allergies. SuppreMol is a privately-owned company and started as a spin-off of the laboratory of the Nobel laureate Prof. Dr. Robert Huber of the Max Planck Institute of Biochemistry in Martinsried, Germany. The company secured in three financing rounds over 35.0 M Euros since 2006. Contact: SuppreMol GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 30 90 50 68 0 FAX: +49 (0)89 30 90 50 68 68 eMail: info@suppremol.com, www.suppremol.com

Biotech Consulting & Service

System house in any field of computing That’s it as a system vendor supplies support in any field of computing. Main focus are server based computing, open source projects and system security as well as high availability solutions, global access, consulting and data recovery. services include project planning, implementation with ongoing support and training.

Contact: that's it gmbh Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 12 41 39 40 FAX: +49 (0)89 12 41 39 444 eMail: welcome@thatsit-gmbh.de www.thatsit-gmbh.de

Innovations- und Gr端nderzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a 揃 82152 Martinsried

28 Biotech Consulting & Service

Your Partner tackling specific research and development process challenges Who we are THE WORKING GROUP are seven consultants colleagues, all with many years of - complementary - professional practice from industrial work and consultancy experience who help -as member of your team- to tackle the challenges of your specific research and development process. What we do Active support of project teams and managers in your R&D projects as a consultant, sparring partner, coach, trainer, facilitator or project manager reaching noticeable improvements. What is your benefit Strategic management of project and technology portfolio

Structured ideas creation and concept evaluation for new products/services Milestone-oriented, consequent management of current R&D projects Systematic risk mitigation in intensive conceptual phases Contact: THE WORKING GROUP Management Consultants Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70 06 51 51 FAX: +49 (0)911 308 44 40 00 8 eMail: mertens@theworkinggroup.de

DNA/Protein Analytics

Generating new trifunctional antibody drug candidates for a better cancer immunotherapy TRION Research GmbH, founded in 1998, is a Biotech research company and a strategic partner of TRION Pharma GmbH focusing on the generation of novel Triomab速 antibody candidates and the support of non-clinical and clinical development of Triomab速 antibodies. The company offers Immunomonitoring Service, special antibody conjugation support, additional analytical service in tumor biology and further analytical support for reagent control to investigators, study sponsors and CROs. The core competences of the company are: Immunomonitoring and logistical support for clinical and non-clinical studies - Determination of the patients` immune status e.g. FACS measurements, proliferation tests, cytokine multiplex assays and immune activity tests (e.g. XTT,

B-cell depletion assays) - Determination of EpCAM+ tumor cells via cytospin preparations and immunofluorescence - quantitative PCR - Determination of human anti mouse antibodies (HAMA) Supply of purified antibodies (labeled and unlabeled) Development of immunological assays Contact: TRION Research GmbH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70 07 66 0, FAX: +49 (0)89 70 07 66 11 eMail:mail@trionreserach.de www.trionreserach.de

Biotech Consulting & Service

Registration and testing of chemicals The most important business area of Velumetrix GmbH is the registration and testing of chemicals (www.chemtest.de). Because of our good overview over the market and due to volume discounts (resulting from cooperation agreements with our contract laboratories), we help our clients to save a lot of time and money. We support our clients by determining the appropriate tests (among other things, we find out if the biocides guideline applies) scanning the market for the optimal laboratories professional management of the substance registration very good contacts to the authorities

Our second division takes charge of the process management for small and medium-sized companies. We not only develop the concepts but we also help our clients to implement them in the fields of organization and controlling. Contact: VELUMETRIX GMBH Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany FON: +49 (0)89 70 08 85 48 FAX: +49 (0)89 70 92 92 67 eMail: info@chemtest.de www.chemtest.de

Innovations- und Gründerzentrum Biotechnologie IZB Martinsried Am Klopferspitz 19 und 19a · 82152 Martinsried

29 Venture Capital VC

Venture capital for life science companies Vesalius focuses on the creation, financing and growth of early-stage life science companies. The Vesalius funds invest in areas with a high unmet medical need and a significant profit potential: new therapeutics, cutting-edge medical devices, innovative drug delivery technologies and diagnostic tests with a high utility level. The expertise of the team ranges from extensive operations, business development, R&D, and IP management knowhow to corporate governance, M&A, and IPO experience in start-ups and mature life science companies. Furthermore, the individual team members have in-depth technical insights and competitive scouting experience in the life science sector. For

more information please see www.vesaliusbiocapital.com.

Contact: Vesalius Biocapital Christian Schneider, PhD, DVM, MBA Am Klopferspitz 19 in IZB 82152 Planegg-Martinsried/Germany Mobil: +49-172-83 26 097 eMail: c.schneider@vesaliusbiocapital.com www.vesaliusbiocapital.com

Innovations- und Gründerzentrum Biotechnologie IZB Freising Lise-Meitner-Straße 30 · 85354 Freising

Agro, Food, Environment

Modern aroma and flavour analytic Our company is a food chemistry research and development laboratory specialising in aroma and flavour analysis. aromaLAB AG researches and analyses the aroma composition of food on the basis of innovative processes, scientifically established methods and the most recent discoveries in the area of food chemistry. aromaLAB develops aromas for food manufacturers as well as

for the cosmetics, tobacco and consumer goods industries.

Contact: aromaLAB AG Lise-Meitner-Str. 30 in IZB 85354 Freising-Weihenstephan/Germany FON: +49 (0)8161 98 92 28 0 FAX: +49 (0)8161 98 92 28 2 eMail: rainer.schmitt@aromaLab.de www.aromaLab.de

Biotech Consulting & Service

Anerobic technologies and renewable energy systems ATRES is short hand for anaerobic technologies and renewable energy systems. We offer consultancy and laboratory services, focused mainly on production and utilisation of biogas by means of anaerobic digestion. Additionally for industrial applications we design concepts for production integrated environmental protection or process integrated protection (PIUS).

Contact: ATRES Group Lise-Meitner-Str. 30 in IZB 85354 Freising-Weihenstephan/Germany Firmensitz: Schneckenburger Str. 32 81675 München FON: +49 (0)8161 80 60 72 FAX: +49 (0)8161 80 60 70 eMail: service@atres-group.com www.atres-group.com

Innovations- und Gründerzentrum Biotechnologie IZB Freising Lise-Meitner-Straße 30 · 85354 Freising

30 Biotech Therapeutics & Diagnostics

Skin cells grown from the patient‘s own hair roots Euroderm, based in Leipzig, is developing a product called EpiDex, a new skin graft for wounds. It comprises human skin cells grown from the patient's own hair roots, reducing rejection risks and other common complications. The company is also culturing human epidermis for use by cosmetic and other companies wishing to test a product's safety without animal experimentation.

Contact: Euroderm GmbH Lise-Meitner-Str. 30 in IZB 85354 Freising-Weihenstephan/Germany FON: +49 (0)34 14 92 920 FAX: +49 (0)34 14 92 92 70 eMail: wrichter@euroderm-biotech.de www.euroderm-biotech.com

Biotech Therapeutics & Diagnostics

Modernste Lebensmittelanalytik GENidee is a young and innovative biotech company specialized in the development, production and marketing of molecular-biological diagnostic kits for the rapid detection of food-borne pathogens as well as microbial contaminants in food. Fast and reliable PCR diagnostics is guarantied by a parallel analytics suited to the individual customer requirements. GENidee offers molecular-biological service of highest quality. Using our kits directly in the production facilities enables the results of microbiological analytics to be supplied much sooner than by conventional diagnostics. The individual care of our customers and the consequent customer satisfaction is our top prioriy.

Contact: GENidee Lise-Meitner-Str. 30 in IZB 85354 Freising-Weihenstephan/Germany FON: +49 (0)81 61 80 68 186 FAX: +49 (0)81 61 80 68 185 eMail: info@genidee.eu

Bioinformatics

Innovative products and solutions in the bio process technology A short outline of our proposal Expertsystems for brewery Lautermanager, Filtermanagernew Ultrasound measuring systems: SonoFerm™, SonoFill, SonoSnap Software products: Fuzzy-Studio, Virtual Expert Provision of services: Software and hardware development, technological consulting, development of "Virtual Expert" systems

Contact: gimbio mbH Lise-Meitner-Str. 30 in IZB 85354 Freising-Weihenstephan/Germany FON: +49 (0)8161 986 4480 FAX: +49 (0)8161 986 5661 eMail: info@gimbio.de www.gimbio.de

Innovations- und Gründerzentrum Biotechnologie IZB Freising Lise-Meitner-Straße 30 · 85354 Freising

31 Agro, Food, Environment

Technological properties of cereal science The Hans-Dieter-Belitz-Institute for Cereal Grain Research conducts research projects in collaboration with industry. The projects are dealing mainly with the physical and chemical characterisation of different cereal species and the correlation of the results with technological properties. Furthermore, the effect of additives in the breadmaking process and the generation of odorants during baking are investigated. Professor Dr. Peter Schieberle is the scientific supervisor of the institute. He combines the functions of the head of the Institute for Food Chemistry of the Technical University of Munich and the director of the German Research Centre for Food Chemistry. As a result, a close contact between the two institutions is established,

giving the Hans-Dieter-Belitz-Institute the possibility to solve difficult problems in cereal science by using approaches including both, applied and basic research. Contact: Hans-Dieter-Belitz-Institut für Mehl- und Eiweißforschung HDBI Lise-Meitner-Str. 30 in IZB 85354 Freising-Weihenstephan/Germany FON: +49 (0)89 28 91 41 74 FAX: +49 (0)89 28 91 41 83 eMail: manfred.krausbeck@lrz.tum.de www.hdbi.de

Biotech Therapeutics & Diagnostics

Anticalins, a unique class of target protein therapeutics Pieris AG is an independent, clinical-staged biotechnology company advancing its proprietary Anticalin® technology to create differentiated drugs that are safer and more effective than conventional approaches. Exclusive to Pieris, Anticalin-based drugs promise to address high-unmet medical needs and expand the therapeutic potential of current targeted approaches. Pieris‘ pipeline ranges from its lead compound, PRS-050 (anti-VEGF, oncology) that recently completed a Phase I clinical trial, to multiple Anticalins in preclinical development across a range of therapeutic areas. The company has four ongoing discovery and development collaborations: Daiichi Sankyo, Takeda San Francisco, the

Sanofi Group and Allergan. Privately held, Pieris has been funded by premier biotechnology-focused venture capital, including lead investors OrbiMed Advisors and Global Life Science Ventures. For more information, please visit: www.pieris-ag.com. Contact: Pieris AG Lise-Meitner-Str. 30 in IZB 85354 Freising-Weihenstephan/Germany FON: +49 (0)81 61/14 11 400 FAX: +49 (0)81 61/14 11 444 eMail: info@pieris-ag.com www.pieris-ag.com

Biotech Environment, Instruments

High quality enviromental monitoring and measuring The Umwelt-Geräte-Technik GmbH (UGT GmbH) is a medium enterprise, which operates successful in the field of environmental monitoring and measuring technologies since 1992. According to the company profile, the UGT GmbH develops, produce and distribute measurement and diagnostic tools for soil-water-air-analytics and modules for the environmental monitoring. The installation of complex soil hydrologic and meteorological measuring stations in agriculture, forest and water ecosystems is in the area of operation, as well as the installation of control stations at landfill and mining sites for remediation. To meet the requirements of a growing national and inter-

national market, the UGT GmbH establishes the branch south in Freising-Weihenstephan, close to important scientific centres. Contact: Umwelt-Geräte-Technik GmbH Niederlassung Süd Lise-Meitner-Str. 30 in IZB 85354 Freising-Weihenstephan/Germany FON: +49 (0)81 61 23 46 441 FAX: +49 (0)81 61 23 46 443 Mobil: 01 60-94 90 94 20 eMail: info-sued@ugt-online.de, www.ugt-online.de

Innovations- und Gründerzentrum Biotechnologie IZB Freising Lise-Meitner-Straße 30 · 85354 Freising

32 DNA/Protein Analytics

Highest quality and fast turn-around services in functional genomics Established in 2000, vertis Biotechnologie AG is a privately held company with its core competence in the field of functional genomics. It was founded as a spin-off from the Technische Universität München-Weihenstephan. VERTIS offers highest quality and fast turn-around molecular biology services in the field of functional genomics. The company has developed an innovative technology platform which significantly accelerates the identification of candidate genes and enables the discovery of the world of naturally occurring non-coding small RNAs (sncRNA), the prototype of which is MicroRNA (miRNA). Newest results exhibited that especially the sncRNAs play a central role in the development and preservation of life.

Contact: vertis Biotechnologie AG Lise-Meitner-Str. 30 in IZB 85354 Freising-Weihenstephan/Germany FON: +49 (0)81 61 14 11 211 FAX: +49 (0)81 61 14 11 212 eMail: info@vertis-biotech.com www.vertis-biotech.com

Biotech Therapeutics & Diagnostics

XL-protein: Improved biopharmaceuticals with extended plasma half-life XL-protein is a biopharmaceutical company utilizing its proprietary ‘PASylation®’ technology to develop second generation biopharmaceuticals with prolonged plasma half-life. PASylation of therapeutic proteins allows less frequent and lower dosing combined with better tolerability, also opening perspectives for the life cycle management of approved biopharmaceuticals. ‘PASylation’ – the genetic fusion with conformationally disordered polypeptide sequences comprising the amino acids Pro, Ala, and Ser – provides a superior way to attach a solvated random chain with large hydrodynamic volume to a biologically active protein. Thus, its typically rapid clearance via

kidney filtration can be retarded by one to two orders of magnitude while the PAS moiety is biochemically inert and easily degradable.

Contact: XL-protein GmbH Lise-Meitner-Str. 30 in IZB 85354 Freising-Weihenstephan/Germany FON: +49 (0)81 61 53 73 090 FAX: +49 (0)81 61 53 73 099 eMail: info@xl-protein.de www.xl-protein.de

Select IMGM as your outsourcing partner and we will provide you with a complete solution exactly matching your needs.

RNA Services • • • • •

Whole genome microarray screening (Agilent platform) microRNA profiling (Agilent microarrays, TaqMan® qPCR) Gene expression studies (TaqMan® qPCR, AB 7900HT) TaqMan® Arrays (96- and 384-format) RNA isolation and quality control service

DNA Services • Next Generation Sequencing (NGS) (Roche 454 GS FLX & Junior, Life Technologies 5500xl SOLiDTM) • NGS target enrichment (amplification & hybridization) (Fluidigm Access ArrayTM, Agilent SureSelect) • NGS assay development (e.g. targeted resequencing) • NGS-based metagenomics and microbial diversity • Standard DNA sequencing (Sanger, AB 3730XL) • CNV analysis using oligo array-CGH • CNV validation with TaqMan® Copy Number Assays • SNP genotyping (Pyrosequencer, TaqMan®) • Absolute quantitation of target sequences (e.g. bio-distribution) • High-resolution HLA typing

Bioinformatics IMGM Laboratories GmbH Lochhamer Str. 29 82152 Martinsried Germany ph.: +49.89.895578.40 fax: +49.89.895578.41 info@imgm.com www.imgm.com

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Analysis of NGS data (internal & external) Analysis of genome-wide gene expression data Analysis of array-CGH and CNV data Development of gene signatures (SVM algorithms) Identification of biomarkers

Consulting • • • • •

Development & validation of NGS applications Development and optimization of diagnostic tests Performance optimization of instruments Quality control studies Biostatistics

www.imgm.com

Regensburg – at the head of the Danube The BioPark Regensburg GmbH is the management and administrative headquarters of the biotechnology research cluster known as BioRegio Regensburg in East Bavaria. Located strategically at the northernmost point of the Danube, in the Austrian-Czech-German triangle, the area is regarded as the gateway to the East of the extended European Union. Currently 44 firms with over 2600 employees are active in the field of life sciences in BioRegio Regensburg. As a result it has become the most important region for Biotechnology in Bavaria, second only to Munich.

BioRegio Regensburg

Welcome to Regensburg The over 2000 year-old City of Regensburg is located at the northernmost point of the Danube, about an hour's drive from both Munich and Nuremberg. With a population of nearly 150,000 Regensburg has become the center of Eastern Bavarian conurbation with 2.5 million inhabitants, which in past years has experienced a remarkable economic and technological upswing. And with the fall of the Iron Curtain of the earlier Western European border it has made its way back into the center of Europe.

Biotechnology – The Industry of the Future Following the technical revolution of the steam engine in the 19th century and chemistry and semiconductors in the 20th century, bio- and gene technology alongside information and telecommunication technology (IT), is the key technology of the 21st century. Today biotechnology is already driving a rapidly growing market in all areas of life. Worldwide over 4,700 companies turnover 70 billion € in this sector. Particularly in the medical field

biotechnology has become essential for example in the fight against cancer and infectious diseases. Currently there are 147 medicines registered in Germany that are manufactured using gene technology. These recombinant medicines make at 4.7 billion Euros already 16 % of pharmaceutical sales in Germany. Important areas of application include diabetes (insulin), multiple sclerosis and rheumatoid arthritis (immunomodulators), cancer (monoclonal antibodies), congenital metabolic and clotting disorders (enzymes, clotting factors) and preventative vaccination (cervical cancer, hepatitis B).

Research at University Campus in Regensburg With its university, the University of Applied Sciences and its Medical Centre, the City of Regensburg possesses the youngest and most modern institutions in Bavaria, where 7,000 employees and 28,000 students have significantly embossed the dynamic economic location of Regensburg. The individual professorial chairs have, through various means, proven the top-class university-standard

research achievements in the field of the biological sciences (the socalled life sciences). In addition to special fields of research of the German Research Association (DFG), particularly in metabolic physiology and immunology, several project assistance measures provided by the Federal Ministry of Education and Research (bmb+f ) have been injected into the neurosciences for example. The José Carreras Foundation has been obtained for hematological therapies using adult stem cells. The Human Tissue & Cell Research Foundation was founded on site for the development of new methods for therapy for patients with liver disease. The development of vaccines against the HIV virus (AIDS) is funded significantly by the Bill and Melinda Gates Foundation. In the field of infection biology the Medical Centre is a partner of the World Health Organization (WHO). Beyond that, research is being performed in Regensburg on therapies to combat cancers. The University of Applied Sciences is just starting the biologization of medical engineering by creating a study course in “Biomedical

BioRegio Regensburg

Engineering”. This program combines biological and conventional materials of the medical technology with mechanical engineering.

External University Research Activities Since 2008 the Fraunhofer Project Group for the Diagnosis and Treatment of Tumors, Metabolic Disease and Disease associated with Ageing and since 2011 the Fraunhofer Project Group for Sensor Technology Materials has been located in the BioPark as an external university research unit. In 2008 the research network “BayImmuNet” has commenced its activities in Regensburg. The goal is the development of new therapies and medicines for infectious diseases, tumor diseases, autoimmune and rheumatic diseases. In 2011 followed the establishment of Pro-Retina, a new endowed chair for retina research and development of novel diagnostic methods for the prevention of blindness. Additionally the Centre for Interventional Immunology (GKC) started up and links existing medical and scientific excellence in the field of immunotherapy and transplantation medicine in East Bavaria. The GKC intends to later branch out as an external university institution and in the long term become established as the first institute of the Leibniz-association in Regensburg.

The Business Location of Regensburg The Development of Innovative Technologies in and around the city is booming. Regensburg and the surrounding area have developed into one of the strongest economic regions in Bavaria in the last few decades. Leading international high-tech companies like BMW AG, Infineon AG, Continental AG, Osram Opto Semiconductors GmbH and GE (General Electric Company) have set up in Regensburg. Mid-sized

With the opening ceremony of the third construction phase on 23.09.2011, the history of success of the BioPark continues on. (from left to right): HS (Lord Major Regensburg), BH (Secretary of State BMWI), MZ (Acting State Premier)

companies such as Krones AG and Maschinenfabrik Reinhausen GmbH have been able to develop. With 1.4 billion € in turnover and a total of 15,500 employees, the healthcare industry has developed into an important economic sector in the city. The six Regensburg clinics currently have 8,500 employees, including 604 practicing doctors, 134 dentists and 46 pharmacists on site.

The BioPark Regensburg Through the foundation of the BioPark Regensburg GmbH in 1999, the City created a further catalyst for this aspiring futurefocused sector. With support from the State of Bavaria, the German Government and the European Union, the BioPark was erected for 42 million € in three construction phases in 2001, 2006 and 2011 directly on the grounds of the University. The multifunctional buildings offer in total 18,000 sqm state of the art laboratory, office and storage facilities for companies and institutes in the field of biotechnology, medical technology and associated services. In addition to use of the university infrastructure and small distances between buildings on site, Regensburg’s own motorway connection facilitates direct and rapid connections to Munich, Frankfurt and Berlin. Currently 31 leaseholders with 550 employees are active in the BioPark.

Success Made in Regensburg The BioPark Regensburg celebrated its 10 year anniversary in 2009. In this period over 25 million € has been invested in the development of the “life sciences” of this solely 102 million € in venture capital. 37 companies have been founded since 1999 and the number of employees has increased more than six-fold to 2600. The BioPark companies have regularly received awards of excellence for their innovative business ideas, e.g. the German Foundation Prize (Antisense Pharma) or the European Biotechnica Award (Geneart, today part of US Life Technologies Inc.). AMGEN Research GmbH is the first research center in Europe that is from one of the largest Biotech companies in the USA. In 2006 application of the BioPark for BioRegio Regensburg to be accepted as a biotech network in the federal initiative “Competency Networks Germany” was successful. In 2008 BioPark Regensburg was awarded “Landmark” by the Federal Initiative “Germany – Land of Ideas“. Since 2007 the BioPark has been part of spokesman circle for the Council of German Bioregions and since 2011 a board member of the German Association of Innovation, Technology and Business Incubation Centers (ADT).

BioRegio Regensburg

36 Production in the Region A range of companies at BioRegio Regensburg have developed into international production locations for clean rooms. These include pharmaceutical companies such as Bionorica AG and Haupt Pharma Amareg GmbH, and also biotechnology companies such as Syntacoll GmbH, PAN Biotech GmbH and medical technology companies such as RKT Roding Kunststoff-Technik GmbH, Raumedic AG and Gerresheimer Wilden AG.

Interdisciplinary Projects Innovation and success require constant analysis and development, and this is also true for the BioPark in Regensburg. In regular location analyses, the potential for development of BioRegio Regensburg has been analyzed and founded the Agency IA-Biotech realize this. In the applied fields of molecular diagnostics and biochips, as well as biofunctional surfaces, regional companies in the areas from the glass industry, engineering, electronic technology, textiles and nutrition were brought together via workshops with the companies from BioRegio Regensburg. Through this new network spanning these technologies, the dynamic in the Cluster was able to be increased by a further 11 regional companies. A further extension is the Sensor Technology cluster platform. In addition to the successful company PreSens Precision Sensing GmbH (Chemo- and Biosensors), now the cluster management of the Sensor Technology Strategic partnership is located in the BioPark and no has founded in 2009 the new network optical technologies in photodynamics. The goal is to implement medical applications such as tumor diagnostics or tumor control with the aid of novel optical technologies.

With the opening in-house of our own St John’s nursery “bamBIOni” in BioPark III, the compatibility of having a career and a family was promoted.

Conclusion Since its opening, the BioPark has undergone a very fast-paced and unmatched development. The end of the line still cannot be anticipated. A satisfaction survey resulted in 85% of our customers being satisfied with our performance and the quality of our work. Whatever the future might have in store: We are well-prepared!

Companies of BioRegio Regensburg (Status 2012) www.bioregio-regensburg.de

Biotech-Companies (to OECD) 2bind GmbH (founded in 2011, 1 employee) service provider to quantify bi-molecular interactions (synthesis and modification of the substrates by microscale thermophoresis method).

based Amgen Inc., the world's largest biotechnology company that discovers, develops, manufactures and markets human therapeutics based on advances in cellular and molecular biology. Antisense Pharma GmbH (in the BioPark, founded in 1998, 74 employees) develops new medicines based on antisense oligonucleotides to treat cancer (brain tumors, bowel cancer, pancreatic cancer and melanoma). BioGents AG (founded in 2002, 6 employees) develops biological attractants and repellents for pest insects. Involves the research and development of monitoring systems. Molecular biological analysis. Subsidiary Brazilian Ecovec Ltda.

Active Motif Chromeon GmbH (founded in 2005, 4 employees) develops and produces fluorescent dyes, nanoparticles, LED compatible fluorophores and fluorescence-conjugated molecules (DNA, peptides, antibodies and other proteins).

Biometric GmbH (founded in 1996, 10 employees) is a laboratory for microbiological and chemical analysis - dealing with the analysis of water, hygienic control and providing microbiological analyses of pharmaceutical products, medical devices, cosmetics and food.

Amgen Research GmbH (in the BioPark, since 2001, 20 employees) is a subsidiary of US-

Davids Biotechnologie GmbH (founded in 1996, 9 employees) production of polyclonal antibo-

BioRegio Regensburg dies (in both chicken egg yolk and rabbits), development of monoclonal antibodies, production and purification of antibodies from cell cultures and bioreactors. Transient transfection of cells in cell cultures and purification of the produced proteins. Development of diagnostic methods. Development of cell bases diagnostic methods. Delphitest GmbH (founded in 2004, 7 employees) works on DNA diagnostics and focuses on paternity tests and other genetic analyses for private customers. Entelechon GmbH (founded in 1999, 15 employees) combines bioinformatics, molecular biology, DNA synthesis and protein expression into a versatile environment for projects such as the development of diagnostic assays, directed evolution, protein engineering, or the identification and validation of cancer biomarkers. Geneart / Life Technologies Inc. (in the BioPark, founded in 1999, 185 employees) service provider for gene synthesis and downstream processes (DNA engineering and processing). Provides key technologies for projects in Synthetic Biology and for customers of Pharma- and Biotech-industry. Since 2010 Geneart belongs to the US-based Life Technologies Corporation. Hepacult GmbH (in the BioPark, founded in 2002, 7 employees) develops and markets cell culture technology based on human liver cells and other human organs for novel drug development and new therapy for liver cell transplantation. Hyperthermics Regensburg GmbH (in the BioPark, founded in 2002, 7 employees) develops and mar-

kets cell culture technology based on human liver cells and other human organs for novel drug development and new therapy for liver cell transplantation. IRIS Biotech GmbH (founded in 2001, 10 employees) specializes in reagents for peptide synthesis, carbohydrates and products for life science research and supplies from grams for research organizations to multi-ton lots for productions. Labor Friedle GmbH (founded in 2003, 35 employees) Certified chemical-analytical laboratory for food ingredients, analytics of chemical residues, nutrient content analytic, examination of human biological matrices, microbiological examinations and examination of indoor air pollution. LipoFIT Analytic GmbH (in the BioPark, founded in 2004, 20 employees) is the leading company in commercial NMR-analytics in Europe. It offers the simultaneous analysis of hundreds of substances in one sample by modern and patented methods, which are predominantly in use in clinical, pharmacological and biological studies. Lisando GmbH (founded in 2009, 4 employees) designs and develops novel effective antibacterials to combat bacterial pathogens: ARTILYSINâ&#x201E;˘ are proteins that are designed by LISANDO in order to efficiently destroy bacteria, using an enzymatic mechanism. Lophius Biosciences GmbH (founded in 2002, 19 employees) is a research based biotechnology company specialized in the development, sales & distribution of novel T cell test kits for diagnosis and concomitant treatment of infectious diseases and autoimmune disorders. Lophius uses its

37 proprietary innovate platforms to this end: the UREA-technology and the Reverse T cell signaling technology (RTT). NeuroProfile GmbH (founded in 2001, 2 employees) develops novel pharmaceuticals for diseases like Parkinsonâ&#x20AC;&#x2122;s, Alzheimerâ&#x20AC;&#x2122;s, schizophrenia and depression by using innovative neuronal targets (disease-related genes or proteins). Services. Oxford BioLabs Ltd. (in the BioPark, founded in 2009, 9 employees) is a science-based company tackling Androgenetic Alopecia (AGA). The company is developing novel therapies for the treatment of AGA, which is commonly known as male and female pattern baldness. PAN Biotech GmbH (founded in 1988, 36 employees) partner in the field of cell-culture, especially for serum-free systems, cell culture media, custom-made products and research. Application-oriented product optimization. PAN Systech GmbH (founded in 2001, 12 employees) develops, produces and markets a broad palette of innovative biotechnological systems related to cell-culture and laboratory automation, including the newest applications of bio-process technology. PolyQuant GmbH (founded in 2007, 4 employees) provides a powerful technology for the absolute quantification of proteins, targeting drug discovery and biomarker validation. Main advantages of the technology are rapid assay development and a high accuracy. PreSens GmbH (in the BioPark, founded in 1997, 60 employees) developer and manufacturer of chemical optical

BioRegio Regensburg

38 sensors and systems for customers in Biotechnology, Pharmacy, Medical Devices, Food Industry and in many other scientific fields. rent a scientist GmbH (founded in 1995, 13 employees) Service provider, working contractually in the field of applied research and the development and optimization of ready-for-themarket products and chemicaltechnical processes.

medical devices and components. The company has provided comprehensive OEM services and a complete range of finished and CE-marked products made of silicone. DSM Pharma Chemicals GmbH (since 2001, 33 employees) The company offers services in the field of chemical process development and synthesis of chemical intermediates and active substances.

Schmack Biogas GmbH (founded in 1995, 280 employees) technology and market leader of the German biogas industry. Planning, construction and operation of ready-to-use peripheral biogas plants. Part of the Viessmann Group since 2010.

nal von minden GmbH (founded in 2004, 90 employees) specialized in rapid tests, Elisa and homogenous enzyme immune assays in the fields of gynecology, infectious diseases, cardiac infarct markers, detection of cancer, urology and especially drug of abuse.

Life Science Companies (Pharma, Medical Engineering, Analytics)

Cfm Oskar Tropitzsch e.K. (founded in 1985, 8 employees) is specialized in rare chemicals and the contract manufacturing according to customers needs. Core areas of activity are fermentation products, phytochemicals, pharmaceutical raw materials, enzymes, venoms, metals and metal salt dilutions. Degania Silicone Europe GmbH (founded in 2002, 4 employees) is a leading silicone manufacturer of

Medical Device Partners GmbH (founded in 2001, 3 employees) is a consultancy with the following main aim: to support our clients in bringing products and services successfully to the medical device market. Multi-Service-Monitoring (in the BioPark, founded in 2003, 14 employees) offers services for the conduct of clinical studies in Germany, Austria, Switzerland, Czech Republic, Slovak Republic and Hungary.

Syntacoll GmbH (founded in 1927, 70 employees) develops and manufactures innovative collagen products for medical and pharmaceutical use (implants and tissue engineering).

Bionorica SE (founded in 1933, 489 employees) develops and produces drugs from plants under GMP-conditions (phytotherapeutics). Subsidiary Bionorica Ethics GmbH (former Delta 9 Pharma GmbH, founded in 2002) develops new active substances and medicines in the field of pain relief.

of tumor data and clinical studies, consults life science institutions in questions concerning IT, and executes computer forensics.

Spring awakening at BioPark Regensburg

Gerresheimer Regensburg GmbH (350 employees in medical technology in Bavaria) The Gerresheimer Group is a leading company in the business fields of tubular glass, moulded glass, life science research and plastic systems Haupt Pharma Amareg GmbH (founded in 2003, 262 employees) Focus on pharmaceutical contract manufacturing (GMP production, packaging of solid enzyme products, liquid and semi-solid medicines). ManaThea GmbH (in the BioPark, founded in 2004, 15 employees) develops medical software for the statistical analysis

Novapura Deutschland (in the BioPark, founded in 2009) Swiss based company which develops and sells innovative disinfection procedures (bacterial measurement). Pharma Stulln GmbH (founded in 1984, 130 employees) produces sterile pharmaceutical products with experience of over 20 years in the manufacturing of preservative-free eye drops in single dose units. Contract manufacturing for international pharmaceutical industry. Raumedic AG (founded in 2004, 420 employees) supplier for medical and pharmaceutical companies. Development and production of innovative diagnostic and acute therapeutic systems for the sectors of neurosurgery, urology, gastroenterology and traumatology.

BioRegio Regensburg nology for in sterilization, air dressing and combating of hospital-acquired infections.

RKT Rodinger Kunststoff Technik GmbH (founded in 1974, 50 employees in medical technology) develops plastic components for medical technology engineering, for example biosensors and different pharma/medical applications. Sensorik-Bayern GmbH (in the BioPark, founded in 2007, 10 employees) supports the “Strategic Partnership for Sensor Technologies” with handling of common partner projects and offers services in research and development, innovation management and business consultancy. Transcatheter Technologies GmbH (in the BioPark, founded in 2005, 2 employees) develops a transcatheter aortic heart valve prosthesis.

Interdisciplinary Companies (with Life Science Projects) aquagroup AG (founded in 2004, 22 employees) ensures a supply of bacteria-free drinking water right at the location of use and offers holistic hygiene concepts. Delta Entwicklungsgesellschaft mbH (founded in 1994, 10 employees) works in development projects on a contracting basis for manufacturers of tables for patient positioning and automotive equipment manufacturers in Germany and abroad. emz-Hanauer GmbH & Co. KGaA (founded in 1948, 650 employees) develops and manufactures mechatronic systems for domestic engineering, household appliances and environmental engineering. eswegee Vliesstoff GmbH (founded in 1928, 450 employees) is a global supplier of the widest

SCHOTT-Rohrglas GmbH (founded in 1970, 1000 employees) Tailor-made products and services for international growth markets such as pharmaceutics, electronics, automotive and environmental technology.

The companies in the BioPark and the BioRegio Regensburg are well networked by the Cluster Biotechnologie Bayern in the State of Bavaria and have an international presence

range of nonwoven technologies for industrial applications as well as for the apparel industry. Linhardt Metallwarenfabrik GmbH & Co. KG (founded in 1943, 1200 employees) develops and produces aluminum and plastic tubes as a partner to the cosmetics and pharmaceutical industries and as a provider of a comprehensive range of special solutions. MISTER Mikrosystemtechnik Regensburg (founded in 1997, 2 employees) develops sensor technology in biosensors, diagnostics, instruments for laboratory and process control. Pfleiderer Teisnach GmbH & Co. KG (founded in 1881, 220 employees) develops, produces and distributes tailor-made solutions in paper for various applications (e.g. for food packaging) Reinhausen Plasma GmbH (founded in 2004, 20 employees) a highly innovative company offering plasma solutions for surface processing. Develops new tech-

Ullrich GmbH (founded in 1980, 42 employees) manufactures semi-finished glass products for the automotive industry as a primary product for lenses in xenon headlights. Service provider in special machine construction for the glass industry. Zwiesel Kristallglas AG (founded in 1872, 630 employees) World's market leader for crystal glass in top-class international gastronomy and the hotel industry. Innovation pioneer in Tritan® technology and Biofunctional Surfaces.

Author:

Dr. Thomas Diefenthal CEO

BioPark Regensburg GmbH

Josef-Engert-Str. 13 D-93053 Regensburg/Germany Phone: +49- (0)9 41 - 920 46 0 Fax: +49- (0)9 41 - 920 46 24 E-mail: info@biopark-regensburg.de www.bioregio-regensburg.de

IGZ Würzburg – where knowledge becomes business

IGZ Würzburg

Würzburg has huge potential to offer when it comes to the health industry, biomedicine and biotechnology as well as medicine and medical technology. For ten years now, the "Innovations- und Gründerzentrum" IGZ Würzburg (innovation and business incubation centre) has been a major player in developing, profiling and networking the local scientific and business community. IGZ Würzburg is the largest business incubation centre in Lower Franconia. Opened in December 2001, it has since provided some 2,500 m2 lab and 3,000 m2 office space to technology-oriented entrepreneurs in their formative stages at competitive prices. All labs have hightech equipment and can be upgraded to the higher security standard S2. It also provides conference and seminar facilities as well as consultancy services, which are currently being used by 23 companies with some 300 employees. The centre aims at safeguarding jobs, creating networks and synergies as well as promoting the region scientifically and economically. The facility is run by a separate operating company whose shareholders include the city and district of Würzburg, Sparkasse Mainfranken (savings bank) and the Würzburg-Schweinfurt chamber of commerce (IHK).

Würzburg – a force to be reckoned with in life sciences With its research centres, research groups, and postgraduate schools of medicine and life sciences, the Julius-Maximilian University ranks among the most successful universities in Germany. The Rudolf-

IGZ, the innovation and business incubation centre, is located in the science park on the Würzburg-Ost industrial estate (Gewerbegebiet)

Virchow Centre for Experimental Biomedicine is one of the DFGfunded centres of excellence focussing on the identification of new target proteins in cancer, cardiovascular, auto-immune and inflamma-

Possibly a future drug to prevent the increase in cranial pressure in craniocerebral trauma: the test substance VAS203 from the company vasopharm

tory diseases, which can be the basis for improved diagnosis and treatment. The Comprehensive Cancer Centre (CCC) was established at Würzburg university hospital in 2011 and is recognised as a centre of excellence for oncology by German Cancer Aid (Deutsche Krebshilfe). The new Comprehensive Heart Failure

Centre (CHFC) performs excellent research into cardiovascular diseases. Würzburg is home to one of five German banks of biomaterials and data which are an important prerequisite for a better understanding of diseases and disease mechanisms. The dual centre of internal and operative medicine (Doppelzentrum für Innere und Operative Medizin) of the University clinic Würzburg was completed in 2009. It provides excellent technical facilities and optimal conditions for patient care as well as basic and clinical research.

Networking – locally and in Bavarian clusters At the IGZ Würzburg, a structured program is pursued above all in order to further develop the potential of life sciences in the region. Start-up companies, company relocations and existing companies are promoted and given especially intensive support in cooperation with the Bavarian Ministry of Economic Affairs, the

IGZ Würzburg Würzburg university colleges, the netzwerk nordbayern and the city of Würzburg economic development department. The incubation centre promotes cooperation of regional companies and partners from different sectors like health care, medical engineering, silicate research, plastics technology, and imaging. Furthermore, as regional partner in Lower Franconia, IGZ Würzburg ensures efficient networking with Bavarian biotechnology and medical engineering cluster initiatives.

Support for entrepreneurs Together with local universities and netzwerk nordbayern, IGZ Würzburg has developed a comprehensive program for promoting start-up activities in the region. Young scientists are offered advanced trainings courses with an economic and branch-specific focus. Technology scouts at colleges and research institutions in the region are screening research results for new business concepts with high economic potential at early stages. Once promising concepts and entrepreneurial teams are identified, start-up projects are individually and intensively supported during the whole start-up

The research focus of the international biotech company Patrys lies in the development of human antibodies for the treatment of cancer

phase. IGZ Würzburg thereby provides continuous support in team-building right at the academic origins of the start-up companies. Through intensive coaching and support the IGZ tries to ensure a smooth transition for company founders between their academic and entrepreneurial careers.

reflected in the scoring of various Würzburg start-up projects in the Northern Bavaria business plan competition: since 2007 prizewinners have come regularly from Würzburg life sciences with the teams Calportin Pharmaceuticals, Xenopharm, CoBalt and SmartmAb. In order to promote business ideas it was possible to gain over 5 million Euros in public funding (GO-Bio, VIP, EXIST-Forschungstransfer and EXIST-Gründerstipendium). Three start-up companies that have emerged from the pre-seed start-up programs have moved into the IGZ. Further start-up companies are expected in the coming years. Contact: Klaus Walther Director

Start-up support bears fruit In recent years, in close cooperation with universities and netzwerk nordbayern, IGZ Würzburg has done the initial work for creation of many new jobs at the incubation centre. Successful support by the IGZ and partners is

IGZ Würzburg has a comprehensive service package for young companies: Hire of 3000 m2 office space and 2500 m2 lab space at competitive prices Flexible rental possible - from small units to building tracts High-tech equipment, labs can be upgraded to the S2 security standard Provision of a variable and suitable infrastructure Support in preparing business plans Advice on business strategies, business models, patent and brand strategies, quality management and quality assurance, corporate management questions; Advice on financial planning and financing, support in investor talks and financing rounds as well as when negotiating with strategic, licensing and cooperation partners.

IGZ Würzburg 97076 Würzburg Phhone: +49-931-270 58 14 Fax: +49-931-270 58 16 E-Mail: klaus.walther@stadt.wuerzburg.de

Dr. Christian Andersen Project Manager

Phone: +49-931-270 62 94 Fax.: +49-931-27 95 92 13 E-Mail: christian.andersen@igz.wuerzburg.de

Dr. Gerhard Frank Project Manager

Other tasks include the following: regional and supraregional networking networking academic and industrial partners collaboration in the creation and further development of a constructive climate between regional companies and institutions in Würzburg and the Mainfranken region

Phone: +49-931-27 95 92 14 Fax.: +49-931-27 95 92 13 E-Mail: gerhard.frank@igz.wuerzburg.de

Bavarian Research Cooperations

Tremendous advances in stem cell and genome research For the scientists led by Professor Wolf Mutschler at the Department of Surgery and Outpatient Clinic of the LMU Munich, the beginning of 2012 marks the end of an era: for almost three and a half years, they have been developing new forms of treatment for degenerative diseases of the musculoskeletal system (e.g. osteoporosis, disc degeneration and the degeneration of tendons) as part of the ForZebRA Research Cooperation. ForZebRA is funded by the Bavarian Research Foundation and is one of currently 14 Research Cooperations in Bavaria that bring together experts from various scientific disciplines. Four Cooperations are currently active in the biotechnology sector: three are researching medical subjects, while FORPLANTA (see page 42) focuses on green genetic engineering.

ForZebRA:

hope for people with degenerative diseases Conventional therapies used to treat degenerative diseases are based on damage limitation - whereas the goal of ForZebRA was to eliminate that damage. Regenerative medicine has set itself the goal of cell-based renewal and repair of damaged tissue instead of limiting itself to drugbased and/or surgical improvement of the function of existing tissue.

From fundamental research … To research the molecular causes of degenerative diseases, investments first had to be made in fundamental research and models developed in parallel in which therapeutic strategies could be verified under suitable biomechanical conditions. The spectrum therefore ranged from the scrutiny of stem cell biology to large animal models.

Subproject 1: Cell biology and genomics

In subproject 1, led by Professor Franz Jakob from Würzburg, a platform for “cell biology and genomics” was created that focused on gene expression in mesenchymal stem cells (precursor cells of connective tissue) and in stem cells during the course of their differentiation. The researchers paid particular attention in the process to the differences in the gene expression patterns in younger and older people. The results represent significant advances in the understanding of stem cell biology. The team was able, for example, to characterise the first therapeutic

target molecules that appear to be suitable for initiating countermeasures against aging and degeneration. … to regenerative therapy The findings from the first platform were factored into a second: “cell application and cell tracking”. The researchers led by Professor Peter Bartenstein and Professor Matthias Schieker, both from the LMU, were able to develop molecular and also functional imaging methods that allow the therapeutic strategies tried out in pre-clinical animal testing to be pursued with regard to the cells involved, the vitality of the newlyformed tissue and ultimately its function. The third platform, “large animal models”, is particularly important for musculoskeletal diseases since only it is able to simulate suitable biomechanical conditions of the type found in humans. During the course of ForZebRA, the researchers on this subproject led by Professor

Subproject 2: Cell application and cell tracking

Bavarian Research Cooperations

post-natal glial cells (“support cells” in the brain) of mice into specific, synapse-forming subtypes of nerve cells. This conversion of astroglial cells into specific neurons could offer a valuable alternative to the transplantation of nerve cells which can be obtained from embryonic or neural stem cells.

markedly impaired, the long-term oral administration of Fluoxetine can increase the new formation of nerve cells by a third and that this effect is mediated by the neurotrophins BDNF and GDNF. This study could lead to new pathways in the treatment of the neuro-psychiatric symptoms of patients with Parkinson’s disease.

Fluoxetine stimulates neurogenesis A further area of focus lies in the pre-clinical testing of substances capable of mobilising endogenous, i.e. the body’s own, stem cells. A study by the working group led by Professor Jürgen Winkler, Department of Molecular Neurology in Erlangen, used an animalbased Parkinson’s disease model to investigate the influence of

New technology for the non-invasive monitoring of differentiation Electrical activity or membrane depolarisation plays an important role in the neural differentiation of stem cells and in the maturity, integration and function of neural cells. Channel rhodopsin-2 (CHR-2) is a protein which, following activation by light, forms an ion-permeable channel. By integrating CHR-2 into the cell membrane of neural cells, light stimulation causes the cell to depolarise. Dr. Albrecht Stroh and his colleagues have succeeded for the first time in expressing this optogenetic protein in embryonic stem cells and thereby optically stimulating stem cells and neurons differentiated from stem cells. Thanks to an automated microscopy system, researchers are therefore able to demonstrate the direct causal role of depolarisation in the neuronal differentiation of stem cells. The possible uses range from the non-invasive monitoring of the differentiation of stem cells to cell tracking and the detection of their functional integration in a neuronal network in vivo. www.bayfor.org/forneurocell2

Subproject 3: Large animal models

Eckard Wolf (LMU) and Professor Angelika Schnieke (TUM) developed the principles for cloning pigs that have an immune deficiency and which are therefore suitable for trialling human cellbased constructs without triggering rejection reactions. This will mean that a highly attractive large animal model will be available in future for the validation of innovative therapy options in the field of regenerative medicine. www.forzebra.de

ForNeuroCell II: new treatment methods for Parkinson‘s and other diseases The central domain of research of the ForNeuroCell II Research Cooperation, funded by the Bavarian State Ministry of Sciences, Research and the Arts, is the regulation of adult neural stem cells and their potential for regenerative cell replacement therapy. Great hopes are being pinned on the therapeutic use of stem cells for diseases of the nervous system, such as Parkinson’s, Alzheimer’s or even paraplegia. Specifically programming stem cells The specific programming of an individual's stem cells represents one strategy for the replacement of lost nerve cells. In a modified approach, the team led by Dr. Benedikt Berninger and Professor Magdalena Götz from the Helmholtz Centre in Munich/Institute for Physiological Genomics at the LMU successfully reprogrammed

Nerve cells from glial cells: Immunostaining reveals several neurons (GFP green) that have formed from the insertion of neurogenin 2 from astroglial cells obtained from the postnatal cerebral cortex

Fluoxetine on the new formation of nerve cells in the hippocampus (adult neurogenesis). Adult neurogenesis plays an important role in learning and memory formation, as well as in emotional processes such as anxiety and depression. Findings from various studies indicate that there is a probable link between reduced adult neurogenesis and the development of anxiety and depression. Depressive symptoms are also seen in 4070 % of patients with Parkinson‘s disease before the development of motor symptoms. The study now shows that, in this animal model, in which adult neurogenesis is

FORPROTECT: Diagnosis and treatment of infectious diseases and cancer In contrast to ForZebRA and ForNeuroCell II, FORPROTECT focuses on medical microbiology. FORPROTECT is funded by the Bavarian Research Foundation and focuses its re-

Bavarian Research Cooperations

44 search on the development of new approaches to the diagnosis and treatment of infectious diseases and cancer. In FORPROTECT, scientists from the LMU Munich, the Universities of Würzburg and Regensburg and partners from industry all work together. After the first two funding phases, the experts were already able to demonstrate clear results in the diagnosis of infections.

RecomLine Yersinia 2.0 IgG, IgA [IgM] from Mikrogen GmbH. The new PsaA and MyfA antigens allow serological differentiation between Y. pseudotuberculosis and Y. enterolitica infections

Electron microscopy image of Aspergillus-infected human epithelial cells

A new test for differentiating strains of Yersinia Researchers at the Max von Pettenkofer Institute in Munich have been able to identify two new antigens for the serological diagnosis of Yersinia infections that can lead to intestinal diseases (enteropathogenic Yersinia). The subsequent evaluation of these antigens was carried out by industry partner Mikrogen GmbH in Neuried, a company specialising in diagnostic tools for infectious diseases that leads the way on the national and international stage. The tests are now complete, and the improved test entitled recomLine Yersinia 2.0 IgG, IgA [IgM] now allows differentiation between the two strains of Yersinia Yersinia enterocolitica and Yersinia pseudotuberculosis. Improved treatment thanks to new uses for mass spectrometers The introduction of “matrix-assisted laser desorption/ionisation – time of flight” mass spectrometry (MALDI-TOF MS) to identify bacteria is one of the most

important advances in the field of microbiological diagnostics in recent years. The team at the Max von Pettenkofer Institute is working with the leading manufacturer of these devices, Bruker Daltonik, to research possible uses in the field of antibiotic sensitivity testing of multi-resistant pathogens. The aim is to significantly shorten the analysis period while at the same time ensuring high levels of precision, which would lead to faster and more specific treatments for life-threatening infections. The scientists are also working on more sophisticated methods for diagnosing fungi and the use of mass spectrometry methods for epidemiological problems such as the mapping of infection chains and sources of outbreaks. www.bayfor.org/forprotect

The main sponsors in Bavaria are the Bavarian Research Foundation and government ministries, the most active being the State Ministry of Sciences, Research and the Arts. The Bavarian Research Alliance (BayFOR) is a reliable partner to the Bavarian Research Cooperations. It takes care of the coordination of joint activities, networks the Cooperations and their members at European level and provides support for their PR activities. www.bayfor.org

Contact:

Anita Schneider

Collaborative research – a model for success Alongside interdisciplinarity, collaboration between universities and industry also helps to expand the borders of scientific disciplines and yield new findings. Many groundbreaking results in biotechnology would not have been possible without this collaboration. Bavaria therefore provides considerable support for collaborative research.

Public Relations Officer

Bavarian Research Alliance (BayFOR) Prinzregentenstr. 52 80538 München Phone: +49 (0)89 - 9901888-191 Fax: +49 (0)89 - 9901888-29 E-mail: schneider@bayfor.org www.bayfor.org

Effective antibody therapies Biopharmaceuticals in oncology and transplantation medicine

The main development activities are focused in the fields of oncology and transplantation medicine. ATG-Fresenius S is a polyclonal antibody that has made an important contribution to the prevention and therapy of organ rejection for more than 30 years. It has already been used safely and successfully in thousands of patients worldwide for immune suppression in connection with organ transplantations - an indication for which ATG Fresenius S is being approved in over 50 countries worldwide. ATG-Fresenius S is

EpCAM-positive carcinomas. With its trifunctional mode of action, Removab速 is the first antibody of a new generation. The aim of therapy with Removab速 is to achieve an enhanced immune reaction against cancer cells, which are the main cause of the formation of malignant ascites. Through simultaneous binding to cancer cells and to various cells of the immune system, T-cells and accessory cells are stimulated and activated mutually. The result is an enhanced immune response leading to the destruction of cancer cells. currently, however, being increasingly successfully used in stem cell transplantation and is already approved in several countries worldwide (including Germany and Austria). ATG-Fresenius S can thus be marketed for the prevention of Graft-versus-host disease (GvHD) occurring after stem cell transplantation. The basis for authorisation is the proven significantly lower GvHD complication rate after therapy with ATG-Fresenius S. The trifunctional antibody Removab (Catumaxomab) has been approved in the EU since April 2009 for the causal therapy of malignant ascites in patients with

Fresenius Biotech development sites are based in Germany and the USA. The Commercialization of the products ATG-Fresenius S and Removab速 is managed by own marketing operations or by cooperation partners.

Contact: Fresenius Biotech GmbH Frankfurter Ring 193a 80807 M端nchen Phone: +49 89-306593-738 Fax: +49 89-306593-292 info@fresenius-biotech.com www.fresenius-biotech.de

Biopharmaceuticals

Fresenius Biotech GmbH is a globally operating biotechnology company specialising in the development and marketing of biopharmaceutical therapeutic agents. The key competencies of Fresenius Biotech are in the development of immunologically active biopharmaceutical products, the international authorization and marketing for specialized indications.

EU research funding

EU research funding for biotechnology projects

Research funding accounts for a large proportion of the EU budget: at around Euro 54 billion, the 7th Framework Programme (FP7, term: 2007-2013) is the world‘s largest funding instrument of its kind. The Bavarian Research Alliance (BayFOR) provides information about opportunities that are available for scientists and entrepreneurs in relation to this funding. The EU has anchored biotechnology in its FP7 programme in two main areas, for which it is providing a total of Euro 8 billion: “Health” (red biotechnology) and

Plants that yield higher crops and are resistant to pests and disease are one of the goals of green biotechnology

KBBE (Knowledge-Based Bio Economy; green and white biotechnology). The focal areas of the “Health” programme lie in

translational research, i.e. in the translation of the results of fundamental research into clinical applications, as well as in the development and validation of new treatments, processes for health promotion and prevention, diagnostic tools and technologies. The KBBE programme focuses on the sustainable generation and management of biological resources and the development of modern technologies for industrial purposes. The FP7 is a “top-down” programme: the EU Commission announces the topics being funded and publishes them once a year.

ation of national and regional research activities through specific projects (ERA-NETs). Of relevance to biotechnology here are NEURON (neuro-sciences), TRANSCAN (translational cancer research), ERA-Age (age research), ERASysBio+ (system biology) and EUPHRESCO II (plant health). Of particular interest to SMEs is EuroTransBio, in which suggested topics are submitted (“bottom-up” principle) and which supports transnational R&D projects between academics and SMEs.

Excellent opportunities for small and medium-sized companies

The Innovative Medicine Initiative (IMI, 2008-2017) is a special

The research projects put forward by funding applicants should ideally lead to the solution of hitherto unresolved questions and thereby bring EU citizens recognisable benefits. The EU‘s aim is also to strengthen small and mediumsized companies (SMEs). Consequently, industrial involvement is desirable – and in some cases even mandatory – and increases the chances of winning funding considerably. This trend will continue to grow even further for the future research programme entitled “Horizon 2020” (2014-2020). Universities of Applied Sciences, which are generally in close contact with industry, could fare particularly well here. Another of the FP7’s areas of focus is the improved coordin-

Overcoming barriers to innovation together

Drug development is to be improved through close collaboration between science and industry

funding instrument financed by the EU and industry. Its aim is to overcome barriers to innovation in the development of drugs through greater cooperation between science and the pharmaceutical industry. EUREKA Eurostars supports SMEs in the development of innovative products and processes. The programme encourages transnational initia-

EU research funding

tives and operates on the “bottom-up” principle.

Finding a way through the maze of EU funding programmes The diversity of funding opportunities can present potential applicants with a set of complex challenges: identifying a suitable funding programme and making a successful application requires comprehensive expertise. This is where the Bavarian Research Alliance (BayFOR), which is sponsored in part by the Bavarian State Ministry of Sciences, Research and the Arts, provides extensive assistance for Bavarian institutions. BayFOR offers information about funding opportunities, carries out training courses and in particular provides active support for initiating projects, setting up international consortia and sub-

mitting applications. If the evaluation is successful, it can also offer assistance with contract negotiations with the European Commission and can, if necessary, take care of project management and PR issues. BayFOR has an excellent network at regional and international level. Its EU Liaison Office in Brussels represents the interests of Bavarian universities, raises their visibility and acts as their contact mediator to European institutions. BayFOR also coordinates the joint activities of the Bavarian Research Cooperations and supports their networking efforts at European level. The Scientific Coordination Office BavariaQuébec/Alberta/International facilitates bilateral research projects in these regions and develops these in part within the context of European research fund-

ing. As a partner in the Enterprise Europe Network (EEN), BayFOR also provides targeted consulting services for SMEs who are interested in taking part in EU research projects or who wish to cooperate across national borders. As a partner in the Bavarian “Haus der Forschung” (“House of Research”), BayFOR also works closely with Bayern Innovativ, the Innovations- und Technologiezentrum Bayern (ITZB) and the Bavarian Research Foundation (BFS). The collaboration between the four partners provides a central advisory service for European, national and Bavarian research and technology funding opportunities.

Links: www.bayfor.org/veranstaltungen www.hausderforschung.bayern.de Author:

Dr. rer. nat. Iana Parvanova Head of Unit Life Sciences and Medicine

Bavarian Research Alliance (BayFOR) Prinzregentenstr. 52 80538 München Phone: +49 (0)89 - 9901888-150 Fax: +49 (0)89 - 9901888-29 E-mail: parvanova@bayfor.org www.bayfor.org

Bavarian Genome Research Network

The Bavarian Genome Research Network: A special support program shows success In 2005, “Biotechnologie in Bayern” first reported about the Bavarian Genome Research Network (BayGene). The network, which links and promotes cutting-edge projects of functional genome research, has assumed the role of setting new benchmarks for the research environment in Bavaria. The goal of the twelve promoted projects and the associated partnerships between science and industry was to intensify the cooperation between outstanding research projects in an integrated network and to guarantee the dialogue between the individual groups at all times. This way it has been possible to promote and ensure efficient research and a fast technology transfer. After seven years of funding through the Free State of Bavaria we can look back upon an impressive amount of awards and important publications in renowned journals. For the Bavarian Genome Research Network, the year 2011 was a year of research awards and good news. Not only have all the group leaders been able to consolidate their positions at the universities, we also received three awards in the fall of 2011 thanks to the excellent research performance of our projects: First of all, on 27th of

Fig. 1: Professor Dr. Gunter Meister receives the “Young Investigator Award” during the fall meeting of the Society for Biochemistry and Molecular Biology in Frankfurt

September 2012, Professor Dr. Gunter Meister, head of the chair of biochemistry at the University of Regensburg, was honored with the “Young Investigator Award” of the Schering foundation during the fall meeting of the Society for Biochemistry and Molecular Biology (Gesellschaft für Biochemie und Molekularbiologie e.V.) in Frankfurt (fig. 1). He received the award endowed with 10.000 Euro during a festive ceremony for his outstanding fundamental research in the area of RNA biochemistry. In her

laudation, the representative of the Schering Company emphasized the exceptional contribution of Professor Meister to the understanding of the function of non-coding RNAs. His main research topics include the basic insight into gene regulation through microRNAs (miRNAs), molecules which are often involved in neurodegenerative diseases and play an important role in the formation of cancer. MiRNAs associate with members of the argonaute (ago) protein family and interact with partially comple-

Bavarian Genome Research Network

one of the highest distinctions in this area and is endowed with 1 million Swiss francs. It was given to him for his fundamental research on the formation of metastases. Since summer 2011, Professor Klein has also been leading a Fraunhofer project team in Regensburg, which was cofounded by the Fraunhofer ITEM and the University of Regensburg.

Fig. 2: Gene regulation through Micro RNAs. (Source: Professor Dr.Gunter Meister, University of Regensburg)

mentary sequences in 3’-untranslated regions (UTRs) of target mRNAs (fig. 2). This leads to the repression of translation or to the degeneration of the mRNAs. Individual miRNAs can regulate several different mRNAs and miRNA-ago-protein-complexes are embedded in large regulatory networks. In humans more than 700 miRNAs have already been detected; this indicates that a large part of the human genome is under miRNA control. Research from recent years has shown that the expression of miRNAs is affected in many tumor types. In order to understand the biology of such miRNA-misexpressions and their consequences for tumor pathogenesis, it is crucial to identify the individual target mRNAs and their respective miRNA-networks. So far there are very few suitable methods to analyze these networks. This is why Professor Meister works on the further development of tools, such as monoclonal anti-ago-antibodies, which he then uses to analyze regulatory miRNA interactive networks.

One week later, on 7th of October, we were pleased to congratulate Professor Dr. Christoph Klein on receiving the “Dr. Joseph Steiner Award for Tumor Research” (“Dr. Josef Steiner Krebsforschungspreis”) during a festive act at the University of Bern (fig. 3). He leads the BayGene project on molecular analysis of early metastasis and of minimal tumor residual disease at the University of Regensburg. This award, also known as the “Nobel prize of tumor research”, is

Fig. 3: Professor Dr. Christoph Klein, who received the “Dr. Joseph Steiner award for tumor research” in Basel

“In tumor therapy we often find ourselves at a point where the cancer seems to have been overcome; but some years later, there are new malignant cell accumulations that in many cases even lead to the patient’s death. These are cells which have distanced themselves from the original tumor site; after years of silent sleep they restart growing in another part of the body and become life threatening metastases” explaines Christoph Klein. How can these cells survive for years without being detected and which signals eventually trigger new growth (fig. 4)? Professor Klein seeks to answer these questions in the context of BayGene, in order to develop new drugs and therapies against tumor diseases. One important goal is the development of adjuvant therapies to prevent lethal metastasis of human carcinomas. His approach integrates tumor biology, tumor genetics and immunology and is based on the direct genomic analysis of these hard to find cells, which have left the site of the original tumor early on. By analyzing complex genetic mouse models he is able to improve efficiency and intensify the search for suitable target structures as well as effective immune effector mechanisms. His research group closely cooperates with clinics in Regensburg and Munich, as well as Bavarian biotechnology companies. This way the research is focused on practical outcomes and quick implementation from an early stage on.

Bavarian Genome Research Network

After the isolation of early disseminated tumor cells from the bone marrow of a carcinoma patient, their genome is analyzed with highly sensitive comparative genomic hybridization and thorough transcriptome analysis. This is how genotype and phenotype characteristics, i.e. definite mutations and molecular expression patterns of these malignant cells, can be identified. This approach allows for the first time the target identification of so far inaccessible tumor cells, which are the crucial origin of lethal distant metastases after the complete resection of the primary tumor and are thus the actual target cells of adjuvant, i.e. preventive therapies. Professor Klein has already been able to demonstrate the typical situation of early tumor cell dissemination in transgenic mouse models. In a mamma carcinoma model disseminated tumor cells can be isolated from bone marrow or other organs in a very early stage of oncogenesis. This experimental system presents the so far only possibility to identify novel therapeutic target structures of tumor diseases under in vivo conditions. In November 2011, BayGene received news that the research cooperation between the chair of genetics of the Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) headed by Professor Dr. Falk Nimmerjahn (fig. 5), Harvard University, Oxford University and the Scripps Institute in the United States will receive eight million US dollars from the Bill and Melinda Gates Foundation for their investigation of new HIV vaccination strategies. Although it is nowadays possible to suppress the immunodeficiency AIDS which is caused by the human HI-virus, there is so far no functioning vaccination strategy to prevent an infection and available

Fig. 4: Many aspects of metastases formation remain unclear, for example: Which cells disseminate early on from the primary tumor site? Which circumstances allow them to survive at other areas in the organism and which of these cells are able to grow metastases? (Source: Professor Dr. Christoph Klein, University of Regensburg)

drugs can cause some strong side effects. In this project funded by the Bill and Melinda Gates Foundation new techniques and methods should be developed, which allow a quicker proof of the success of new vaccination strategies. One pressing problem in the development and appliance of new vaccines consists in the large time span elapsing between vaccination and the moment when evidence for successful protection from infection can be retrieved. This causes large delays in the enhancement and optimization of new vaccination strategies, which would be essential for protection against the HIV infection. Professor Nimmerjahn and his work group at FAU will use their expertise on the function of antibodies in this project (fig. 6). New findings indicate that antibodies could play a crucial role in the prevention of infection with the HI virus. Antibodies are protein molecules which can be produced precisely fitting to intruding microorganisms, thereby preventing an infection with the same pathogenin the future. An important aspect in the functionality of virus-specific antibodies lays within the sugar side chains. Therefore, the research in this project is

focused on developing immunization strategies, which can generate virus-specific antibodies with a certain sugar structure capable of efficiently destroying infected cells. Having received the “Paul Ehrlich and Ludwig Darmstädter Award for Young Academics” (“Paul Ehrlich- und Ludwig Darmstädter- Nachwuchspreis”) only last year, this is already the second major award given to Professor Nimmerjahn for his research project in the context of funding through the Bavarian Genome Research Network. In addition to these spectacular achievements, the program has

Fig. 5: Professor Dr. Falk Nimmerjahn, who receives funding by the Bill and Melinda Gates foundation to develop a new vaccine against the immunodeficiency AIDS in Africa

Bavarian Genome Research Network

Bavarian Research Network for Molecular Biosystems have become an integral part of research funding in the Free State of Bavaria. The state investments have also been profitable for the Free State of Bavaria as proven by the high international reputation in genome research of the Bavarian research environment and the rapid development of the regional biotechnological industry. These long-sighted funding measurements have helped Bavaria more than any other federal state to achieve an international cuttingedge position in this research area and its industrial environment.

is funded by the Bavarian State Ministry of Sciences, Research and the Arts.

Fig. 6: Classic mouse models are not capable of displaying the complexity of the human immune system. This is why Professor Falk Nimmerjahn developed the humanized mouse

shown severable notable results: All together 375 publications have been released during the funding period. Furthermore the BayGene project leaders have accomplished several patents and the foundation of two biotechnology companies. Professor Hans Jürgen Wester founded the company SCINTOMICS as early as 2006 and nowadays enjoys growing international reputation. At SCINTOMICS radioactive tagged tracer molecules are being produced for positron emission tomography (PET-CT) for molecular imaging diagnostics and therapeutic methods. In November 2011, Professor Gernot Längst in cooperation with Nano Temper, a company already associated with BayGene, founded “2bind Molecular Interaction Services”, a bio-

technology company that provides measurements of interactions between biomolecules. The total of 12 projects, of which two have already completed their research, has proven in an impressive manner how the cooperation of several outstanding project groups in an integrative network can lead to a real added value overall. Both, the enhancements of important new technologies as well as the analysis of complex structures with already established analytic methods are equally important. Anconstant exchange of experiences further accelerates the work on individual research questions. Research networks such as the Bavarian Genome Research Network, the Bavarian Immunotherapy Network, many of the research associations or the newly founded

Authors: Dr. Ulrike Kaltenhauser Managing Director of the Bavarian Genome Research Network

Bavarian Genome Research Network Gene Center, LMU Munich Feodor-Lynen-Str. 25 81377 Munich

M. Sc. Claudia Szeibert Assistant to the Management of the Bavarian Genome Research Network

Bavarian Genome Research Network Feodor-Lynen-Str. 25 81377 Munich

Where innovation is born

Innovation

Innovation happens when a discovery or an invention is turned into a product; when it is, in other words, put into application. But what conditions need to be in place, what is the right environment? Where is it that innovation is born? Innovation rarely happens as a result of targeted research and development. It seeks out its own path. A good 60 years ago, the Engelhorn family, owners of pharmaceuticals company Boehringer Mannheim, established biochemical research and development operations in Tutzing on the shores of Lake Starnberg. They were keen to enable the newly discovered possibilities of enzymes to be used for medical purposes. Professor Hans Ulrich Bergmeyer, whom they had brought in to aid them in this endeavour, was well networked in the new scientific field and was in contact with hospitals and clinics. The first products were auxiliary agents that found use in enzyme research. Against all expectations, however, their efforts did not lead to any new medical drugs at that time. Instead, as the years progressed, a brand new sphere of medicine emerged at Lake Starnberg – biochemical analytics. This modern method of laboratory testing set new standards of accuracy over conventional chemical methods, and did not require the use of any environmentally damaging substances. What it did was determine biomarkers using biological reagents. Tutzing thereby turned out to be the birthplace of a modern diagnostic procedure that is today responsible for worldwide reven-

ues in excess of 30 billion euros. So why did this cradle of medical biotechnology develop here, of all places? The business‘s attractive location to the south of Munich doubtless had something to do with its ability to attract a skilled staff. More importantly though were the surrounding scientific and clinical facilities. At LMU Munich, Feodor Lynen, one of the world’s leading biochemists, had just discovered the basis of fat metabolism, for which he won the 1964 Nobel Prize. It was this discovery in turn that helped with the establishment of the Max Planck Institute in Martinsried. Many of the Tutzingbased researchers and developers had originally come from Lynen‘s lab or had been in his scientific environment. Furthermore, the two major university hospitals run by Munich’s LMU and TU offered numerous opportunities for cooperation in trying out new testing systems on clinical material. No long journeys were needed for materials or people. Moreover, all of the relevant academic researchers were pleased to come to Tutzing and Munich on a regular basis. The first medical biotechnology cluster had been born, though it wasn’t known by that name yet. Innovation happens in clusters, in places where excellent research and professional application come

together – but only if the two sides communicate with each other. Being frank enough to dialogue beyond cross-sectoral boundaries is an important innovation factor. Boehringer Mannheim produced the glycoside digoxin from the foxglove plant as the basis for manufacturing drugs to treat cardiovascular disease. And in the interests of counteracting intoxication caused by a possible overdose, they began to develop an antibody directed against the steroid digoxigenin that could render the active ingredient harmless in the blood. This anti-digoxigenin antibody had initially been developed for therapeutic purposes only. Back then, it was common in Tutzing for a group of scientists to take a stroll along the lake after lunch. As they walked, they would animatedly discuss topical scientific issues. Once, when they were talking about a new publication which described the possibility of labelling DNA non-radioactively with biotin/streptavidin, it occurred to them that they could use digoxigenin, found only in the digitalis plant, instead of the ubiquitous biotin. They believed this would significantly reduce the background noise in biological materials. Antidigoxigenin marking is, in the meantime, a standard method used around the world for the non-

Innovation radioactive labelling of DNA and immunoassay test systems. Industry needs to open up, as well. Until the early 1990s, it was common for pharmaceutical research to take place behind the closed gates of the company concerned. Moreover, pharmaceutical research had an almost exclusively chemical focus, and companies were not keen for outsiders to find out exactly how they synthesised new drugs. When some scientists at Boehringer Mannheim in Tutzing and later in Penzberg (Roche Diagnostics from 1997 onwards) began to move away from test reagents and diagnostics towards biological drug development, they were regularly faced with the need to adapt to new methods, as these were consistently developing with great speed. These included X-ray structural analysis, which was still undergoing a stage of rapid technological development in the early 1990s. One of the world’s leading laboratories in this field was located at the Max Planck Institute of Biochemistry in Martinsried. It was headed by Prof. Robert Huber, who had just been awarded the Nobel Prize for the structural elucidation of the first photosynthesis system. Instead of the scientists in Penzberg building up their own structural research department in the company, which is likely to have been obsolete within a few years anyway, they asked Prof. Huber whether he could conceive of a joint structural research group at the Max Planck Institute. In fact, Huber was thrilled with the idea, even though it did push lawyers for the Max Planck Society and the company itself to the limits of their flexibility. What they established was a joint working group, funded by industry and fed with the latest knowledge from the academic side. This working group, at that time unique and now a prime example of a technology transfer entity, was

the crystallisation seed for many new substances and structures. Yet innovation also happens when funding is not only used for the purpose for which it was planned. In management literature this is known as “bootlegging”. Experience has shown that such projects are often particularly successful. The Max Planck scientists occasionally used industry funding for similarly ‚illicit‘ purposes to work on their own ideas and projects alongside the official ones. Uwe Jacob, for instance, who held a position in industry, carried out structural analyses of crystals which Peter Sondermann had produced and which he wanted to study for purely academic reasons. This cooperation resulted in an interesting biological substance that demonstrated potential for use with autoimmune disorders. The two scientists teamed up with Prof. Huber to found the company SuppreMol in 2002 and began the exciting work of developing a brand new therapeutic principle for diseases which could previously only be treated symptomatically – and usually with considerable side effects. The active molecule SM101, the soluble part of an immune receptor (sFcγRIIb), can very precisely tone down the exaggerated immune reaction that occurs in autoimmune disorders like rheumatism, multiple sclerosis and lupus; this was demonstrated in animal experiments. In 2009, the drug began to be tested on humans, initially on healthy volunteers. Once the substance had proved to be well tolerated, a clinical study was initiated on ITP patients in 2010. ITP stands for immune thrombocytopenia, a disease in which the immune system attacks platelets in the blood (thrombocytes), which play an important role in blood clotting. Patients suffer from extensive reddening of the skin and bruises and, in serious cases, have to live with the risk of dying of internal bleeding. The first part of the study

was completed in 2011. Another study, this time on the disease lupus (SLE), was initiated in 2011. Lupus is a very complex, serious disease which often leads to kidney failure and other severe impairments. To this day there is no reliable treatment for lupus, either. An initial evaluation of the ITP study shows not only that the rate of side effects was also extremely low in ITP patients, but that signs of an interesting efficacy profile were identified as well: in some patients, not only did the thrombocyte count rise to the expected value over the two-month treatment period, it also stayed there throughout a three-month followup observation period. Patient numbers are still too small for definite conclusions to be drawn. But if this result were to be confirmed in further studies, it may signify a therapeutic breakthrough of great benefit to patients. Thus it was that a potential new therapeutic drug was born of scientific roots: A discovery turned into a potential innovation because basic research and application were brought together to act in concert from an early stage. The surrounding infrastructure had something to do with it, of that there is no doubt. The path to a marketable product is still long. But if the first promising results can be confirmed and the drug eventually achieves regulatory clearance, this will be a new and innovative product “made in Germany”. Author: Prof. Dr. Peter Buckel CEO

SuppreMol GmbH Am Klopferspitz 19 D-82152 Martinsried/München Phone: +49-89-309050 68-0 Fax: +49-89-309050 68-68

e-mail buckel@suppremol.com

VERTIS innovative RNA-seq Service

Ribonucleic acid (RNA)

RNA is central to the metabolism of all living things Ribonucleic acid (RNA) plays a central role in the metabolism of all organisms. The various RNA species represent the working copies of the genomes and play a central role in the development and preservation of life. So-called messenger RNA (mRNA) carries the information encoded in the genes for the synthesis of proteins, ribosomal RNAs (rRNA) and transfer RNAs (tRNAs) are responsible for the production of the proteins and a large number of non-coding RNAs (ncRNAs) represent an important part of adjusting screws, through which the activity of genes can be regulated. The class of small RNAs, only 20 to 30 nucleotides long, was discovered only a few years ago because they were simply overlooked because of their small size.

Transcriptomics The sum of all RNAs contained in a cell or an organism is termed as transcriptome and accordingly, the genome-wide analysis of the RNA molecules is referred to as transcriptomics. Because of the central role of the RNAs in the cellular metabolism, transcriptomics is in the focus of studies dealing with development, stress and illness phenomena. For example, the transcriptomes of stem cells and cancer cells are of particular interest to researchers, which examine the processes of cell differentiation and carcinogenesis. Only small proportions of the genomes of higher organisms (animals, plants and fungi) code for mRNA (in humans only 1-2% of the entire genome) and it is goal-oriented and economical to analyse RNA rather than entire genomes. Although it was shown that due to post-transcriptional gene regulation processes the

concentrations of mRNA and the encoded proteins are often not closely correlated, the measurement of RNA quantities remains an indispensable tool to determine how the transcription machinery of the cell is influenced by external signals (e.g. drug treatment) or to find out, how healthy cells distinguish themselves from diseased cells.

RNA-seq - a revolutionary new approach to the analysis of transcriptomes RNA-Seq is a recently developed approach to analyse whole transcriptomes using the new highthroughput Next Generation Sequencing (NGS) methods. The new ultra high-throughput technologies generate millions of reads per run, which, depending on the platforms, are 35 to 1100 bp long. The three most widelyused technologies are summarized in Table 1.

and

Tab. 1: Comparison of the performance of next-generation DNA sequencer

Ribonucleic acid (RNA) NGS studies have already massively expanded our knowledge of the size and complexity of pro- and eukaryotic transcriptomes. RNA-Seq provides a far more accurate measurement of levels of transcripts and their isoforms compared to other methods such as microarray analysis. Specifically, a new set of regulatory RNA elements have been identified with NGS, including siRNAs, piRNAs, miRNAs, sRNAs, CRISPRs, riboswitches and RNA thermometer. These elements allow fine tuning of gene expression within complex signal networks. The following is a brief summary of the main goals of RNA-Seq experiments: Quantification of gene expression levels: "digital gene expression" Classification of transcriptomes for different cell types or developmental stages Discovery of new genes and transcripts alternative splicing, new exons, alternative transcription start sites, new regulatory RNA molecules

sues, fluids, individual cells, environmental samples) is extremely difficult and requires much experience and secondly, the reliable conversion of the RNA in sequenceable cDNA is technically very tricky. VERTIS is specialized to prepare high-quality cDNA from all RNA species and from the whole range of variation of organisms, tissues and environmental samples. In its twelve-year history, the company has developed techniques that allow reliable production of cDNA, which is optimally suited for the analysis with the new ultra-high throughput sequencing techniques.

55 criptomes. Bacteria are in the central focus of important social challenge such as infectious diseases and they are of enormous economic interest as for white biotechnology or food industry. On the other hand, the production of high-quality cDNA from bacteria is highly demanding, since the bacterial mRNA is very unstable and due to the absence of 3’ poly(A) tails, it's enrichment is much more difficult. For this reason VERTIS has developed efficient techniques which enable a very accurate and deep analysis of bacterial transcription start sites. VERTIS provides a complete range of products, ranging from project consulting, nucleic acid isolation, sample preparation as well as DNA sequencing, bioinformatics sequence analysis and data mining. VERTIS has set itself the objective to provide its customers access to the potential of the new RNA-seq technologies in a reliable and cost-effective manner.

Identification of fusion genes Identification of allele-specific gene expression Quantifying mixed transcriptomes e.g. RNA-seq analysis of hostpathogen interactions Metatranscriptomics – analysis of the transcriptome (gene activity) of environmental samples and complete communities

Vertis RNA-Seq Service The analysis of RNA is a major challenge, since the isolation of the various RNA species in high quality from the different biological starting materials (animals, plants, fungi, microorganisms, tis-

The method development was focused in particular on: Enrichment of the different RNA species from eu- and prokaryotes with enzymatic, biochemical and electrochemical methods. Preparation of strand-specific cDNA from all RNA species that is optimally suited for the analysis with the different NGS platforms (see Table 1) and which allow strand-specific analysis of the sense and antisense RNA molecules. Special emphasis of VERTIS lies in the analysis of bacterial trans-

Contact: Dr. Fritz Thümmler CEO

vertis Biotechnologie AG Lise-Meitner-Straße 30 85354 Freising Phone: 08161-141 1211 Fax: 08161-141 1212 thuemmler@vertis-biotech.com

analytica 2012 Gathering for innovations

Messe München

The 23rd analytica, the International Trade Fair for Laboratory Technology, Analysis and Biotechnology, opens its gates from April 17 – 20, 2012. When it does, Munich will once again be a gathering for leading decision-makers in the pharmaceuticals, chemistry and several other industries. For four days, manufacturers along the entire value chain will present new products, ideas and research results. In addition, the scientific analytica Conference and the practice-oriented program of related events promote the transfer of knowhow and invite participants to network.

Bavaria is considered one of the top three regions for biotechnology in Europe. With more than 350 companies in the life-science sector including seven that are listed on the stock exchange, Bavaria is the leading German state in this sector. It has a sizeable lead, especially in the development of new therapeutic and diagnostic products. Every two years, analytica is not just the center of the Bavarian biotech cluster, it is also an international gathering for the entire analysis, laboratory-technology and biotechnology industry. Users and decision-makers in the chemicals, medical and pharma sectors as well as from industrial and government research come here to inform themselves about the latest analysis and laboratory techniques and about the state of the art in the live sciences. As a source of momentum for research and industry, analytica promotes new developments and sets trends for the future. This impact is not just the result of the classic exhibition: The extensive program of related events including its scientific conference and practice-oriented forums also contribute to the fair’s success. In 2012, new elements such as the Live Labs serve as

The industry is meeting at the 23rd analytica in Munich from April 17 – 20,2012

additional visitor attractions and create even better synergy between theory and practice.

The laboratory world For the first time ever, analytica and the Live Labs invite everyone to experience a genuine laboratory world. In portions of Halls B1, B2 and A3, well-known companies will present their products and solutions on the topics of forensics, medial diagnostics, plastics analysis and food and water analysis in real laboratory surrouun-

dings. The special show invites visitors to come and exchange information with exhibitors, have new products explained and discuss specific applications. The equipment on display at the laboratory benches includes all classic laboratory products, from chromatographs to analysis scales. Visitors can also look forward to Mark Benecke, Germany’s bestknown criminal biologist. At the Biotech Forum in Hall A3, the expert in the field of forensic entomology will show how the latest DNA analysis techniques can be used to draw conclusions about crimes and/or criminals.

Forum Biotech: Best Practice for users The Biotech Forum, the slogan of which is “From Practice – For Practice”, invites visitors to attend interesting lectures and reports based on actual experience on all four days of the fair. In many branches of industry such as the food industry, forensics and the pharma industry, biotechnology has become a permanent fixture and calls for specific applications and methods. The forum program examines the latest issues in practice, which are then discussed with experts at the forum.

Messe München

analytica Conference

analytica 2012: Innovations gathering

Start-ups in the limelight This special section of the InnovationArea covers the sector for research and development in the life sciences. As a result, analytica is taking into account the highly dynamic innovative nature of this sector. New companies and research institutes will present their innovations, services, research findings and business ideas in Hall A3. In 2010, the compact platform featured new biotech companies, and organizations in the nanochemistry, microreaction technology and bioinformatics sectors were also represented. Given the enthusiastic response during the last few years, innovative start-ups from Germany can participate in the “Made in Germany” joint exhibits again in 2012. analytica is supporting this initiative of Germany‘s Federal Ministry of Economics and Technology for the third time, allowing new companies to present their ideas to an audience of international professionals. Two “Made in Germany” stands are planned: one near the InnovationArea and the Biotech Forum in Hall A3, and one near the Laboratory & Analytics Forum in Hall B2.

Finance Day: Financing tips for life-science companies Anyone who wants to better understand how financiers work should attend Finance Day on the last day of the fair. Biotech entrepreneurs who do so can meet with investors and attend lectures and roundtable discussions that will inform them about the latest financing trends and models for the biotechnology sector. Topics range from “Early financing: Are HTGF and business angels defying the financial and economic crisis?” and “Venture capital: A shortage of growth capital for life-science companies” to “Industrial biotechnology – Germany’s pioneering role in a key industry of the future” and “Biotech companies listed on the stock exchange: A healthy environment for life sciences?”. An event featuring so-called elevator pitches is a special format for those who are particularly quickwitted: They can introduce themselves and their business ideas to participating investors in a brief presentation just five minutes in length.

The analytica Conference, which is traditionally held on the first three days of the fair, invites participants to exchange ideas and information. The conference and its application-oriented format is an established part of the fair. It gives visitors an overview of the latest scientific developments and their potential applications in the industry. The analytica Conference covers a wide range of topics, from high-science fields such as genomics to application fields in information processing such as chemo- and bioinformatics. Besides the presentation of innovations, interaction between theory and practice plays an important role. In half-day symposia, more than 100 leading international scientists will report on the latest topics and explain what modern methods are capable of, where they can be used and what their limits are. The extensive program of events gives each visitor an opportunity to take home the latest news about their specific area of expertise. The analytica Conference is organized by Forum Analytik, an organization that comprises three leading Ger-

analytica Conference: Science at the highest level

Messe München

analytica is firmly established on the Asian market with three spin-off events

man scientific associations, i.e. the German Chemical Society (GDCh), the Society for Biochemistry and Molecular Biology (GBM) and the German Society for Clinical Chemistry and Laboratory Medicine (DGKL).

Biotech boom in Asia analytica is firmly established on the Asian market with three spinoff events, i.e. in China, India and Vietnam. The last time these events were held, they attracted a total of some 800 exhibitors and 22,000 visitors. Biotechnology plays a key role in all three countries. For example, the Chinese

analytica China in Shanghai

analytica 2012: Facts and figures Tuesday – Friday,April 17 – 20,2012 Messe München,West Entrance Halls A1,A2,A3,B1,B2 Opening hours: Tuesday – Thursday: 9 a.m.– 6 p.m. Friday,9 a.m.– 5 p.m. www.analytica.de analytica Conference: Tuesday – Thursday April 17 – 19,2012 www.analytica.de/conference Price of admission: 1-day tickets start at EUR 27 (online) Online ticket orders: www.analytica.de/tickets

government is using strong financial support – investments in genome research are particularly high – to promote ongoing development in this sector. According to the experts, biotechnology currently accounts for an approximately seven-percent share of China’s overall pharma market. The core business of most Chinese biotechnology companies focuses on biomedicine, which predominantly produces affordable generics. This phenomenon is also manifesting itself in India. Thanks to the production of affordable biopharmaceutical medications, the subcontinent is now considered the fourth largest manufacturer of medications in the world. At the same time, it turns out that India is a perfect partner for testing new medications and carrying out clinical studies for international companies. Expectations for biotechnology are also high in Vietnam. The fair’s three spin-off events – analytica China (October 16-18, 2012), analytica Vietnam (April 18–20, 2013) and analytica Anacon India (Autumn 2013) – deal with these developments every two years and open doors to new markets for international companies. Autor:

Susanne Grödl

Trade-fair dates: Venue:

Messe München GmbH

81823 München e-Mail: info@analytica.de

The catalog and participation in the analytica Conference are included in the price of admission.

Internet: www.analytica.de

Your key to the European Research Area

You have an innovative idea in the field of medicine or biotechnology and are looking for Bavarian partners for your European research project? Talk to us today! Our expert team will help you identify the suitable research or business partner and actively support your application for EU funding.

Bavarian Research Alliance Unit Life Sciences & Medicine Prinzregentenstrasse 52, 80538 Munich /Germany Phone: (089) 9 90 18 88-0 Fax:

(089) 9 90 18 88-29

E-mail: parvanova@bayfor.org

No patent protection for inventions that rely on human embryos

Patent Law

The stem-cell decision of the European Court of Justice Introduction

The patent in suit

In such an ethically and morally charged field as stem cells, an objective explanation of the recent decision rendered by the European Court of Justice (ECJ) seems in order1. This holds all the more given the fact that (public) interest groups have already, shortly after rendition, exploited the decision of the highest European judicial authority for their own purposes. The decision concerns the patentability of human embryonic stem cells (hESC) as well as methods that employ embryos as a source material. This decision does not affect research freedom; the existing regulations in the field of embryonic stem cell research remain untouched. Furthermore, the ECJ has reasoned in its decision that it does not intend a scientific or moral assessment. Rather, the court saw its task in the clarification of the legislator‘s intent in drafting the European Directive 98/44/EG2 (the Directive), solely with regard to the question of patentability. The intended clarification was only partially achieved; on the one hand the ECJ’s interpretation of the Directive is unnecessarily strict, and on the other it gives rise to new problems as regards legal implementation.

Claim 1 of the patent 19756864 (Brüstle) reads:

“Isolated, purified, progenitor cells with neuronal or glial properties, obtained from embryonic stem cells, comprising no more than 15% primitive embryonic and non-neural cells obtainable by the steps of: a) cultivation of ES-cells to embroid bodies b) cultivation of the embroid bodies into neural precursor cells, c) proliferation of the neural precursor cells in growth factorcontaining serum-free medium, d) proliferation of the neural precursor cells from step c) in another growth factor-containing serum-free medium and isolation of the purified neural precursor cells and e) proliferation of the neural precursor cells from step d) in another growth factor-containing serum-free medium and isolation of the purified precursor cells with neuronal or glial properties, or a’) […] c’) d’) proliferation of the neural precursor cells from step c’) in another growth factor-containing serum-free medium to spheroids with neuronal or

glial differentiation potential and isolation of the neural spheroids e’) proliferation of the neural spheroid from step d’) in another growth factor-containing serum-free medium up to the development of a cell layer consisting of glial precursor cells and isolation of the purified precursor cells with glial properties.” Claim 6 specifies that the source of the ESCs may be embryonic germ cells (which are pluripotent, but not totipotent). Claim 8 specifies that the cells may be of human origin. Further claims are directed to the use of the resulting neuronal progenitor cells in therapy. It is important to note that the method for obtaining the hESCs is not part of the claims and the application describes, as paper examples, non-destructive ways of obtaining hESCs.

The first instance In the first instance, the German Federal Patent Court ruled in its decision 3 Ni 42/04 that the patent was partially invalid as far as it concerns subject matter that is derived from totipotent ESCs. The Federal Patent Court reasoned in its decision that at the time of filing, the only way of

Patent Law

generating hESC involved the destruction of a human embryo and, therefore, that the products and methods claimed necessarily involved the “use of human embryos”. The Court also interpreted this use as a “use for industrial or commercial purposes”, which is excluded from patentability under §2(2)(1) No.3 of the German Patent Act.

Law on Stem Cells (StZG), and which falls within the scope of the patent, cannot be contrary to ordre public since the legislator explicitly allowed just this use on behalf of and for the benefit of the people. The present case requires the interpretation of the Directive, in particular what is meant by “use of human embryos for industrial or commercial purposes”.

The referring decision of the Federal Court of Justice BGH)

The BGH referred the following questions to the ECJ while staying the proceedings before the Court

In the second instance, the German Federal Court of Justice (BGH) held in its decision Xa ZR 58/07 that the patentability of the claimed methods ultimately depends on the interpretation of Art. 6(2)(c) of the Directive (in particular with regard to whether or not an activity represents “a use of human embryos for industrial or commercial purposes”). The BGH further noted that the Directive provides no definition of the term ‚embryo‘3. The BGH further found that the subject matter of the claims cannot be excluded from patentability under § 2(1) PatG if there is at least one way of legally exploiting4 the invention. Importantly, it was noted that not every exploitation that may be prohibited by law or regulation is automatically contrary to ordre public. For example, a use that is allowed under certain circumstances under the German

“1. What is meant by the term “human embryos“ in Art. 6 (2) (c) of the Directive No. 98/44/EC? a) Are all stages of development of human life beginning from the fertilization of the egg cell comprised or must additional requirements be fulfilled as for instance reaching of a certain stage of development? b) Are the following organisms comprised too: (1) unfertilized human egg cells in which a nucleus from a mature human cell has been transplanted; (2) unfertilized human egg cells which have been stimulated to separation and further development by way of parthenogenesis? c) Are also stem cells comprised which have been derived from human embryos in the blastocyst stage?

2. What is meant by the term “use of human embryos for industrial or commercial purposes”? Does it encompass every commercial exploitation in the sense of Art. 6 (1) of the Directive5, in particular also a use for the purposes of scientific research? 3. Is a technical teaching excluded from patenting pursuant to Art. 6 (2)(c) of the Directive also in case that the use of the human embryos is not part of the claimed technical teaching of the patent but a necessary requirement for the application of this teaching, a) because the patent concerns a product whose manufacturing requires the previous destruction of human embryos, b) or because the patent concerns a method for which such product is needed as starting material?”

The Decision of the ECJ The questions of the BGH go precisely to the heart of the matter. Unfortunately the ECJ does not answer all the questions as precisely, the answers being: “1. Article 6(2)(c) of Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 on the legal protection of biotechnological inventions must be interpreted as meaning that: – any human ovum after fertilisation, any non-fertilised human ovum into which the cell nucle-

Fig. 1: Open questions: When is a "use" a "use of a human embryo" in the sense of the ECJ's interpretation of the Directive?

Patent Law

Fig. 2: Human stages of development. The decision, whether pluripotent stem cells from blastocysts represent patentable subject matter now lies in the discretion of the national courts (in this case the Federal Court of Justice, BGH)

us from a mature human cell has been transplanted, and any nonfertilised human ovum whose division and further development have been stimulated by parthenogenesis constitute a ‚human embryo‘; – it is for the referring court to ascertain, in the light of scientific developments, whether a stem cell obtained from a human embryo at the blastocyst stage constitutes a ‚human embryo‘ within the meaning of Article 6(2)(c) of Directive 98/44. 2. The exclusion from patentability concerning the use of human embryos for industrial or commercial purposes set out in Article 6(2)(c) of Directive 98/44 also covers the use of human embryos for purposes of scientific research, only use for therapeutic or diagnostic purposes which are applied to the human embryo and are useful to it being patentable. 3. Article 6(2)(c) of Directive 98/44 excludes an invention from patentability where the technical teaching which is the subject-matter of the patent application requires the prior destruction of human embryos or their use as base material, whatever the stage at which that takes place and even if the

description of the technical teaching claimed does not refer to the use of human embryos.”

Discussion In answering the first question, the ECJ defined a very early stage of human development as an “embryonic stage” but the Court did not address the BGH’s question as to whether “all stages of development” must be regarded as an embryo. This partly incomplete answer creates significant uncertainty regarding which developmental stages of the human body may or may not fall under the term “human embryo”. In its reasoning for the broad interpretation of the term “human embryo”, the ECJ referred to the recitals of the Directive, which repeatedly emphasize the protection of human dignity. As will be discussed further below, however, this interpretation appears ambiguous. First, the ECJ clearly ignores the legislator‘s express intention of fostering research in the field of biotechnology (Recitals 17 and 18 of the Directive6, see also Chapter 1.1 of „Stem Cell Patents: European Patent Law and Ethics Report“, 20067,8). The ECJ‘s decision is also restrictive; according to its holding, use in research is

also to be regarded as an industrial or commercial exploitation. Furthermore, the ECJ does not question why the legislator had left the term “human embryo” undefined. The report of an expert commission in 20059 gives rise to the impression that the legislator did not seek unification on this specific point, the prevailing views in the field of stem cells being too different for such a consensus. Instead the Directive left it to the discretion of the national legislations to exclude from patent protection what they considered contrary to the ordre public. Unfortunately, the ECJ now establishes a binding, restrictive interpretation of this term. Not only does the ECJ define an “embryo” as the earliest possible developmental stage, but it also fails to define when the developmental stage of an “embryo” ends. This second point is a grave shortcoming which is crucial for future practice. This is all the more critical in view of the further deliberations of the ECJ in relation to the third answer, according to which subject matter is to be excluded from patentability if it “requires the prior destruction of human embryos or their use as base material, whatever the stage at which that takes place and even if the description of the claimed technical teaching does not refer to the use of human “embryos”. Interpreted strictly, any human material, such as any human cell, can be traced back in some way to a human embryo. Since the ECJ does not define when the embryonic stage ends, it remains unclear which products of the human body, or which methods employing these products, do not conflict with the exclusion clause of the Directive. Moreover, the Directive explicitly allows that isolated parts of the human body may constitute patentable subject-matter. It is also not readily apparent why

Patent Law human dignity would preclude an embryo as the source of valuable therapeutic products (as long as that the embryo does not suffer any damage), while the Directive otherwise fundamentally views the human body as an allowable source of such products. So if the use of adult stem cells does not offend human dignity, why should the use of (non-destructively obtained) embryonic stem cells do so? If one takes the opinion of the Advocate General as a supplementary means for interpretation the Decision, the only conclusion is that any stage of development of the human body falls under the term “embryo”10. The decision of the ECJ thus creates a significant legal uncertainty for the patenting of subject matter derived from the human body (at any stage of development). In this respect the ECJ goes beyond the decision G2/06 of the Enlarged Board of Appeal of the EPO. G2/06 ruled that only subject matter necessarily involving destruction of an embryo is to be excluded from patentability.

whether a diagnostic method, which e.g. makes use of cells of an embryo, is excluded by Art.6(2)(c) (because it makes use of an embryo for commercial purposes) or allowed (because the diagnosis benefits the embryo)? The scientist‘s work in the lab is not directly impacted by the ECJ’s decision in the short run. However, it is conceivable that in the wake of the ECJ’s decision many companies maintaining projects in the field of stem cell research may now scale down or cancel funding of such projects due to an anticipated deferral of return on their investment. The original intention of the Directive was to promote research in the field of Biotechnology in Europe. At least for some sectors of this industry, the ECJ’s broad and yet incomplete interpretation of the term “embryo” seems to reverse this intention into an impediment. 1

Decision C-34/10 dated 18.10.2011

Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 on the legal protection of biotechnological inventions (OJ 1998 L 213, p. 13)

According to Paragraph 8(1) of the German ESchG, an embryo is a fertilized human ovum capable of development from the time of karyogamy, and any totipotent cell removed from an embryo which is able to divide and develop into an individual under the necessary conditions required.

“Exploitation” in this context are actions defined in §9 PatG, i.e. (a) the making, offering, putting on the market or using a product which is the subject matter of the patent (b) the use of a process which is the subject matter of the patent and (c) offering, putting on the market, using a product obtained directly by a process which is the subject matter of the patent. §9 PatG corresponds to Art. 28(1) TRIPS.

Art. 6(1) reads: “1. Inventions shall be considered unpatentable where their commercial exploitation would be contrary to ordre public or morality; however, exploitation shall not be deemed to be so contrary merely because it is prohibited by law or regulation.”

Open Questions One of the open questions after the ECJ‘s decision is the point in time at which the use of the human body as a source material constitutes “use of a human embryo” which would exclude the invention from patent protection. For example, is the use of fetal cells (e.g. from cord blood) in line with Art.6(2)(c) of the Directive? Another important question remaining is the definition of when a use for therapeutic or diagnostic purposes, which is applicable to the human embryo, is for its (the embryo‘s) advantage. For methods involving prenatal diagnosis or also pre-implantation diagnostics (PID), the answer to this question may depend on the diagnostic outcome of the relevant method. How should a patent office or national court decide

Recitals 17 and 18, emphasis added (17) Whereas significant progress in the treatment of diseases has already been made thanks to the existence of medicinal products derived from elements isolated from the human body and/or otherwise produced, such medicinal products resulting from technical processes aimed at obtaining elements similar in structure to those existing naturally in the human body and whereas, consequently, research aimed at obtaining and isolating such elements valuable to medicinal production should be encouraged by means of the patent system; (18) Whereas, since the patent system provides insufficient incentive for encouraging research into and production of biotechnological medicines which are needed to combat rare or ‚orphan‘ diseases, the Community and the Member States have a duty to respond adequately to this problem; http://www.nottingham.ac.uk/~llzwww/ StemCellProject/reports.htm; Aurora Plomer (Ed.) FP6 ‚Life scien-

ces, genomics and biotechnology for health‘ SSA LSSB-CT-2004- 005251, Seite 18, Verweis auf COM(85) 310 final: Completing the Internal Market: White Paper from the Commission to the European Council (Milan, 28-29 June 1985), p. 37, Absatz 149 8

SEC (91)/629 Communication from the Commission to the European Parliament and Council: Promoting the Competitive Environment for the Industrial Activities based on Biotechnology within the Community and COM (93) 700 final Growth, Competitiveness and Employment: the Challenges and Ways forward into the 21st Century White Paper from the European Commission to the Council of Ministers.

Report from the Commission to the Council and the European Parliament - Development and implications of patent law in the field of biotechnology and genetic engineering (SEC(2005) 943)

From the conclusions of the Advocate General: “The concept of a human embryo applies from the fertilization stage to the initial totipotent cells and to the entire ensuing process of the development and formation of the human body. That includes the blastocyst.”

Authors: Dr. Franz-Josef Zimmer

Dr. Benjamin Quest

Grünecker Kinkeldey Stockmair & Schwanhäusser Leopoldstraße 4 80802 München/Germany Phone: +49 89 21 23 50 Fax: +49 89 22 02 87 E-mail: zimmer@grunecker.de www.grunecker.de

The Bavarian Center for Molecular Biosystems

BioSysNet

During recent years the Bavarian State government has made a great effort to strengthen functional genome research and biotechnology in Bavaria. The high international reputation of the Bavarian research environment in these key technologies and the rapid development of the biotechnological industry have clearly shown that the funding of the state of Bavaria can be considered an impulse to this positive development. The newly founded Bavarian Research Center for Molecular Biosystems provides further proof for this successful concept. Aiming at the concentration of biosystems research in Bavaria, a research institute shall be founded, which will be of vital importance to the innovation capacity of all academic and economic activities in biomedicine. In view of the development in recent years, it has become

clear that genome research is focusing increasingly on the behavior of complex systems. By now, an impressive expertise in this area has emerged in Bavaria. This development became apparent through the success of the Bavarian Genome Research Network and the Bavarian Immunotherapy Network. The molecular biosystems research represents in many ways the future of biology. The Bavarian Research Center for Molecular Biosystems granted by the state government is led by a strategic council consisting of Professor Dr. Patrick Cramer (Gene Center of LMU), Professor Dr. Reinhard LĂźhrmann (Max-Planck-Institute Gottingen) and Professor Dr. Horst Domdey (BioM AG). It includes the Bavarian Research Network for Molecular Biosystems (BioSysNet) under the scientific coordina-

tion of Professor Dr. Horst Domdey, a Core Center at the LMU Munich, as well as activities in technology transfer. The Core Center will coordinate the activities and is buttressed by the new Research Building for Molecular Biosystems (BioSysM) (fig. 1) on the Munich campus GroĂ&#x;hadern/Martinsried (fig. 2), which can be attributed to the expertise of the Gene Center and the excellence cluster CIPSM and will be completed by 2015. The Bavarian Research Center for Molecular Biosystems will not only promote cutting-edge research in this innovative field, but also educate a new generation of interdisciplinary thinking scientists, who represent Bavaria in this interdisciplinary area on a highly competitive international level. Networks, in which outstanding research projects of different universities in the Free

Fig. 1: This is what the new Research Building for Molecular Biosystems (BioSysM) shall look like.The construction will start in the fall of 2012

BioSysNet

Fig. 2: The site of the planned Research Building on the campus GroĂ&#x;hadern/Martinsried

State of Bavaria cooperate over an extended period of time and under a consistent scientific-administrative direction, will become more than ever a necessity for the successful implementation of new research and innovations.

Bavarian Research Network for Molecular Biosystems The newly granted BioSysNet, in which new independent junior research groups are established at different universities in Bavaria, is such a project association, which complements perfectly the Core Center of the Bavarian Center of Molecular Biosystems in Munich. In addition to the five independent new research groups, scientists who already actively do research in this field at Bavarian universities are going to be integrated into the network, in order to ensure the further development of existing expertise. By co financing up to 20 more research groups this aspect shall be taken into account. The objective is to concentrate expertise in the area of molecular biosystems research in Bavaria and thus create ideal research conditions for outstanding research groups in the state. At the same time, BioSysNet should be an incentive to scientists abroad to come to

Bavaria in order to contribute their expertise and bring new technologies to Bavarian universities. A close cooperation with the industry shall be achieved through continuous effort in technology transfer. Practice oriented research and creative interaction with young and established companies is one of the main goals of the program. This is how results shall be effectively implemented and findings shall be integrated into the Bavarian economy. There are various scientific questions that BioSysNet will be working on: Which are the components of a biological system? How do these components interact? How does the system react as a whole when left to itself or when disturbed? These questions have always been in the center of life sciences â&#x20AC;&#x201C; but only nowadays and in the follow up of the achievements of genome research has it become possible to study components, interactions and perturbations on a molecular level with a sufficient quantitative definition. The analysis of complex biological regulatory systems is a basically interdisciplinary undertaking and requires the cooperation of biochemistry, genetics, bioinformatics, synthetic chemistry, bio imaging and biophysics as well as medicine (fig. 3).

The concept of the planned BioSysM at the Munich high-tech campus shall focus on a central and extensive problem of biology, the regulation of gene expression. The research topics at BioSysNet will also build on this. The regulation of gene expression and thus the activity of genes is the fundamental process in the development and functioning of all organisms. The challenge of this subject lays on the one hand in studying the sub-steps of gene expression in mechanisticstructural high definition; on the other hand it lays in understanding the interaction of individual steps in a living cell, in tissue and in the organism as a whole. These control processes include the regulation of cellular processes on all levels and can be investigated in simple biological systems such as yeast cells, as well as in complex model organisms or even in vertebrates. Whereas genomic, proteomic and metabolomic techniques are applied, the development of new experimental and theoretical methods is also required. Overall this research aims at understanding the function and malfunction of cells and organisms or even the malfunction in diseases such as cancer and neurodegenerative symp-

BioSysNet

Fig. 3: Computational Biology at the Gene Center, LMU. Source: Patrick Cramer

toms. This implies a broad range of research which permits to integrate important developments in Bavaria into this network. The funded research projects can thus emerge from different areas of biology, biochemistry, chemistry, medicine, physics and mathematics. The objectives of the program are correlated to the current level of knowledge and the methodological accessibility and are based on the existing strengths on the area of systems biology in Bavaria. Outstanding scientists account for specific topics such as stem cell research, functional genome research, structural biology and bioinformatics. They were chosen during an external evaluation by a renowned international board of reviewers out of 120 applications. The importance of this project for the Free State of Bavaria was highlighted by the personal presence of the state minister at the selection meeting, who discussed the goals of the scientific environment of this state with the cutting-edge international board of scientists. The state of Bavaria is associated worldwide with the high standards of its biotechnological research in academia and industry. This can mainly be attributed to the excellent

Bavarian universities and research institutions, as well as promising local conditions, which have reached a high international level based on the funding of the State of Bavaria. Outstanding research locations in the USA (Harvard, Seattle and Stanford) have always had programs on systems biology, which are currently culminating in a second round of institute foundations due to intense state funding programs by the NIH or NSF. In Europe this development is also apparent and can be seen in programs such as SystemX in Switzerland and the Center of Genomic Regulation in Barcelona. Further initiatives such as BioQuant (with focus on virology) in Heidelberg and the newly founded Berlin institute for medical systems biology at the Max-Delbruck-Center for molecular medicine indicate how strong and outstanding research centers are further developing into this direction. This causes strong competitive pressure on the Bavarian research institutions and biotechnological companies, both on a national and international level. Therefore, molecular biosystems research has to be expanded in all areas in Bavaria, in order to keep up with the efforts of other states and regions in

the future. The establishment of the Bavarian Research Center for Molecular Biosystems with the Core Center in Munich and the Bavarian Research Network for Molecular Biosystems represents a positive impulse in this direction. The profile of the scientific and educational environment is strengthened and thus ensures a future oriented alignment of the state of Bavaria, which is a front-runner on the area of functional genome research compared with other European countries. In order to enhance this status, the knowledge and human resources for the formation of a new generation of companies and the extension of existing companies have to be promoted. Only this way can the dynamic development of the Bavarian biotechnological industry be ensured.

is funded by the Bavarian State Ministry of Sciences, Research and the Arts.

Authors: Prof. Dr. Patrick Cramer Chair of the Bavarian Center for Molecular Biosystems

Gene Center, LMU Munich Feodor-Lynen-Str. 25 81377 Munich

Dr. Ulrike Kaltenhauser Managing Director of the Bavarian Research Network for Molecular Biosystems

Gene Center, LMU Munich Feodor-Lynen-Str. 25 81377 Munich

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FORPLANTA – harvest in times of climate change

Forschungsverbund FORPLANTA

“Plants fit for the future” – opportunities and risks of Green Gene Technology

The Bavarian research association FORPLANTA was honored on 16th of November 2011 as one of the awardees of the nationwide innovation contest “365 Places in the Land of Ideas” (“365 Orte im Land der Ideen”). Under the patronage of the Federal President, the regional initiative “Germany – Land of Ideas” (“Deutschland – Land der Ideen”) in cooperation with Deutsche Bank honors 365 outstanding projects every year, which shall ensure Germany’s innovative capacity in the future. In the ceremonial hall of the castle of Erlangen, Katrin Henning and Bernd Sauter, representatives of “GermanyLand of Ideas” and Deutsche Bank, handed over the award to Professor Uwe Sonnewald in representation of the whole research association (fig. 1). The motto of the festive ceremony was “harvest in times of climate change”. The lectures covered interesting details on plant breeding, yield increase and yield stability in modern plant breeding research, as well as the humannature relation within the area of

Fig. 1: Award for the research association FORPLANTA as a place of ideas in the innovation contest “365 Places in the Land of Ideas”, in the ceremonial hall of the castle of Erlangen. (Laudators from left to right: Prof. Dr. Jürgen Soll, speaker of the research association FORPLANTA, Prof. Dr. Karl-Dieter Grüske, president of the university Erlangen-Nürnberg, Bernd Sauter, Deutsche Bank, Prof. Dr. Uwe Sonnewald, project leader at FORPLANTA University Erlangen-Nürnberg, Dr. Max Lehmer, member of the German Bundestag.)

conflict of Green Gene Technology. At the reception that followed the official ceremony, scientists and interested citizens were able to engage in a personal dialogue with experts and research directors. The scientists of “FORPLANTA – Plants fit for the future”, which is

funded through the Bavarian Ministry of Sciences, Research and The Arts, are investigating the adaptation capacity of plants to stress situations like dryness, heat and pathogens on the model plant Arabidopsis (thale cress) (fig. 2). Their aim is to clarify the molecular mechanisms that protect

Forschungsverbund FORPLANTA

Fig. 2: Thale cress (Arabidopsis)

plants against multiple stress conditions with latest technologies and methods. The upcoming climate change causes notable weather and temperature changes and thus increasing periods of draught and heat. On the other hand, more frequent heavy rains on other parts of the earth lead to massive soil deterioration and erosions. These factors of stress heavily affect our agricultural crop and increase their sensitivity towards diseases caused by fungi and bacteria. The genes which protect plants against those kinds of situations of stress have been neglected in our moderate climate for centuries and in many cases have been lost during classic plant breeding. Climate changes like for example the global shortness of water weigh heavily on our agricultural crop and threaten to affect both directly and indirectly future yield security. In order to cope with these challenges, it is necessary for specific plant physiological and genetic engineering studies to complement classic agricultural approaches. The significance of plant research in times of climate change on the one hand, and the funding of

interdisciplinary cooperation in science on the other hand, have led the Bavarian state government to set up this research association. Given the current environmental developments, it is its main task to develop new genetic engineering concepts for stress resistant plants. In August 2010, the Bavarian research association “FORPLANTA – Plants fit for the future” was granted. Under the direction of Professor Jürgen Soll at the biocenter of the Ludwig-Maximilians-University Munich, the project leaders Professor Erwin Grill at the Technical University of Munich, Professor Uwe Sonnewald at the Friedrich-Alexander-University in Erlangen, Professor Rainer Hendrich at the Julius-Maximilians-University Würzburg, Professor Christian Kummer at the Munich School of Philosophy and Professor Bernhard Gill at the Institute for Sociology of the Ludwig-Maximilians-University Munich work together on six subprojects. Four of the mentioned groups are involved in the natural scientific and plant physiological aspects of the main question. The philosophic and sociologic projects aim at understanding reservations against Green Gene Technology within the general public and help to engage in constructive dialogue. The goal of the natural scientific research is to discover how plants protect themselves under different stressful circumstances and how these mechanisms can be used optimally in the future. The model plant Arabidopsis thaliana (thale cress) appears in different ecotypes due to its global occurrence. An ecotype is a type of plant that in comparison with other populations of the same species shows a different genetic constitution and has developed different adaptation mechanisms to the respective environmental conditions. Some ecotypes are thus adapted to dry and hot areas,

69 while others prefer cold climates. The use of genetic resources and the different reactions to varying situations of stress in different plant types are being examined. The implications of multifactorial stress on metabolic flows in the plant cell are characterized in a biochemical and biomolecular way and integrated in summary of modified metabolic networks related to stress responses. This way, scientists can draw conclusions on the genetic adaptation of the individual ecotypes. The mediumterm goal is to systematically generate biotic and abiotic stress tolerant plant variations of these results in order to stabilize and increase the yield of agricultural crop in the long run. In previous studies only singular stress types and their implications on plants were analyzed. New to this research association is the focus of investigating the effect of combined stress factors. One central element of research is thus the plant‘s own regulation of water balance. Plants need water not only for growth like all living organisms, but also for cooling the leaf area during heat. This is achieved through transpiration of the stomata (pores), which are regulatory valves on the lower surface of the leaf in the outer wax-coated cell layer, the epidermis (fig. 3). The opening width of the stomata is also decisive for the intake of the photosynthetic gas carbon dioxide (CO2, also known as climate killer) and thus also for the plant‘s carbohydrate production. By assimilating CO2 plants are of outstanding relevancy to the development of our climate. They produce 80 gigatons of oxygen and fixate 100 gigatons of carbon dioxide a year. The biomass produced by plants holds an energy content of 2x1023 Joule: This is equivalent to six times the amount of energy consumed by humans annually. For this, plants use about 1% of the “clean” solar energy

Forschungsverbund FORPLANTA

Fig. 3: Stomata (pores) on the lower surface of the leaf are regulatory valves that regulate water balance and gas exchange of plants

reaching our planet and convert it to material energy trough photosynthesis. The opening width of the stomata is affected by environmental factors, with the water stress hormone abscisic acid (ABA) playing a central role in mediating the stress adaptation of the plant. Plants with optimal ABA-impact, which show a better adaptation to stress and permit a more efficient use of the amount of water available to the plant, should be generated by investigating the mechanism of stomata movements. The more efficient use of water in agricultural crop is especially important considering that water is by far the most limiting factor to agricultural production, also in western industrial nations. About one third of the global agricultural area (about 380 million hectare) suffers from insufficient water supply; even in those areas where annual precipitation is adequate, an uneven distribution of rainfall can cause considerable yield loss. Taking into account that on a global level more than 80% of fresh water goes into agricultural production, it becomes evident that optimization of water usage by agricultural crop is a topic of importance for the society as a

whole. The water reserves on this planet are limited, while the world population is growing continuously. Looking at an individual plant, the efficiency of water usage, i.e. the capacity of the plant to produce as much biomass with as little water as possible, can be increased by changing the ratio of assimilation to transpiration. This has already been successfully proven through external treatment with the plant hormone abscisic acid (ABA). An ABA-mediated moderated closing of the stomata can reduce the water usage up to 30% without significant yield loss. Apart from playing an important role in CO2 and water balance, the stomata also represent points of entry for hazardous bacteria and fungi. This is why parallel research will be done on the impact of a modified guard cell opening on pathogen tolerance. In order to understand the consequences of modified guard cell opening, it is essential to understand the underlying metabolic processes. By applying single cell analytics, guard cell specific mechanisms will thus be investigated, which come along with changes in gene expression and metabolism during the closing movement. Furthermore, impor-

tant membrane transport mechanisms involved in this process should be identified (fig. 4). The breeding of agricultural crop with high yield stability in a changing climate presents a challenge due to scenarios of multifactorial stress. On the one hand, irregular climate events and unpredictable climate changes make the selection of elite lines on the field difficult; on the other hand, plant breeding is very time consuming. We are thus running the risk of merely reacting to upcoming problems and not being able to treat them in a preventive manner. This is why the traditional plant breeding industry often takes years and high financial means to generate a new cultivated plant. Moreover, the success of the breeding process cannot be foreseen initially. One of the goals is thus to create molecular markers for the selection of elite lines already in the seedling stage. Research work on biochemical and biomolecular characterization of multistress genes hereby provides a chance to identify genes that correlate positively with increased stress tolerance. The use of transgenic agricultural crops for assurance, quality intensification and improvement of sustainability and yield stability of

Forschungsverbund FORPLANTA agricultural production has always been discussed intensively and controversially by the general public and the media. Despite its potential as a key technology in light of essential challenges of the 21st century such as overpopulation, climate change and world hunger, hardly any other technology is subject to as much controversial dispute in its research and appliance as in the case of Green Gene Technology. Although the debate has been ongoing for two centuries with the participation and consideration of society, a gradual approach of viewpoints remains unseen; instead, the debate has developed into a ritualized dispute with virtually unchanging arguments. Better communication between scientists and the general public can not only be achieved through a more intensive depiction of scientific facts, but also relies on clarifying the correlation of benefits of Green Gene Technology and their social evaluation. This is why a philosophic and a sociologic project accompany the natural scientific investigations of the research association. From a philosophic point of view, the relationship between humans and nature should be investigated and a connection to Green Gene Technology is to be established. Images of nature play a formative role in the ethical discourse of green technology. An analysis of these perceptive patterns and normative evaluations of nature as well as of the human-nature relationship is a key factor to better understanding of the debate. Images of nature hereby imply all images, ideas, concepts and models which people are familiar with in terms of nature and the human-nature relationship. The question of our instrumental handling of natural resources such as water, soil and air has always been affecting the debate about agricultural production and has reached a new level

Fig. 4: Gel electrophoresis is used to separate proteins according to their size

of explosiveness given the already tangible and imminent consequences of climate change. It is thus to be considered closely linked to the human-nature relationship. The understanding of this conflict can help rationalize the discussion about Green Gene Technology in Bavaria. The leading question in this research association as to how genetic optimization of multifactorial stress tolerance in a model plant should be used to optimize agricultural crop in times of climate change therefore has to take into account not only the technically-mediated supply of genetic markers, but also the culture effective changes of a systematic technological intervention. The main focus of the sociologic project lays on benefits of green technology and their social evaluation. This study aims to describe the ethical relevance to a broader public in a generally relatable and at the same time appropriate manner. The proximity to the public debate between the citizens, politicians and scientists is greatly supported especially in the public relations sector of the association. FORPLANTA regularly organizes symposia, panel discussions and discussion evenings in order to maintain in close contact with the general public. Additionally,

71 an expert group of renowned scientists of various disciplines at the Center for Advanced Studies (CAS) of the Ludwig-Maximilians-University Munich and at the Institute Technology-TheologyNatural Sciences (TTN) will develop an ethic assessment model on Green Gene Technology. Based on the cooperation of projects from natural sciences, humanities and social sciences, an interdisciplinary research network is emerging in Bavaria, which integrates and links the existing competencies of various Bavarian universities and promotes interdisciplinary exchange.

funded by the Bavarian State Ministry of Sciences, Research and the Arts

Authors: Prof. Dr. JĂźrgen Soll Speaker of the scientific research network FORPLANTA Biology Department

Bio Center, LMU Munich GroĂ&#x;haderner Str. 2-4 82152 Planegg-Martinsried

Dr. Ulrike Kaltenhauser Managing director of the scientific research network FORPLANTA

Gene Center, LMU Munich Feodor-Lynen-Str. 25 81377 Munich

Establishing a Centre for Metastasis Research in Bavaria

Personalized tumor therapy

Background It is widely known that cancer generally becomes life-threatening and difficult to treat only when metastases have grown at distant sites. Usually, the primary tumor, i.e. in the colon or in the breasts, can easily be removed trough surgery. However, once metastases are diagnosed, most patients will die from the disease. Decades of cancer research have achieved little to change this; overall, the therapeutic success of treating many cancer types in advanced, but also in early stages of the disease, has been limited, although over 200 billion dollar have been invested into cancer research over the past decades. Given the importance of metastasis for the fate of the patient, it is astonishing that metastasis research on a national and international level has only been discovered a relevant topic during recent years. The German Cancer Research Centre (DKFZ), for instance, lacks a research program dedicated to metastasis up to date. It is the main concern of the joint effort of the Chair of Experimental Medicine and Therapy Research at the University of Regensburg and the Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) in Hannover to overcome this

shortcoming. A project group of ITEM aiming at efficiently integrating academic and non-university applied research was recently founded in Regensburg through start-up funding by the Free State of Bavaria. It will focus on either preventing the outbreak or at least improving the therapy of generalized cancer in the future.

Why are systemic cancer therapies failing to succeed? Slightly simplified, one can state that 5-year survival rates in cancer patients with and without metastases have improved less than 10 % during the last 40 years for the most relevant cancer types such as breast, prostate, lung and colorectal cancer. Beyond doubt, there is currently a greatly optimistic mood due to several new drugs; however, there is no reason to believe that radical progress is imminent during the next few years. This skeptical point of view is based on the nature of the disease: The tumor progression is driven by the selection and adaptation of continuously changing cells, which eventually develop growth advantages over neighboring cells. While normal, healthy cells are mostly stable in their genetic constitution, cancer cells are changing constantly. There are reasons to believe that a tumor

of one billion cells does not contain two cells with identical genomes. This instability and diversity consistently allows certain cells to adapt to varying conditions or to escape a targeted therapy. Following this idea, those cells that have best adapted to their environment and have gained a growth advantage over neighboring cells are then considered most â&#x20AC;&#x153;fitâ&#x20AC;?. To date it has been assumed that the evolutionary processes of these metastatic cells mainly take place within the primary tumor; consequently, predictions about the genetic changes of the disseminated cancer cells (DCC) are being made based on the primary tumor. For years, research and industry have been relying on the primary tumor as the most relevant model for selecting the right therapy for a patient; this is based on the assumption that the disseminated founder cells of the metastases (during the so called adjuvant chemotherapy situation) or the metastases themselves (in a more advanced stage of the disease) resemble the primary tumor cells. As this assumption is rarely challenged, the patients are basically treated blindly â&#x20AC;&#x201C; without knowledge about the molecular properties of the actual target cells of a systematic therapy. With this blind approach, several million

Personalized tumor therapy Euros and many years are being wasted in clinical studies, because it can only be observed empirically which drugs are effective. During recent years it has become obvious that the correct assignment of drugs to the individual patient, mostly according to the molecular properties of the tumor cell, is crucial. As the primary tumor and DCC follow separate lines of progression early on and DCC undergo an independent evolution, it is now time to directly focus on the target cells of systemic therapy and to distance ourselves from using the already surgically removed primary tumor as a measure for all therapies.

Novel ways to investigate metastasis Many, so called neoadjuvant studies, where systemic chemotherapy is given prior to the surgery, have shown that the response of a primary tumor to the drugs does not allow predictions to be made on the disease courses. Also, DCC are frequently detected even after chemotherapy. As most patients do not (yet) show signs of metastases at the time of the primary diagnosis, they can in principal be cured. It all depends on whether after the operation DCC in the patient have the potential to form metastases or not. But how can we locate disseminated founder cells of metastases before actual metastases are being formed? More than 20 years ago, DCC were first discovered long before the detection of metastases. It became apparent that the epithelial protein Cytokeratin is currently the most specific marker for tumor cells in bone marrow and blood. For most of the epithelial tumors it was shown that in approximately 20 to 50 % of the patients (depending on the tumor type DCC were present in the bone marrow, although clinical methods had failed to detect metastases. However,

these DCC are very rare; only about one to two tumor cells are found in two million bone marrow cells. Despite this sparsity, it has become evident that patients in whom such cells are found develop metastases faster and survive for a shorter period of time. With this detection method, early systemic cancer has for the first time ever become available to direct molecular analysis. In order to use these findings in patient therapy, new directions are taken in Regensburg. The Institute of Pathology of the University of Regensburg is one of the few accredited pathologic university institutes in Germany; this suggested linking the Specialized Laboratory for Disseminated Tumor Cells (SLDTC) at the Chair of Experimental Medicine to the process of accreditation at the Institute of Pathology. Currently, the SLDTC is most likely the only accredited laboratory in Europe authorized to diagnose carcinoma patients with â&#x20AC;&#x153;minimal residual diseaseâ&#x20AC;? based on pathological diagnostics. This laboratory not only establishes the diagnosis of the patients, but with their consent also uses the cell samples for research projects of the Chair of Experimental Medicine. The main focus lies on investigating the molecular properties of certain tumor cells, which allow them to migrate to other organs, survive and eventually form metastases.

New technologies to investigate metastasis Therefore, special technologies for the analysis of individual cells are necessary. It already became clear during the mid-1990s, that either not all cells detected by the epithelial marker in the bone marrow are tumor cells, or not all tumor cells can grow to become metastases. This was derived from the fact that several patients with marker positive tumor cells did not develop metastases. A positive

73 bone marrow diagnosis does therefore not necessarily indicate metastatic growth; the risk, however, is greatly increased in this case. It thus became indispensable to further characterize the cells detected in the bone marrow or in the lymph nodes. Some technical challenges were encountered: On the one hand, the detection methods generally only identified one tumor cell in two million bone marrow cells in only one third of the patients; on the other hand, merely one or two other characteristics (e.g. proteins) could be investigated in addition to the detection marker. This is why at first it was not possible, to characterize these rare tumor cells in detail. Our research group has managed to develop two techniques, which permit first of all the entire genomic DNA of a cell to be amplified and thus analyzed extensively and secondly also the mRNA of a cell. With these two techniques, two main aspects of the biology of individual tumor cells can be investigated. After the replication of the single cell DNA, the presence of genetic defects can be analyzed; these can be point mutations, DNA insertions or deletions and genomic translocations. Multiple kinds of analyses for defects in specific genes and genome wide screens for DNA insertions and deletions are possible with just one single cell. The transcription of mRNA into DNA and the following replication in conjunction with new array technologies then permits the capture of expression of all known genes (fig. 1). In the Fraunhofer project group, we recently succeeded in expanding the repertoire of single cell techniques up to the sequencing of the single cell transcriptome. Moreover, in association with the Bavarian Genome Research Network (BayGene), in particular with the research group of Prof. Rainer Spang, we developed bioinformatic analysis tech-

Personalized tumor therapy

Fig. 1: EA single disseminated tumor cell is separated from the cell suspension. By using a specific live staining, both mRNA and genomic DNA can be isolated from the cell and purified in order to conduct high-resolution microarray analyses. On the right, the hybridization of the amplified cDNA on an comprehensive expression array containing 44000 oligonucleotides is shown

niques for genome and transcriptome data of single cells. In addition to the molecular single cell technologies, we recently managed to expand these rare disseminated tumor cells in cell cultures and in immunodeficient animals. This opens doors to cell biological and functional studies on expanded disseminated tumor cells.

Linking fundamental research to applied research The aim of applied metastasis research is to broaden our understanding of the human disease and to use this knowledge in therapy. Although animal and cell culture models are helpful, a clear insight into the mechanisms and processes, which take place in patients, is essential. This is why fundamental research ought to be not only linked to applied research, but also to clinical routine and clinical therapeutic studies. Fig. 2 shows an overview of the Regensburg concept. By means of the Specialized Laboratory for Disseminated Tumor Cells, it is now possible to conduct research projects on numerous patient samples at the Chair of Experimental Medicine with public funding (BayGene, DFG, Deutsche Krebshilfe etc.).

The technologies developed at the Chair of Experimental Medicine and the subsequent findings are then used in the Fraunhofer project group for the development of new therapeutic test procedures, which shall also be suitable for routine and high throughput applications. Another main focus of the Fraunhofer project group is to propose to pharmaceutical companies the molecular characterization of DCC via these diagnostic-analytic tests in early clinical studies, as the response of patients to therapy has been shown to depend on the molecular properties of the target cells. The development period of new therapies would certainly be reduced drastically, if a better assignment of therapy to the individual patient were achieved, i.e. if it could be predicted which patient benefitted the most from which therapy. However, with new drugs in particular, this learning process requires tedious clinical studies, usually involving a large number of patients and thus being very expensive. Single cell technologies and molecular tests can now directly assess signaling pathways, which are relevant in the effect of the respective drugs on the target cells of a therapy.

Therefore, the molecular properties of DCC shall directly be used as a biomarker, backing up the companion diagnostics of therapy which are increasingly requested by regulatory authorities (FDA, EMA). Moreover, the Fraunhofer team is currently allocating expanded DCC for pre-clinical in vitro and in vivo sensitivity tests; this results in a portfolio of test procedures, which will be of useful assistance to the development of new cancer drugs. Ultimately, the University of Regensburg, the Faculty of Medicine and the University Hospital Regensburg are also actively involved in the establishment of a new Centre for Metastasis Research. The University of Regensburg is funding the construction of an accredited tumor tissue bank linked to the Tumor Centre Regensburg; also, a collaborative research initiative for metastasis research has formed, with the aim of making metastasis research in Regensburg to a key focus of the Faculty of Medicine. With this trio constellation of University, Fraunhofer society and University Hospital, a nucleus has been established that could help Regensburg evolve into a centre for the development of new therapies in the area of systematic cancer.

Personalized tumor therapy

Fig. 2: Concept for a Centre for Metastasis Research in Regensburg. The uncolored elements are still in the planning and application phase and are not yet incorporated

Author: Prof. Dr. Christoph Klein

Lehrstuhl für Experimentelle Medizin und Therapieverfahren Universität Regensburg Franz-Josef Strauß Allee 11 93053 Regensburg/Germany

Fraunhofer ITEM Projektgruppe Regensburg / Personalisierte Tumortherapie Josef-Engert-Str. 9 93053 Regensburg/Germany

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