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Das erste Zitat zeigt den Sinn ganz gut: Einmal zu wenig weglaufen bedeutet, dass man nicht wegläuft, obwohl es nötig gewesen wäre, "einmal zu oft" demenstprechend, dass man wegläuft obwohl es nicht nötig war.

Active Oldest Votes. Eigentlich ist der Sinn der Phrase klar, daher versuche ich es mit einem Beispiel zu erklären: Jemand spielt mit einem Revolver russisches Roulett.

Improve this answer. Hubert Schölnast Hubert Schölnast 97k 11 11 gold badges silver badges bronze badges. Das sechste Mal ist kein Spiel, sondern Suizid.

Abgesehen davon, dass schon die ersten fünf Versuche kein Spiel sind, dass ich spielen würde. Philipp: Erstens gibt es Revolver mit unterschiedlich vielen Kammern.

Da gibt es welche, die nur 5 Kammern haben, und welche, die man mit bis zu 30 Patronen beladen kann. Zweitens drehst ja jedesmal die Trommel bevor du den Abzug betätigst.

Die Wahrscheinlichkeit, dass sich ein Schuss löst ist bei jedem Spiel gleich. Natürlich, der berühmte 7-Kammer-Revolver : en. Trotzdem ein blödes Spiel.

Philipp: Du unterliegst einem Denkfehler! Aber die Wahrscheinlichkeit, so weit zu kommen, das man das hundertste Mal abdrücke kann, die ist verschwindend gering ungefähr ein Millionstel Prozent.

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Erdmandel-Chips, mit Agavensirup. The amount of external funding received is a result of hard scientific work and high-quality proposals - a remarkable achievement considering the Increasing competition for external funding.

Equally gratifying is the significant Increase in scientific cooperations with industry - a fact which also manifests Itself In the finan- cial volume stemming from such coop- erations: In it reached about DM 5 million.

Apart from these intensive efforts to win independent funding, an increasingly Important role In compensating some- what for the stagnant situation in basic funding is also played by private dona- tions and estates dedicated to cancer research.

Patent Situation Alongside fundamental research, the Deutsches Krebsforschungszentrum also attaches growing importance to the exploitation of research results.

In this context, the patent initiative of the Research Ministry has clearly set the right course. Technology transfer bridges the gap between research and commercial application.

Hopefully, the increasing collaboration between sci- ence and industry will encourage syner- gy effects that will help preserve the in- novative resources and competitive- ness of the German economy and create new jobs.

In the light of this ar- gumentation, technology transfer can be seen as a management task and thus represents an important part of the policy of a research center.

In spring , the Center began to re- establish its unit for technology transfer, which reports directly to the Manage- ment Board. Indeed, the ultimate aim behind patenting special know-how and Inventions Is their ex- ploitation, normally in the form of a li- cense agreement.

The fact that today it Is possible to both publish and patent an idea within a short space of time leaves little room 23 for argument against such an applica- tion.

This means, patenting does not exclude publishing. A registration can be carried out within just a few days, and thus the proprietary rights are se- cured - whether or not a patent Is later awarded.

The Center bears all patent application and maintenance costs. In , these amounted to more than 1 million DM.

In , the revenues will exceed the costs. For companies working In bio- technology, a field marked by global connections, it is particulary important to have licensed not only a national, but also an international patent.

For the Deutsches Krebsforschungszentrum this means that patent application and maintenance costs will probably in- crease over the next few years.

The Deutsches Krebsforschungszen- trum grants inventors a share of 30 per- cent of the license revenues from an In- vention. The decision taken by the Federal Min- istry for Education, Science, Research, and Technology in spring to place percent of the revenues from the economic exploitation of patents at the disposal of the research center Instead of 60 percent as in the past is a posi- tive and welcome incentive to utilize patents.

I am pleased to be able to report that at the beginning of , the total number of patents awarded or pending at the Deutsches Krebsforschungszentrum amounted to about and that a con- tinuing increase can be observed In the number of applications.

In the field of biosciences, it often takes a long time before the material benefits from the li- censing of patents can start to flow back, because in many cases lengthy and expensive clinical trials have to be conducted first - something which is not necessary, for example, in an area such as mechanical engineering.

As a rule, several years elapse between the granting of a patent license to a compa- ny and the introduction of a corre- sponding product onto the market.

One obstacle to the licensing of patents continues to be the stipulation in appen- dix IV of the financial statute of the HGF facilities, according to which it is not per- mitted to grant an exclusive license the latter requiring an individual application for permission from the sponsor , i.

In view of the long amortization period of the develop- ment and patenting costs, this Is a mat- ter that calls for action.

To avoid misinterpretation I should like to stress once again that the Deutsches Krebsforschungszentrum continues to be a facility engaged in application oriented fundamental research.

It is not intended to restrict these activities in any way. BioRegio In fall , the Rhein-Neckar triangle was chosen as one of the three winning regions out of 17 entries of a competi- tion organized by the German Re- search Ministry.

The Deutsches Krebs- forschungszentrum made a crucial con- tribution to the entry of the region and has strongly supported the realization of the concept.

The BioRegio competi- tion has turned out to be a strong cata- lyst for the advancement of biotechnol- ogy.

Feder- al funding now goes into these projects with the Industrial partner bearing up to 60 percent of the overall project costs.

Several new companies offering dozens of highly-qualified jobs have al- ready been established and we expect further foundations of new companies from existing organizations, including the Deutsches Krebsforschungszen- trum.

Alongside providing advice to po- tential founders of new companies, the Center supports them in every possible way, e.

These three components are meanwhile well established, and the first projects have been granted sup- port. The next few years will tell wheth- er this Interaction of science and econ- omy fulfills its promises and whether the perceptible new trend towards the creation of a sound basis for biotech- nology in Germany will persist and con- tinue to create new jobs.

Guidelines of the Federal Research Ministry The guidelines for a strategic reorienta- tion of the existing research structures 24 Conditions and Structures in Research in Germany issued in summer by the Research Minister have initiated a discussion which has also influenced the HGF research facilities.

The institutes are then given the opportunity to apply for these funds on a competi- tive basis by submitting project applica- tions.

For the Deutsches Krebsfor- schungszentrum this means that funds of several million are not initially as- signed to the budget, but have to be applied for on a competitive basis.

The additional burden that the application procedures entail is evident. Whether the new strategy fund will really pro- mote a shift of focus towards the key technologies of the 21st century re- mains to be seen.

However, one critical remark seems appropriate here: the promise of linking the strategy fund - i. The tools for achieving more flexibility in the management of budgets as pro- vided by the Research Ministry fail to meet the expectations of the research institutes.

Essential demands, e. These mea- sures, however, will become essential in order to be able to cope with the above-mentioned budget and person- nel restrictions expected in the coming years.

Here we must intensify our en- deavors to convince the politicians that these are necessary instruments for flexibility. The main demands for the coming years will be to further improve the ad- ministrative and scientific framework and structure of the Deutsches Krebs- forschungszentrum: - Analogous to private-sector organ- izations, the freedom of action con- cerning policy decisions of research facilities should be significantly ex- panded.

The control of these facil- ities should lie in the hands of the boards board of directors, board of trustees , instead of being subject to the restrictive interpretation of vari- ous regulations.

Attention should be given to the development of a specific salary agreement for re- search. Vacancy periods of up to 2 years - frequently needed for the ap- pointment negotiations to be con- cluded - should be dramatically re- duced to an appropriate period of a few months.

Over the next few years, the Deutsches Krebsforschungszentrum will have to walk a fine line between maintaining and further raising its high level of sci- entific performance on the one hand and coping with a difficult administrative environment on the other.

Furthermore, the Deutsches Krebsforschungszen- trum will have to answer the question of whether the positive developments be- coming apparent in the prevention and therapy of cancer will have the predict- ed effects and thus be of benefit to mankind.

Josef Puchta Administrative Member of the Management Board of the Deutsches Krebsforschungszentrum 25 I Mission and Structure of the Deutsches Krebs- forschungszentrunn The Deutsches Krebsforschungszen- trum DKFZ was founded in on the initiative of the Heidelberg surgeon Prof.

Bauer, who died in at the age of By decision of the government of the State of Baden- Wurttemberg, it was set up as a foun- dation of public law.

It in- volves considering the interests of sci- entists who approach the problem of cancer from different methodological angles and assigning them different pri- orities in the competition for financial resources.

On the other hand, the po- tential benefits to be gained by the sci- entists in solving their research prob- lems from the discussion and collabora- tion with a large number of experts from all fields relevant to cancer research gathered together in one research insti- tution are enormous and cannot be pro- vided by any other form of organization.

Since , the Deutsches Krebsfors- chungszentrum has been operating with a new organizational structure. The former institutes have been re- placed by subject-oriented Research Programs Forschungsschwerpunkte , which are represented by coordinators and as a rule are limited to a working life of six years.

This period can be ex- tended depending on the results achieved. Alongside the existing per- manent divisions, temporary divisions operating under a time limit of, as a rule, five years have also been estab- lished.

This concept is designed to give young scientists between the ages of 30 and 35 the opportunity, at an early age, to take on responsibility for run- ning an independent research unit.

This makes it possible to better respond to the rapid developments in cancer re- search. The flexible structure of the Deutsches Krebsforschungszentrum also fosters the exchange of experiences between scientists from a wide range of disci- plines.

In addition, it facilitates the rapid changeover to new tasks once a work- ing program is considered as fulfilled. The complex problems of cancer re- search and the fight against cancer touch upon a large number of disci- plines from the biosciences, natural sci- ences, as well as the social sciences.

The only way to tackle them with some prospect of success is a close national and international collaboration of scien- 26 Fig.

The scientific mission of the Deutsches Krebsforschungszentrum is to make substantial contributions to the under- standing of carcinogenesis, the identifi- cation of cancer risk facts, and also the prevention, diagnosis, and therapy of cancer.

The sheer number of different types of cancer that can affect man gives a clue to the complexity of the problems faced in scientific analysis.

Cell Differentiation and Carcinogene- sis 2. Tumor Cell Regulation 3. Cancer Risk Factors and Prevention 4. Diagnostics and Experimental Thera- py 5.

Radiological Diagnostics and Thera- py 6. Applied Tumor Virology 7. Tumor Immunology 8. The thematically oriented research program reflects a general shift towards molecular-biologi- cal approaches in cancer research and indicates a new focus on the analysis of human tumors.

In , a resource center of the German Genome Project was set up in Heidelberg and Berlin si- multaneously; the Heidelberg project is led by Dr.

Annemarie Poustka, head of the Division of Molecular Genome Anal- ysis of the Deutsches Krebsforschungs- zentrum, the Berlin project by Prof.

Hans Lehrach from the Max Planck In- stitute for Molecular Genetics. The Hei- delberg group is responsible for the creation and quality control of gene li- braries, i.

They are made available to working groups, which can use them to search for specific genes. In addition, scientists from research institutes and industry 27 are offered the opportunity to send DNA samples to Heidelberg and have the gene libraries searched for a gene they seek to identify.

Thanks to the ex- istence of joint resource centers in Hei- delberg and Berlin, smaller research la- boratories now also have access to the material and technology resources of the German Genome Project, which is supported by the Federal Ministry for Education, Science, Research, and Technology.

The clinical cooperation units have been further extended. The clinical research groups are established at the clinics for a period of five years each.

In this con- cept, the Deutsches Krebsforschungs- zentrum provides the medical treat- ment, while the clinics provide the hos- pital beds and the clinical infrastructure.

The aim of the clinical cooperation units is to facili- tate a swift transfer of results from basic research Into clinical practice. While the selction of promising re- search approaches in the past tended to be somewhat fortuitous and acciden- tal, i.

Changes in the gneome or in the ex- pression of specific genes in somatic cells are In many cases reponsible for the early events of carcinogenesis, leading to fundamental disturbances in the social and growth behavior of cells.

In functional terms, two different princi- ples of tumorigenesis can be distin- guished: 1 enhanced activity of onco- genes may lead to uncontrolled growth; 2 the failure of genes suppressing cell transformation, the tumor suppressor genes, may have the same effect.

The research program Cell Differentiation and Carcinogenesis therefore directs special attention at finding and analyz- ing those genes and their products that might play a role in carcinogenesis.

Cell biological and molecular biological methods are used to find genetic probes for specific chromosome chang- es, for gene mutations or for integrated viral genes which may be applied in tumor diagnostics as well as possibly in the prevention of cancer, such as the identification of patients at risk.

Another line research is directed at the examination of disturbances In gene expression and In the synthesis of cer- tain gene products.

Differences in gene expression between normal and trans- formed cells, between resting and pro- liferating cells, and between cells in various states of differentiation are de- tected using appropriate nucleic acid probes or monoclonal antibodies against specific gene products.

In addition, the research program examines the biological func- tion of the proteins and hormones in- volved in the regulation of gene expres- sion and the growth and metastatic spread of certain kinds of cancer.

Embryonic development of an organism including the controls of cell division and tissue formation provides the mas- ter plan for the normal and healthy cor- relations of cell proliferation and differ- entiation.

An understanding of these elementary life process will therefore point the way for future experimental cancer research.

Consequently, the di- vision Molecular Embryology has re- cently been established in the research program to study fundamental process- es in embryonic development.

Cell Differentiation and Carcinogenesis Coordinator of the Research Program: Prof. Werner W. Franke Divisions and their heads: Cell Biology: Prof.

Franke Molecular Biology of the Cell I: Prof. Gunther Schutz Molecular Biology of the Cell II: Prof. Ingrid Grummt Development Genetics: Prof. Bernard Mechler Molecular Embryology: Dr.

Christof Niehrs 33 The Structure of the Cytoplasm 2. Other unicellular organisms lend shape to their cell by means of a hard shell.

In contrast, amoebas appear to be miss- ing any sort of framework. Their shape constantly changes. Nonetheless, they do not completely dissipate and can in individual cases become very large.

In- vestigations employing the electron mi- croscope have shown that a complex network of fibrillar and filament-forming proteins are responsible for this change in form.

Research in cell and molecular biology during the past 20 years has shown that this network or cytoskeleton principally consists of the same mole- cules in all eukaryotic cells, the cells of higher organisms.

The Filamentous Components of the Cytoskeleton The cytoskeleton mainly consists of three, different, independent filament systems: 1 microfilaments with a di- ameter of 7 nanometers nm , 2 mi- crotubules, tube-shaped filaments with a 25 nm external diameter, and 3 intermediate filaments that were so named, because their diameter at 10 nm lies between that of the microfila- ments and microtubules.

Every eukar- yotic cell contains microfilaments and microtubules; both are essential for life, even for simple organisms such as yeast.

In contrast, intermediate fila- ments have until now only been found in animal organisms, not in plants, pro- tozoans or simple multicellular organ- isms.

They mainly consist of pseudo-crystalline, intermedi- ate filament bundles that are intercon- nected and arranged in parallel.

In the s, research into the structure of pro- teins with x-rays began with their exam- ination In Wladimir Engelhardt clearly characterized the first cytoskeleton pro- tein, myosin, and its function.

It is seen with increasing clarity that almost every cellular movement and all intracellular transport processes depend on filaments.

Even cellular mo- tion that employs flagella and cilia, the 34 The Cytoskeleton: A Complex System of Dynamic Structural Elements transport of vesicles or the distribution of chromosomes to the daughter cells during cell division is based on the interaction between ATP adenosine tri- phosphate splitting motor proteins and filaments.

It is easy to imagine that such a state of complex mobility exter- nal movement accompanied by simul- taneously occurring diverse internal transport processes can very rapidly degenerate into a state of complete chaos.

Structure of the Intermediate Filament Proteins The histochemical analysis of many cell types in the s, especially in hu- mans, yielded the finding that the tis- sues of the more developed verte- brates contain a third filament system.

These so-called intermediate filaments are present in addition to the microfila- ments and the microtubules in almost every cell. The intermediate filaments do not form any polar structures and cannot, therefore, be used by motor proteins for directed movements.

Using immunological methods, one recog- nized that intermediate filaments are extremely heterogeneous in their com- position although they cannot be exter- nally distinguished from one another, not even with the electron microscope.

A human being possesses approxi- mately 50 different intermediate fila- ment proteins; these are comparable in their composition and similar in biologi- cal structure.

However, their primary sequence, the genetically determined order of the amino acids in the different intermediate filament proteins, varies greatly.

Scientists conclude from this that filaments formed from such pro- teins can possess very different proper- ties and can, therefore, usually not form any mixed complexes.

This is also the reason why two different intermediate filament systems may exist indepen- dently of one another in a single cell. All kinds of different proteins belong to the family of intermediate filament pro- teins: lamins are transported Into the cell nucleus where they stabilize the nuclear membrane and the nuclear pores; neurofilament proteins fill out the long axonal processes in nerve cells; vimentin Is found in connective tissue cells and the lens of the eye; and the cytokeratins CK that pervade the cyto- plasm of internal epithelial cells and covering tissues, ranging from the ex- ternal nuclear envelope to the plasma membrane; they are the main protein in the epidermis.

Along with Interconnect- ing proteins, the cytokeratins, after the cells that produce them have died, form scales, hair, feathers and nails.

The long quills of the porcupine are an un- usual creation of nature that consist of interconnected, quasi-crystalline, inter- mediate filament bundles arranged in parallel order.

Such a diversity of proteins may con- fuse non-specialists and may appear insignificant to them. Because of this, it Is possible to determine the histoge- netic origin of a tumor by immunologi- cally ascertaining the type of intermedi- ate filament protein.

Thanks to their intermediate filament protein profile, very small tumors and micrometastases can also be quickly identified. This pro- cedure has in the meantime become a main technique in tumor diagnosis.

Initially, standardized and uniform minifilaments above are created. These subsequently combine, one after another, to form long cords as shown in the center and below At the Deutsches Krebsforschungszen- trum more than 50 different monoclonal antibodies have been produced that are routinely used throughout the world to diagnose tumors according to the ex- pression catalog for cytokeratins com- piled by Roland Moll and Werner W.

Franke in the Division of Cell Biology. Detailed knowledge of the protein rec- ognized by the antibody with respect to its biochemical properties as well as its tissue-specific expression is a neces- sary prerequisite for using the cytokera- tins in diagnostic procedures.

This means that closely related intermediate filaments must also be distinguished from one another. Often this proves dif- ficult since several of the identified cy- tokeratins were originally viewed by many scientists as being degradation products of a frequently occurring cyto- keratin of the skin.

In our laboratory, Christine Collin was, for example, able 35 2 to demonstrate that CK2e and CK2p are indeed distinct cytokeratins.

This cytokeratin is only synthe- sized in very few cell types, but Is Inval- uable in tumor diagnostics. In combina- tion with antibodies directed against other cytokeratins, antibodies specific for CK20 are employed in the differen- tial diagnosis of adenocarcinomas.

Significant progress resulted from real- izing that intermediate filament proteins release relatively stable fragments the -helix coiled coils during the decom- position of tumor cells.

These frag- ments are in turn easily detectable with immunological methods even when present only in very small quantities. In the early stages of certain types of lung tumors, fragments from cytokeratin 19 CK19; cloned by Bernhard Bader in our laboratory can be detected in the blood.

In this case, an early detection of cancer Is possible by simply drawing blood and employing serodiagnosis. Function of the Intermediate Filament Proteins What are the advantages for a multicel- lular organism consisting of organs and tissues in synthesizing such a large number of different proteins and regu- lating them in such a complex diversity that is specific for each cell type?

Why is this necessary? In the end, only a single system of apparently similar fila- ments is maintained In the cells. What happens when the synthesis of these 36 Fig.

The organizational structures in the cells find their counterpart in the form of a complex structure outside of the cells that is not lacking in diversity when compared to the internal structures.

This so-called extracellular matrix that is located near the cells is, for example, mainly excreted by fibroblasts in epithe- lial tissues.

Transmembrane proteins, of the inte- grin type among others, bind the extra- cellular matrix to the internal cytoskele- ton by means of specific protein com- plexes.

Other transmembrane proteins, the cadherins, assume the task of coupling the cytoskeletons between in- dividual cells.

In this manner, a trans- cellular cytoskeleton pervades the en- tire tissue. Cytoskeleton and matrix pro- teins have a unique quality that distin- Fig.

Biophysical examinations of the three filament systems have shown that they are fundamentally different in one pa- rameter, namely in their viscoelasticity.

For example, under torsional stress the ability of the intermediate filaments to react elastically increases. A redistribution of the molecules in the filament is probably responsible for this.

In contrast, microfilaments and microtu- bules break under such conditions. Among the intermediate fila- The Cytoskeleton: A Complex System of Dynamic Structural Elements ment proteins there are relatively large differences with respect to their viscoe- lastic properties that are additionally in- fluenced by the proteins, with which they are associated.

These findings from experiments con- ducted on tissue cultures readily led to the assumption that intermediate fila- ments may also have something to do with stabilizing cells against tensile stress in the living organism.

Clarifying the cause of a certain genetically- based skin disease epidermolysis bul- losa simplex has confirmed this in an Impressive manner.

In patients so af- fected the basal cell layer of the epider- mis breaks away upon the slightest pressure, thereby, forming blisters.

These patients are missing an exten- sive Intermediate filament system in the basal cell layer. Intermediate filaments are instead found In aggregates near the cell nucleus.

The cause of this clumping is a mutation that leads to the exchange of an amino acid at a certain location in cytokeratin 5 or How can such an apparently slight change have such drastic effects?

Similar to the dy- namic filament systems of the microfila- ments and microtubules the actual ele- ments of the cytoskeleton, the interme- diate filaments, are not static, rigid cell components.

Already slight variations in the molecule can lead to the formation of flat or clump-like aggregates Instead of the desired filaments.

From this the question arises: what are the possible consequences of such malformations in a filament system for the cells and the tissue in a living or- ganism?

Thereafter, the nerve cells die.

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