Neue Aspekte Wo werden Organellen-Proteine synthetisiert? Polyribosomen kommen entweder frei im Grundplasma vor oder sind den Membranen des endoplasmatischen Reticulums (ER) an der plasmatischen Seite angeheftet. Ihre Produkte, die Proteine, finden sich aber nicht nur im Grundplasma oder in Membranen des ER, sondern auch in anderen Membranen, in nichtplasmatischen Kompartimenten und extrazellul~r. Nach der ,,Signalhypothese" [1] sollen extrazellulfire Proteine zungchst eine Aminos/iurensequenz tragen, die Signalfunktion hat. Sie sei die Ursache daffir, dab sich die Polysomen, die ein solches Protein synthetisieren, an eine ER-Membran festsetzen, und erm6gliche die Passage der naszierenden Polypeptidkette durch die Merebran. Daffir trage die ER-Membran bestimmte, im einzelnen noch unbekannte Rezeptoren. Die Signalsequenz des Proteins soll bei oder umnittelbar nach der Membrandurchquerung enzymatisch abgetrennt werden, das Protein liege dann als kiirzeres Molektil frei in der ER-Zisterne. Ein Beispiel ist die Albumin-Synthese. Der Einbau von Proteinen in Membranen soll nach dieser Hypothese auf fihnliche Weise geschehen. Freie Polyribosomen, so vermutete man, produzieren hingegen die Proteine der nukleocytoplasmatischen Matrix. Kfirzlich untersuchtejedoch G. Blobel yon der Rockefeller University (auf dessen Ideen und Experimenten die Signalhypothese basiert), wo die Catalase und die Uricase der Peroxisomen in Leberzellen synthetisiert werden, und das Ergebnis war unerwartet [2]. Die Peroxisomen sind Organellen mit einer einfachen Membran und spezifischen Enzymen; sie enthalten Catalase als Leitenzym und entwickeln sich direkt durch eine Art Knospung aus dem ER. Man sollte also annehmen, dab die Peroxisomen-Enzyme an Polyribosomerl synthetisiert werden, die an ER-Membranen sitzen. Goldman und Blobel stellten zunfichst fest, dab sie in einem zellfreien in-vitroSystem eine etwa gleichhohe Proteinsynthese-Rate mit Prfiparationen aus freien und ehemals membrangebundenen Leberpolyribosomen erzielen konnten. Wie e r -

wartet, war das Spektrum der Produkte sehr verschieden. Mit Hilfe der ImmunprS~zipitation konnten sie dann nachweisen, dab Albumin an den vorher membrangebundenen Ribosomen gebildet wird, dab aber nur die Population aus freien Ribosomen Catalase und Uricase produziert; und zwar liegen diese Proteine in der Form vor, in der sie auch in den Organellen zu finden sind. Sie passieren also die Merebran ,,post-translational" und nicht ,,cotranslational". Dabei ist zur Zeit noch ungekl/irt, ob das Fehlen einer Signalsequenz, die spS~ter abgetrennt wird, experimentell, d.h. durch im Ansatz vorhandene, 16sliche Signalpeptidasen, bedingt ist oder ob solche Sequenzen zwar vorhanden sind und eine spezifische Membranpassage erm6glichen, aber nicht abgeschnitten werden. Goldman und Blobel nehmen nach diesem Befnnd folgenden Weg f/ir die Bildung der Peroxisomen an: Die Peroxisomen haben spezifische, integrale Membranproteine.

Diese werden an den am ER gebundenen Polyribosomen synthetisiert und co-translational in die Membran eingebaut. Sie tragen Strukturinformationen, die eine Konzentrierung in bestimmten Membranbereichen, ein Aussortieren, erm6glichen. Dadutch entstehen differenzierte ER-Bereiche, die sich dutch Abknospen vom Rest trennen. Die integralen PeroxisomenMembran-Proteine werden erst dann, vielleicht dutch Abspalten einer Signalsequenz, ,,aktiv", d.h, sie binden nun die an freien Polyribosomen gebildeten Peroxisomenenzyme oder ihre Vorstufen und schleusen sie in das Inhere der Organellen. Wtirden sie es schon eher tun, ffinde man die Enzyme auch im ER. Diese Modellvorstellungen sind eine interessante Hypothese, die auch bei der Biogenese anderer Organellen zutreffen k6nnte. 1. Blobel, G., Dobberstein, B. : J. Cell Biol. 67, 835 (1975) 2. Goldman, B.M., BIobel, G.: Proc. Nat. Acad. Sci. USA 75, 5066 (1978)

Cancer: Some Realistic Hopes The International Cancer Congress, held every four years represents an excellent forum for taking stock of the progress achieved and to make plans for the future. The 12th and the latest congress was held by the International Union against Cancer (U.I.C.C.) in October, 1978 in Buenos Aires. In spite of the controversy created by the political situation in Argentina, 8000 delegates from 74 nations, putting the scientific objectives of the Cancer Congress above all others, arrived at Buenos Aires. Cancer is still one of the top killers of mankind and with 10 million new cases being diagnosed worldwide each year, it is hard to assume an air of optimism. Yet, when one looks back at the achievements of the last 4 years presented in 1600 papers one is justified of some realistic hopes for the future. However, whereas our basic knowledge of the cancer problem is making progress, so is also the number Of carcinogenic agents in our environment. Among the known

Naturwissenschaften 66 (1979) 9 by Springer-Verlag 1979

main causes of cancer: radiation, viruses and chemicals, the latest seems today to be posing the greatest danger for industrialized societies. This danger is the more menacing because of our near total ignorance of its dimensions. Among the 4.3 million chemicals now in existence, 63 000 are considered to be in common use. Among these, only a mere 7000 (11%) were, according to Saffiotti of the U.S. National Cancer Institute, tested in animal systems. However, not all these 7000 were tested under carefully controlled conditions; only half of these are accepted to have been tested as reliable. Of these, 750 were found to be carcinogenic in animals. In man, we know of 26 confirmed and 56 less confrmed carcinogens. This leaves us with approx. 56000 environmental chemicals of unknown carcinogenicity. If we add to this the 500-1000 new chemicals introduced annualy, we get an idea of the dimensions of the potential risk to which we are exposed. In spite of improved legislation in recent years, no speedy solution 259

of this problem is expected in the c o m i ~ years. In the U.S.A., the country making the highest investment in the cancer t e s t i ~ effort, only 100-300 chemicals are beii~g tested in animal bioassays per year. Why can this snail tempo not be speeded u p ? The lack of sufficient funds is only one factor. We do not have as yet a reliable short-term bioassay system which can replace the expensive 3-year animal test. Hopes in using the convenient Ames bacterial test as a criterion for assaying the cancer risk in man have been shattered by the recent findings of Lijinsky of Frederick Cancer Research Center, U.S.A. He reported a shocking rate of only 55% correct prediction of carcinogenicity for hydrocarbons and 70% for nitrosamines. Both, Lijinsky and Legator, another authority in this field, indicated on the basis of these results that it would be dangerous to use the Ames test as a sole basis for predicting the carcinogenicity of chemicals. As a consequence, efforts are being intensified on both sides of the Atlantic to develop more reliable short-term bioassay systems. Selikoff presented an interesting epidemiological study on people in the U.S.A. who are working with asbestos, mainly as insulators. In a study of 17 800 insulation workers, it was found that 30 years after exposure, one in every three deaths was due to lung cancer. Strange enough, mesothelioma (cancer of the pleural lining) was also frequently observed among wives and children of these workers. In order to improve the chance of a cure, it is necessary to detect malignant tumors at an early stage. This can be done, in some cases, using low doses of diagnostic X-rays. However, even these low doses are considered now too risky and alternatives are being investigated. Among these, some promising results are being achieved by ultrasound and thermography which might someday replace X-ray mammography in screening for breast cancer. Another approach, exploded into a feverish activity in recent years, is to look for tumor-specific antigens. In particular, for those malignancies where the role of an oncogenic virus is implicated. The role of DNA viruses in human cancer was discussed by zur Hausen (Freiburg), Munk (Heidelberg) and Rapp (U.S.A.). The role of RNA tumor viruses in human malig~ nancies, in particular of the hematopoietic system Was implicated by the studies of Gallo (U.S.A.) and Chandra (Frankfurt). 260

However, there are less specific antigens, e.g., the carcinoembryonic (CEA) antigen and alpha-fetoprotein (alpha-FP) which appear to be elevated in some types of cancer. These antigens are present in normal human embryos and are nearly absent in adults. Their association with cancer, however, is not considered to be close enough to be used as a reliable screening method. In patients where they are found to be elevated, however, it may serve as a monitor for the success of therapy. Improved endoscopic procedures facilitated the detection of cancers in inner organs. A break-through in both screening and therapy depends on improving our understanding of the nature of the malignant alteration, or alterations. This problem should be viewed through the eyes of experts from different disciplines represented at this meeting: the pathologist, the virologist, the geneticist, the immunologist, the membranologist, the cell-culture experts and last but not least, the biochemist. By assembling these different views, we can, with a certain degree of imagination obtain a multidimensional picture of the cancer cell as we know it today. Using the modern histochemical methods, and with the aid of scanning electron microscope, the pathologist can differentiate between normal and cancer cells. Only in some cases, where the cancer cells deviate so little from normal ceils morphologically, is a pathologist unable to make any decision on the nature of the cell. The geneticist's view of a cancer cell has led to several important facts in the last years. We know of several chromosomal anomalies associated to cancer. We also have several examples for genetic mutations which are associated with cancer, e.g.; arginine mutants among leukemia cells; mutant cells lacking DNA repair mechanisms; transformed cells having one or more mutations affecting one or more differentiation factors (such mutants were isolated and are being studied by Sachs in Israel); and mutations interfering with cell communication. This is a fairly new and fascinating aspect of membrane research, which was beautifully illustrated by L6wenstein of Miami University, U.S.A. Looking at the membranes of normal cells in contact with each other, he discovered the presence of membrane channels with a core of 14 A across the membranes of both cells. By introducing a fluorescent dye in one cell by microinjection, Ltwenstein

was able to observe its transport across the membrane channels to the neighboring cell. He now turned his attention to cancer cells. Here, to his great satisfaction, L6wenstein found that malignant cells either do not form membrane channels at all, or they form abnormal ones. The exciting question now was: which human chromosome causes by its loss from the cell, the loss of the ability to form channels? The answere was: chromosome No. 11. He predicted therefore, that a mutation in this gene leading to the loss of ability to form normal membrane channels could then be one of the causes of malignant transformation. The presence of communicating channels was proved by Stoker (U.K.) using a different technique. When a cell previously grown on a labelled RNA precursor was plated on a non-labelled culture, it distributed its radioactivity only into such neighboring cells with which it was communicating, presumably by forming junction channels. One of the fascinating biochemical aspects is the mechanism by which carcinogens exhibit their organotropic response. According to Magee's (U.K.) report, repair mechanisms might play a decisive role in the organ specificity of some carcinogens, such as nitrosamines. He presented evidence to suggest that the inability of the target organ to repair the induced DNA damage is probably responsible for the appearance of tumors in that particular organ, and not anywhere else. We still have many puzzles where biochemists of the future can help solve: What reactions are taking place during the long latent period between chemical induction and the appearance of tumors, this period where promoting agents like croton oil, or other cocarcinogens (Hecker, Heidelberg) can greatly shorten? ttow do protective agents, e.g., cystein, or vitamin A interfere with the carcinogenic process? What biochemical mechanisms exist for the invasiveness and metastasis in vivo ? These are just some examples of areas of research still rea~aining as virgin soil. The last, but the ultimate goal of cancer research, namely cancer cure was discussed in several symposia and panels. While no sensational break-through seemed to have taken place in the last few years, steady progress was reported in the different therapeutic approaches: surgery, radiation, chemo-, immuno- and hormonal therapy. Surgery is still regarded as the major first step in dealing with solid tumors. Improve-

Naturwissenschaften 66 (1979) 9 by Springer-Verlag 1979

merit in radiotherapy includes the use of radiosensitizers to increase the sensitivity of cancer cells towards radiation. The development of potential radiosensitizers is a promising avenue for future research. Chemotherapy is slowly gaining the confidence of therapeutists in treating several types of cancer. After the significant achievements of polychemotherapy against acute childhood lymphatic leukemia, some further progress is being made in the treatment of breast cancer, osteogenic sarcoma and testicular malignancies. The future developments require more specific agents, and meaningful combinations of drugs. The age of "hit and trial" is gone, and we

must look for more scientific and rational approaches for the future. In view of the fairly high risk involved in the above-mentioned approaches, a true improvement in survival while maintaining an acceptable quality of life, can only be attained by a more specific treatment, one which does less harm to normal cells. Immunotherapy would seem to be the logical answer, however, the poor experience obtained so far by such non-specific agents as BCG and similar agents induced Robert Baldwin, the President of the European Association for Cancer Research, to warn of the dangers involved in these approaches. In his admirable Harold Dorn

Memorial Lecture, Baldwin expressed the opinion that cancer immunotherapy should be sent back to the laboratory. Until we get to know more about it, it should not be tried on patients. With the new discoveries in virology, this waiting period in the laboratory will probably not be very long. The promising and rapid developments in the oncogenic viral field, reviewed by Klaus Munk (Heidelberg), Vice-President of the Viral-Oncology Symposium, leave no doubt that several new approaches in the diagnosis and treatment, or prophylactic protection from cancer will emerge in the near future. P. Chandra/Frankfurt

Kurze Origina!mitteilungen Eutrophication Changes Sedimentation in Part of Lake Constance German Mtiller, J. Dominik and A. Mangini Institut ffir Sedimentforschung und Institut ftir Umweltphysik der Universitfit, D-6900 Heidelberg The application of the concept that sediments are a response to the condition of an aquatic system [1] to man-made pollution led to the finding that sediments act as a "depot" for numerous contaminants and bio-elements. 2t~ and t37Cs-dated sedimentary cores permit the study of the historical evolution of specific anthropogenic substances as well as the development of sedimentation itself over the past 100 years [2, 3]. Using a Reineck box corer, a sediment core was collected in August 1977 from the middle of the "Konstanzer Trichter" (approximately 2.1 km off the Konstanz harbour) at a water depth of 53 m in Lake Constance (Fig. 1). The core was split into individual layers of 1 cm thickness immediately after its recovery. Figure 1 presents the results of a textural, mineralogical and chemical study of the sediments from the core which were dated with radioisotopic methods. The results are only part of a multidisciplinary investigation on the evolution of different groups of pollutants in dated lacustrine and marine sediment cores to be published later.

Granulometry, carbonate mineralogy and concentration of A1 (representing detritic alumosilicates such as clay minerals and feldspars) exhibit a clear bipartition of the sedimentary sequence: a) an upper part, comprising the interval 0-4 cm (or 0-5 in the case of AI) with a relatively large medium grain size (median), a high carbonate content of about 60% and a high calcite/dolomite ratio (>15). A1 concentrations are lower than 2%. b) a lower part, below 4 cm (or below 5 cm for A1) with a median smaller than 0.005 ram, a carbonate content below 50% and a calcite/dolomite ratio of less than 10. The A1 concentrations are in all cases higher than 2% with maximum concentrations of around 6%. The transition from the minimum to the maximum is gradual. The bio-elements C, N and P show a similar development with relatively high concentrations in the upper part and low concentrations in the lower part of the core. Above 10 cm, the concentrations of C, N and P increase gradually. The 2~~ distribution in the sedimentary

Naturwissenschaften 66 (1979) 9 by Springer-Verlag 1979

column reveals two different rates of sedimentation : a relatively high rate in the section 0 5 cm and a comparatively low rate of 0.024g.cm-2.y - t ( ~ 0 . 4 4 m m - y -~) below 5 cm. The high rate of sedimentation in the upper part of the core was determined more precisely on the basis of the t37Cs distribution: it amounted to 0.1g-cm Z y - l ( 2 . 0 m m . y - t ) , . T h e d a t _ ing of the sediment core as given in Fig. 1 results from combined 21~ and t37Cs methods. The first appearance of t37Cs within the sediment layer 4-5 cm reflects the first considerable emission of t 3VCs derived from nuclear tests in the higher atmosphere and marks the year 1954 [5]. If the change in the rate of sedimentation took place at 4 cm (as results from textural and mineralogical data), rather than at 5 cm (as can be concluded from the z 10pb data), the 1954 " m a r k " should be placed close to the uppermost portion of the 4-5 cm interval. Thus, the major change in the rate of sedimentation can be dated at about 1960. Stereoscan microscopy shows that the increase of the medium grain size (median) is caused by silt-sized calcite aggregates at the expense of finer-grained particles. These aggregates have the same appearance as fragments of calcite coatings that * A detailed discussion of the age determination of Lake Constance sediments will be published separately [4] 261

Cancer: some realist hopes.

Neue Aspekte Wo werden Organellen-Proteine synthetisiert? Polyribosomen kommen entweder frei im Grundplasma vor oder sind den Membranen des endoplasma...
387KB Sizes 0 Downloads 0 Views