The topic of this years' ~osbach Colloquium was DNA integration. We have tried to bring together experts from different fields of research who are studying natural processes by which DNA molecules from differ ent sources are linked. It has been known for a long time that such linkage occurs between the chromosomes of bacteriophages and plasmids on the one hand and the chromosome of the bacterial host on the other. This process has been especially well studied in bacteriophage A. Since it is controlled in a complicated way, we began with a lecture by M. ptashne on these regulatory processes. H. Nash described the inte gration of bacteriophage A into the bacterial chromosome. To put this site-specific process into perspective, G. Mosig lectured on genetic recombination in prokaryotes in general and K. Murray described the use of bacteriophage A as an artificial vector for genetic engineering. A different kind of bacteriophage integration is shown by bacteriophage Mu, which is much less specific in its choice of an integration site than A. The properties of this phage were described by P. van de Putte.

This article is concerned with the use of viral models for the study of the mechanism of protein biosynthesis and its regulation. The scope is restricted mainly to general aspects of animal viral systems and how these systems may be used to approach the question of cellular regulation. Most information on the regulation of metabolic processes in eukaryotic cells comes from the study of bacteria and from the successful application of this knowledge to higher systems. However, differences in regulation of the translation of genetic information from the messenger RNA into protein may be expected between prokaryotes and eukaryotes. Due to the short half-life of prokaryotic mRNAs, transcription has been considered as the main mechanism controlling gene expression. Nevertheless, during recent years firm evidence has been accumulated for additional regu latory factors operating during translation. This topic was recently reviewed by HASELKORN and ROTHMAN-DENES (1973) and by KOZAK and NATHANS (1972)."

In lymphoiden Zellen Tb-sensibilisierter Meerschweinchen sind sessile Antikorper vorhanden, die in der Lage sind nach Kontakt mit Tuberkulin Komplement zu binden. Dieser Nachweis ist sowohl fluorescenzserologisch als auch - unter Verwendung von Extrakten aus solchen Zellen - mit der Hamagglutination und der Coombs-Technik oder mit dem Konglutinations- verfahren moglich. Sie konnen ferner mit dem Hamaggregationsverfahren nachgewiesen werden. Die sessilen Antikorper besitzen mindestens zwei, nach ihrer immunologischen Spezifitat und dem Mechanismus ihrer cytolytischen Funktion distinkte immunologische Spezifitaten. Die eine ist gegen den Haupt- bestandteil von Alttuberkulin (Tuberkulopolysaccharide) und die andere gegen den von gereinigtem Tuberkulin (Tuberkuloproteine) gerichtet. Beide Anti- korper konnen auf weisse Zellen nicht sensibilisierter Tiere ubertragen werden. Sie sind mercaptoathanolempfindlich und konnen deswegen den Antikorpern vom 19 S-Typ zugerechnet werden. Sie sind nicht identisch mit den cytophilen Antikorpern; auch scheint keine direkte kausale Beziehung zur Tuberkulin- Hautreaktion zu bestehen. Ihre mogliche Bedeutung wird diskutiert. Lymphoide Zellen von Tb-sensibilisierten Meerschweinchen enthalten ausserdem noch einen Faktor, der in vitro Agglutinationsreaktion und in vivo PCA-Reaktionen hemmt. Literatur BAlL, 0.: Ubertragung der Tuberkulinempfindliehkeit. Z. Immun.-Forseh. 1. Orig. 4,470 (1910). BLAZKOVEC, A. A., E. SORKIN, and J. L. TURK: A study of the passive eellular transfer of loeal eutaneous hypersensitivity. Int. Areh. Allergy 27, 289 (1965). BLOOM, B. R., and B. BENNETT: Meehanism of areaction in vitra associated with delayed type hypersensitivity. Scienee 153, 80 (1966). - - Delayed hypersensitivity in vitra: the meehanism of inhibition by antigen of eell migration. Fed. Prae. 25, 355 (1966).

Ever since arbovirus infections became known and their relative importance assessed, experiments were designed to elucidate the mode of transmission and the most important natural hosts responsible for perpetuating the infection in nature. Human infections and the disease in wild rodents, birds, and domestic animals were studied in relation to viremia and distribution of the infectious agent in the organism. With increasing epidemiological studies it became apparent that the neural manifestations of the disease are very uncommon, confined only to a small percentage of individuals of the most susceptible species. Various factors have been proposed to explain why in certain instances the virus becomes establish ed in the central nervous system and causes a serious or lethal disease. For example, differences in the virulence of the virus strains, varying susceptibility of individuals of one species, or intercurrent circumstances facilitating access of the virus to the central nervous system were alleged. Also, various possible routes of entry of the virus into the brain and spinal cord have been considered."

"When we give a definition it is for the purpose of using it." HENRI POINCARE in Science and Method A. Objectives The first version of this paper was written to introduce new students and fellows of my laboratory to the mysteries of herpesviruses. Consonant with this design sections dealing with well documented data were trimmed to the bone whereas many obscure phenomena, controversial data and seemingly trivial observations were discussed generously and at length. There is some doubt as to whether it was meant to be published, but it was not a review. The objective of reviews is frequently to bring order. But alas, even the most fluent summation of credible data frequently makes dull reading and too much plausible order, like very little entropy in chemical reactions, is not the most suitable environment on which to nurture the urge to discover. This version is more charitable but not less inbalanced. The bibliography reflects the intent of the paper and was updated last in December of 1968. It should be obvious without saying that no single account such as this can do justice or injustice, as the case may be, to the several hundred papers published on herpesviruses each year or to the many thousand papers published on herpesviruses since the first of the members of the family was experimentally transmitted to a heterologous host more than half a century ago (GRUTER, 1924). B. Definition 1.

The study of streptococcal infections and their sequelae has in the last two decades yielded several important findings on the biological properties of cellular and extracellular products of group A streptococci. These findings have contributed to a better knowledge of the pathological reactions occurring in the macroorganism during host-parasite interactions. Nevertheless, the pathogenesis of streptococcal infections is not fully understood. So far there has been no success in eliciting experimentally, either through the action of the substances isolated from the cell, or from broth culture filtrate of group A streptococci, symptoms that are fully identical with any type of acute streptococcal infection. It also has not been possible to explain the mUltiplicity of clinical and histological changes caused by streptococci as being due solely to anyone of these substances or a combination thereof. The same applies to the sequelae of streptococcal infections, rheumatic fever and acute glomerulonephritis. We do not know how the group A strepto coccus elicits these diseases and we have only a partial understanding of the pathological processes, initiated by this streptococcus, and resulting in cardiac or renal lesions. It is clear that an organism infected by streptococci is exposed to the action of a complex of substances. A more detailed recognition of the biological activity of the single components and their combination under defined experimental conditions may be capable, it is hoped, to explain the pathologic processes triggered in the course. of the development of group A streptococcal infection."

Several discoveries are noteworthy for allowing us to probe the recesses of the virus infected cell and to search for cryptic viral genomes which might provide clues in our studies of cancer etiology or developmental biology. One of the most notable was the dis covery of reverse transcriptase. This marked a momentous occasion in the history of molecular biology. Not only did it provide insight into the mechanism of persistence of retroviruses but it also provided us with an enzyme that could synthesize a DNA copy of any RNA. This DNA copy could then be used as a hybridization reagent to search for both complementary DNA and viral-specific RNA. Thus one could follow the course of any viral infection or probe in tumor cells for hidden viral genomes. Second, a great deal of credit must be given to the geneticists who isolated the various deletion mutants in the 'avian retrovirus system and thus provided us with the frrst means of isolating gene-spe cific probes. Finally, the laboratories which have mapped the genome have provided us with the framework in which to ask very specific questions with our gene-specific probes. Recently, numerous excellent reviews concerning various aspects of the retroviruses have appeared. In this review I shall not even attempt to present a comprehensive review of retroviruses."

Many of the fundamental concepts of animal virology originated from the study of the variola-cowpox-vaccinia virus system with vaccinia virus serving as the type species (Fen- nerand Burnet 1957; Burnet 1959; Fenner 1976a, b). The importance of the Poxviridae(Fen- ner 1979) for the study of viruses as biologic entities and in defIning the events which occur in virus-infected cells are exemplifIed by investigations which: (a) described the epidemiology of a virus disease in an animal population (Fenner1949, 1959b); (b) em- ployed electron microscopy to study virion structure (Peters 1956, Nagington and Home 1962, Dales and Siminovitch 1961) and to derme the morphologic stages of virion develop- ment in infected cells (Morgan et al. 1954, Dales 1963); (c) dermed and elaborated on the mechanism of nongenetic reactivation for an animal virus (Joklik et al. 1960a, Fenner and Woodroofe 1960, Hanafusa 1960); (d) described the intracellular uncoating of a viral genome (Joklik 1964a, b); (e) studied the antigenic structure and complexity of poxvirions (Loh and Riggs 1961, Woodroofe and Fenner 1962, Appleyard et al. 1964, Appleyard and Westwood 1964); (1) described the use of chemotherapy to treat viral infec- tions (Bauer et al. 1963); (g) fIrst demonstrated the presence of virion-coded enzymes encapsulated within virions (Kates and McAuslan 1967, Munyon et al. 1967); and (h) established the H -2 restriction of cytotoxic T-cell killing of virus-infected cells in the murine system (Doherty et al. 1976).

Immunoglobulin gene expression appears to include a number of unique features (Cohn, 1971; Gaily and Edelman, 1972; Hood et aI. , 1975). First, a variety of genetic and protein structural evidence suggests that two discrete genes - both a variable region gene and a constant region gene - specify each heavy chain and each light chain. This constitutes the twogene-one polypeptide hypothesis. Second, a single differentiated lymphocyte or plasma cell appears to express only one heavy chain allele and one light chain allele at a time. This is the only example of allelic exclusion known in mammalian cells except for X chromosome inactivation. Third, during the course of lymphocyte differentiation, there may be a switch of the heavy chain constant region gene expression but no change in the heavy chain variable region gene expression. Rarely, normal or malignant cells have been found which express two different heavy chain subclasses simul taneously (e. g. see Sledge et aI. , 1976). Fourth, the vast number of different antibodies which can be made by an individual animal has raised the question of whether the generation of diversity occurs during evolution or within the animal, i. e. germ line vs somatic variation. Other aspects of immunoglobulin gene ex pression may be similar to regulation of gene expression in many eukaryotic cells.

This volume is dedicated to the memory of the late Professor WERNER BRAUN, one of the most devoted and active members of the Editorial Board of the Current Topics in Microbiology and Immunology, who passed away, after suffering a heart attack, in November 1972. Dr. WERNER BRAUN was born in Berlin, Germany, on November 16,1914. During his highschool days in Berlin he did research work on problems of genetics as a young guest in the Kaiser-Wilhelm-Institut fur Biologie, in the department of Prof. R. GOLDSCHMIDT. I remember his colourful description of his discussions during this period, while still a teen-ager, with OTTO WAR- BURG. He studied biology and medicine at the University of G6ttingen and received a Ph.D. degree in biology in 1936. In the same year he left Nazi Germany and came to the United States first as a Guest Investigator in Genetics at the University of Michigan at Ann Arbor, and then in Berkeley, where he carried out his work in the Depart- ments of Zoology and of Veterinary Science until 1948. He was engaged during this period in the study of problems concerned with physiological genetics, bacterial variation, immunology and biochemistry.

Binding of various ligands (hormones, neurotransmitters, immunological stimuli) to membrane receptors induces the following changes: 1. Receptor redistribution (clustering, "capping") 2. Conformational changes that can be detected by fluorescent probes 3. Alteration in membrane fluidity (spin label and fluorescence polarization probes) 4. Changes in fluxes of ions and metabolites 5. Increased phospholipid turnover (especially of phosphatidyl inositol) 6. Activation of membrane-bound enzymes (adenyl cyclase, ATPase, transmethylases). Some of the early changes resulting from or associated with the binding (adsorption) of virions to the host cell membrane are of the same type. Adsorption of animal viruses to cells is the ftrst step in a chain of events resulting in the production of progeny virus on the one hand and in damage to cells and tissues on the other. In the classical studies of viral infection, cells are adsorbed with virus, usually for 60 min, and the changes induced by the virus in the host cell are recorded thereafter. In the past decade, more and more studies have been aimed at the events occurring in these ftrst 60 min of the so-called adsorption period. These studies deal with the nature of adsorption, e. g. , the ligand-receptor type of interaction between the virus and the cell membrane. Many receptors for viruses were identifted and so were the viral proteins which take part in adsorption.

Gene cloning for the production of recombinant DNA is usually performed with E. coli. There is, however, no doubt that gene cloning in organisms other than E. coli will assume a much more important role in the future: efficient cloning systems are needed for the analysis of gene expression and its regulation in eukaryotic cells, for the elucidation ofthe genetic mechanisms of transform a- tion, and for the study of the genetic rearrangement during dif- ferentiation and embryogenesis. Furthermore, optimal cloning systems will be required for practical applications in the near future: for the optimal production of antibiotics, amino acids, vitamins, enzymes etc. , for the expression of gene products under favorable energetic conditions for mass production, for the ex- pression of glycolysated animal proteins, for the genetic manipu- 'lation of plants -and in the more distant future, for gene therapy inman. The editors have therefore invited leading scientists to sum- marize the present status and the future applicability of gene cloning systems in their fields of research. To ensure a complete coverage of a genetic system, the editors have generally asked two authors to cover one system. This volume is a frrst and unique account of our knowledge of cloning systems employing organisms other than E. coli such as B. subtilis, pseudomonas, neurospora, saccharomyces and streptomyces, as well as of vectors and selection procedures for animal and plant systems including the liposome technique. October 1981 P. R.