Book 118


Book 136

The Ciba Foundation is an international scientific and educational charity which was established in order to promote international co-operation in biological, medical and chemical research. It organizes about eight multidisciplinary symposia each year on topics ready for discussion by a small body of research workers. This volume embodies the proceedings of a conference on the evaluation of scientific research, held at the Ciba Foundation's offices in London, on 6th-8th June 1988. Topics include the evaluation of research training, scientific institutions, research groups and the link between technology and science.

Book 143

The Biology of Hyaluronan Chairman: T. C. Laurent 1989 Hyaluronan is a unique linear polysaccharide found in cartilage and in soft connective tissues such as synovial fluid and skin. It is an apparently simple homopolymer with a mechanical role as space filler or lubricant which also takes part in cell surface activities of great specificity, as recent work described in this symposium shows. Hyaluronan synthase was first identified in streptococci; isolation of the mammalian enzyme and its properties are discussed. The degradation of hyaluronan is mainly intracellular after receptor-mediated uptake. The catabolic enzymes involved and the fate of the resulting monosaccharides (including their recycling) are becoming understood. Various hyaluronan-binding proteins have been identified, including one in fibroblasts which may help regulate cell motility. Hyaluronan is a major component of the intercellular matrix surrounding proliferating and migrating cells in embryonic tissues, including the developing nervous system. It is involved in inflammation, angiogenesis and wound healing.
High concentrations are found in malignant tissues, the result (in culture at least) of stimulation of hyaluronan synthesis in fibroblasts by tumour cells. Another stimulatory factor, produced by activated blood mononuclear cells, links hyaluronan to inflammatory diseases such as scleroderma and rheumatoid arthritis. High levels are produced in cirrhotic liver disease, malignant mesothelioma and sarcoidosis. The clinical use of hyaluronan as a connective tissue marker is leading to a better understanding of such diseases. The symposium concludes with a discussion of the surgical use of purified hyaluronan, including the development of new molecular forms for use in the control of adhesions, scar formation and tissue regeneration. Related Ciba Foundation Symposia: No 124 Functions of the proteoglycans Chairman: V. C. Hascall 1986 ISBN 0 471 91090 2 No 136 Cell and molecular biology of vertebrate hard tissues Chairman: G. A. Rodan 1988 ISBN 0 471 91885 7 No 145 Carbohydrate recognition in cellular function Chairman: E. Ruoslahti 1989 ISBN 0 471 92307 9

Book 145

Carbohydrate Recognition in Cellular Function Chairman: E. Ruoslahti 1989 Cells interact with their environment and with neighbouring cells by an intricate array of molecular recognition events. This book explores the role of carbohydrates in communication between cells of multicellular organisms. The thermodynamics and spatial restrictions of oligosaccharide - protein interactions are discussed. An analysis of the amino acid sequences required for carbohydrate recognition and the use of a consensus sequence to identify potential carbohydrate-binding proteins are described. Carbohydrates are important components of the different families of Cell adhesion molecules; one example is the mammalian sperm receptor, where the species specificity of egg recognition is achieved by a particular class of oligosaccharides.
Isolated gangliosides and galactosides also mediate recognition processes directly, in nerve cells at least; a specific ganglioside activates a membrane-bound protein kinase in neuroblastoma cells, triggering phosphorylation of several cell surface proteins; and the different subsets of rat dorsal root ganglion neurons express distinct sets of oligosaccharides which are recognized by binding proteins on dorsal root ganglion and spinal neurons. Modification of the carbohydrate moiety of glycoproteins is a frequent occurrence in certain diseases, including those of the immune system. Recent progress in understanding all these areas is described. The discussions after each presentation highlight work that remains to be done. Related Ciba Foundation Symposia: No 143 The biology of hyaluronan Chairman: T. C. Laurent 1989 ISBN 0 471 92305 2 No 136 Cell and molecular biology of vertebrate hard tissues Chairman: G. A. Rodan 1988 ISBN 0 471 91885 7 No 124 Functions of the proteoglycans Chairman: V. C. Hascall 1986 ISBN 0 471 91090 2

Book 146

The Ciba Foundation is an international scientific and educational charity which exists to promote internationalco-operation in biological, medical and chemical research. It organizes about eight international multidisciplinary symposia each year on topics that seem ready for discussion by a small group of research workers. These are the proceedings of a symposium held at the Ciba Foundation in London during March 1989. The topic, photosensitizing compounds, was proposed by Professor Raymond Bonnett. The papers presented cover various aspects of these compounds, their behaviour and their uses.

Book 148

Molecular Control of Haemopoiesis Chairman: D. Metcalf 1990 The many different kinds of blood cells are derived from multipotential stem cells that are induced to differentiate into one or another cell type by the action of regulatory proteins or growth factors. This symposium describes how the binding of these proteins to specific receptors causes changes in gene expression in the nucleus and in the activity of certain enzymes in the cytoplasm, thereby committing the cell to a particular developmental pathway. The haemopoietic growth factors interact with other families of known cytokines, particularly the interleukins; the role of these mutual influences in normal cells and in blood disorders, such as leukaemia, is discussed. The molecular cloning of the haemopoietic factors has enabled them to be produced in sufficient quantities to be used clinically, and they are finding applications in many situations. The most promising studies are those where the factors are used to stimulate production of normal blood cells after depletion by irradiation or by chemotherapy treatment of a variety of diseases.
This book includes reports on the progress of several clinical trials and discussion of future possibilities. Related Ciba Foundation Symposia: No 84 Microenvironments in haemopoiesis and lymphoid differentiation Chairman: M.F. Greaves 1981 ISBN 0 471 91053 8 No 116 Growth factors in biology and medicine Chairman: Sir Michael Stoker 1985 ISBN 0 471 91085 6 No 131 Tumour necrosis factor and related cytotoxins Chairman: L.J. Old 1987 ISBN 0 471 91097 X

Book 153

Steroids and Neuronal Activity Chairman: M.A. Simmonds 1990 Classical studies on steroid hormones have been concerned with their regulation of protein synthesis via the modulation of genomic transcription. However, many of the actions of these hormones occur too rapidly to be explained in this way, particularly their effects on the central nervous system. Recent discoveries have shown that steroids can modulate the activity of certain neurotransmitters. GABA (gamma-aminobutyric acid) is an important regulator of neuronal activity in the CNS; its inhibitory action is mediated by the GABAA receptor and is potentiated by steroids. The mechanisms by which this is achieved are being investigated in electrophysiological and ligand binding studies described in this volume. The effects of steroids on dopamine and other receptors coupled to adenylate cyclase or to protein kinase C are also considered. The binding of steroids to cell membranes, the components involved and the outcome of such interactions are all discussed. These basic studies also have clinical implications.
The use of glucocorticoid steroids in the attenuation of neuronal damage after stroke or other trauma is being investigated, as is the role of ovarian steroids as anaesthetics and as anticonvulsants. The volume concludes with a review of glucocorticoid effects on long-term potentiation in the CNS. Related Ciba Foundation Symposia: No 123 Antidepressants and receptor function Chairman: D.L. Murphy 1986 ISBN 0 471 91089 9 No 152 The biology of nicotine dependence Chairman: L.L. Iversen 1990 ISBN 0 471 92688 4

Book 158

Host-Guest Molecular Interactions: From Chemistry to Biology Chairman: I.O. Sutherland 1991 Host - guest molecular interactions lead to the formation of molecular assemblies containing two or more species. It has long been recognized that such supramolecular' association is of fundamental importance in biological processes, but it is only recently that chemists have begun to design and synthesize novel host molecules. The field is relatively new, but exciting applications are already emerging, for example in the development of molecular sensors, of new chromogenic reagents and of reagents for selective metal ion capture or for the capture of molecules such as urea. In addition, it is expected that improved understanding of the interactions in relatively simple complexes of synthetic host molecules will lead to a better understanding of the much more complex biological systems in which the host molecules are either proteins or nucleic acids. In this book the contributions from experts in the chemical and biological sciences range over intermolecular interactions in both synthetic and natural (biological) systems.
Topics covered include biomimetic chemistry, the design of synthetic host molecules which mimic biological processes such as ion transport across membranes and catalysis, and the concepts of preorganization and template-directed synthesis. Molecular recognition processes involved in binding of antibiotics to peptides and to DNA and in binding of sequence-specific gene inhibitors to DNA are discussed. The potential applications of oligonucleotides with modified phosphate diester linkages as probes of DNA - protein interactions and for anti-HIV treatment are described. Interactions between proteins and other molecules and the computational modelling of interactions are considered. Related Ciba Foundation Symposia: No 119 Synthetic peptides as antigens Chairman: G.L. Ada 1986 ISBN 0 471 99838 9 No 145 Carbohydrate recognition in cellular function Chairman: E. Ruoslahti 1989 ISBN 0 471 92307 9 No 159 Catalytic antibodies Chairman: W.P. Jencks 1991 ISBN 0 471 92962 X

Book 160

Regeneration of Vertebrate Sensory Receptor Cells Chairman: E.W. Rubel 1991 Sensory receptor cells are responsible for our ability to interact effectively with our environment; loss of these cells leads to serious impairment - thus one in 800 babies is born deaf, and one in ten adults suffers hearing loss serious enough to restrict language comprehension. The permanence of sensory disability varies widely across sensory systems and across vertebrate species: in humans, taste buds and olfactory cells are replaced, whereas loss of inner ear and retinal receptors results in permanent disability. Research in lower vertebrates, however, indicates that regeneration after injury can lead to the restoration of normal function, and recent research in birds shows that hair cells proliferate after damage to the inner ear. This finding has stimulated much research activity in the field of sensory cell regeneration. In this symposium an international group of investigators met to discuss progress in our knowledge of sensory structures in lower and higher vertebrates.
Experts in two other relevant fields - the cell cycle, and mitogenic growth factors - also contributed to the search for the precursors and/or stem cells in each sense organ and for the signals which regulate differentiation of those precursors, in normal development and potentially in regeneration. While regeneration of the mammalian inner ear or retina is still some way off, much is already being learned about the cellular processes underlying regeneration in other sensory systems and is being actively applied to the more intractable ones. The symposium should interest a broad range of cell biologists beyond those already involved in sensory receptor function and regeneration.Other Ciba Foundation Symposia: No. 138 Plasticity of the neuromuscular system Chairman: A.J. Buller 1988 ISBN 0 471 91902 0 No. 144 Cellular basis of morphogenesis Chairman: L. Wolpert 1989 ISBN 0 471 92306 0 No. 153 Steroids and neuronal activity Chairman: M.A. Simmonds 1990 ISBN 0 471 92689 2 No. 155 Myopia and the control of eye growth Chairman: J. Wallman 1990 ISBN 0 471 92692 2

Book 183

Circadian Clocks and Their Adjustment Chairman: J. M. Waterhouse 1995 Organisms ranging from unicellular algae to humans display biological rhythms reflecting their ability at the molecular level to keep track of time. In humans, the circadian clock signals when to sleep and wake, adjusts body temperature and modifies cardiovascular, renal, digestive and other functions, correspondingly directing the production of certain hormones, of which the pineal hormone melatonin is the best known. Research on a range of organisms is revealing an increasingly coherent picture of the molecular and cellular basis of biological clocks and the internal pacemakers that generate the rhythms and are synchronized with time cues in the environment such as the light - dark cycle, physical activity, drugs, diet and social factors. This book covers recent advances in all major aspects of research on circadian clocks. The genetic and molecular basis of the clock in Neurospora crassa is described and the molecular background to recent work showing that individual isolated neurons from Bulla gouldiana can act as pacemakers is investigated.
The organization and operation of circadian pacemakers in vertebrates is dealt with in the hamster and the rat; the results and implications of studies of the neuronal pathways involved in the circadian timing system, the intrinsic rhythms generated by the suprachiasmatic nuclei and cross-genotype transplantation of the suprachiasmatic nuclei in the tau period mutant hamster are considered. A discussion of current knowledge of the anatomical, genetic and neurochemical pathways involved in photic and non-photic entrainment in the hamster leads on to the changes that occur with ageing. Aspects of the book with direct relevance to humans include chapters on the importance of circadian time in clinical pharmacology and on the adjustment of the pacemaker by light and melatonin treatment in disorders such as shift-work dyssomnia and jet lag. Related Ciba Foundation Symposia: No. 168 Functional anatomy of the neuroendocrine hypothalamus Chairman: S. Lightman 1992 ISBN 0 471 93440 2 No. 170 Regulation of the eukaryotic cell cycle Chairman: T. Hunter 1992 ISBN 0 471 93446 1

Book 197

The mapping of human genes is proceeding rapidly, and genes associated with specific inherited diseases are being identified, often providing insight into the molecular cause of the disease. At the moment, however, little consideration is being given to the variation present in different human populations. This variation bears a record of the population history of our species and how this has been affected by diseases, ecological adaptations, and pharmacological and nutritional responses. Treatment of inherited diseases that involve several genes will require knowledge of the degree and nature of genetic variation present in a population. This book discusses methods of analysing population genetic data and how contemporary genetic heterogeneity arises during the evolution and migration of human populations. Specific disorders - such as cystic fibrosis, beta-thalassaemia, fragile X, phenylketonuria and tumour development susceptibility - are used to illustrate this genetic variability and mechanisms of gene mutation and evolution.

Book 208

Evolutionary psychology is a new and rapidly expanding area of study. All psychology is in a sense 'evolutionary psychology' since, if we disregard Creationism, the only forces which could have shaped the human mind are evolutionary forces. However, psychologists have traditionally regarded this fact as irrelevant to the practical problems of formulating and testing psychological theories. This book contains chapters by some of the leading figures in this new field. The latest data are presented on evolutionary theories in perception, information, various aspects of social behaviour, language, learning and aggression. A common theme running through the printed discussions in this book is the important problem of how we can develop and test rigorous characterizations of evolved mental adaptations.

v. 162

Biological Asymmetry and Handedness Chairman: L. Wolpert 1991 Morphological asymmetry occurs in most types of living organisms, often with a systematic bias towards either right-handed or left-handed forms. The predominance of L-amino acids can be explained thermodynamically; their characteristics determine secondary structure in proteins but the information is lost at the next stage of protein assembly. Left-right asymmetry in animals arises early in embryogenesis: the mechanism is unknown but examples from a range of organisms - including ciliates, molluscs, Caenorhabditis, Xenopus and mammals - provide several clues. Evidence from fossils suggests that primitive animals were asymmetrical; bilateral symmetry then evolved, followed by the laterality seen in modern chordates - for example, the displacement of the mammalian heart to the left. So far, only one gene involved in the inheritance of laterality, the mouse iv gene, has been identified. Cerebral lateralization is observed anatomically; the relationship of this to human handedness' is not clear.
Similarly, whether models for the inheritance of handedness share any features with those for the inheritance of anatomical asymmetries is an open question. Was there an ancestral left-right gene that gave rise to a family of homologues which specify morphological and functional handedness? This multidisciplinary book, the first on this topic for twenty years, discusses models for the inheritance of anatomical asymmetry and for the inheritance of human handedness. Other recent Ciba Foundation Symposia: No. 144 Cellular basis of morphogenesis Chairman: L. Wolpert 1989 ISBN 0 471 92306 0 No. 155 Myopia and the control of eye growth Chairman: J. Wallman 1990 ISBN 0 471 92692 2 No. 160 Regeneration of vertebrate sensory receptor cells Chairman: E.W. Rubel 1991 ISBN 0 471 92960 3

v. 202

This book explores the possibility that life exists on Mars. It provides an interdisciplinary overview of the early evolution of life in hydrothermal ecosystems on Earth, focusing on the problem of remote sensing and incorporating geological work relevant to the search for evidence of early life on Earth and Mars. It discusses the belief that studying thermal spring deposits as part of this search may be the best opportunity to test whether life on earth is a "unique experiment," or whether there is life elsewhere in the solar system.


Diarrhoea is responsible for many millions of infant deaths in developing countries. In 50% of cases of infant diarrhoeal disease the causative agent is not identified. Diarrhoeal outbreaks in adults and in farm or domestic animals can also present serious problems. This book concentrates on the 'novel' diarrhoea viruses, which have emerged as an important cause of diarrhoea in both humans and animals. The 'novel' or atypical rotaviruses (non-group A), the enteric adenoviruses, several types of small round virus (including astroviruses, caliciviruses and Norwalk virus) and the group of Berne and Breda viruses are all examined. Research workers from various disciplines present the current state of knowledge and discuss the nature of these viruses, their identification and their histopathological effects. Immunological problems in vaccine development and research needs in the field of novel diarrhoea viruses are also considered. This symposium is primarily for virologists, both human and veterinary, and epidemiologists. Molecular biologists, public health workers (especially in developing countries) and pathologists will find it valuable and informative.

No 154

Useful throughout history for their medical as well as other benefits, plant-derived compounds have gained particular importance recently, due to environmental factors. The isolation and characterization of plant products, the identification of their role in the plant, and ways of synthesizing identical compounds or more potent analogues are covered. Also includes methods of culturing plant tissues and genetic engineering as a means of increasing the yield of desired substances from plants. Special emphasis is placed on plants previously unknown to Western scientists.

Interactions Among Cell Signalling Systems Chairman: Y. Nishizuka 1992 The study of mechanisms of cell signalling, including the processes involved in signal transduction, is one of the most exciting and dynamic areas of biological research. As the mechanisms of cell signalling systems have become known in more detail, the importance of interactions between them - cross-talk' - has emerged. Interactions are seen at various levels of receptors, ion channels, coupling factors, second messengers and effectors. The subject of this book is cross-talk and its functional implications for mechanisms of hormone action, synaptic activity, the immune system, gene expression and growth control. The actions of and interactions between various types of protein kinases are a particular feature. There is discussion of the involvement of tyrosine kinases and the recently identified tyrosine phosphatases in growth control and the immune system. Protein kinase C activity in T cell activation mechanisms, stimulation of the enzyme by the synergistic action of diacylglycerol and unsaturated fatty acids, and the role and localization of protein kinase C subspecies are considered.
The convergence of the protein kinase C and Ca2+/calmodulin signal transduction pathways in the control of cytoskeletal - plasma membrane interactions by regulation of the MARCKS protein is described. The roles of GABA and NMDA receptors, calcium, protein kinase C and calmodulin-dependent protein kinase in the mechanisms underlying long-term potentiation are analysed. Other topics covered include G protein regulation of phosphoinositide and phosphatidylcholine phospholipases, growth factor tyrosine phosphorylation of phospholipase C-gamma1, the interaction between the Ca2+ and cyclic AMP second messenger systems in the regulation of insulin secretion and that between cyclic AMP and inositol lipids in activation of B cells. Related Ciba Foundation Symposia: No. 122 Calcium and the cell Chairman: P.F. Baker 1986 ISBN 0 471 91088 0 No. 150 Proto-oncogenes in cell development Chairman: T. Hunter 1990 ISBN 0 471 92686 8 No. 52 The biology of nicotine dependence Chairman: L. L. Iversen 1990 ISBN 0 471 92688 4

The Novartis Foundation Series is a popular collection of the proceedings from Novartis Foundation Symposia, in which groups of leading scientists from a range of topics across biology, chemistry and medicine assembled to present papers and discuss results. The Novartis Foundation, originally known as the Ciba Foundation, is well known to scientists and clinicians around the world.

No 150

Proto-Oncogenes in Cell Development Chairman: T. Hunter 1990 The role of certain genes in the uncontrolled cellular growth that constitutes cancer has been studied intensively for several years. These oncogenes are often viral genes that have been integrated into the genome of the cell. It is now known that these viral genes are mutated versions of normal cellular genes involved in the control of growth and development. The mutant genes fail to respond to regulatory signals in the cell, resulting in unrestrained proliferation. In this book the role of these cellular or proto-oncogenes in normal cell growth is investigated. Several of the proto-oncogenes encode growth factors or their receptors. The latter usually possess tyrosine kinase activity, which phosphorylates specific cytoplasmic proteins thereby initiating the transmission of the signal from the cell membrane to the nucleus. The mechanisms by which this is achieved, and particularly the regulatory aspects, are covered in this book. There are also reports of how phosphorylation of other amino acid residues is used to regulate this transfer of information.
The external stimulus received by the cell results in altered gene expression in the nucleus. The role of nuclear proteins in controlling gene activity is described. Many of the proto-oncogenes are now being found to affect cellular differentiation; the book includes reports on their effects in several specialized tissue types. Finally, the role of proto-oncogenes in the development of the organism as a whole is discussed. These studies are more preliminary but provide an exciting pointer to the direction of future research. Related Ciba Foundation Symposia: No 116 Growth factors in biology and medicine Chairman: Sir Michael Stoker 1985 ISBN 0 471 91085 6 No 142 Genetic analysis of tumour suppression Chairman: E. G. Stanbridge 1989 ISBN 0 471 92299 4 No 144 Cellular basis of morphogenesis Chairman: L. Wolpert 1989 ISBN 0 471 92306 0