Novartis Foundation Symposium 291

The Biology of Extracellular Molecular Chaperones
Chair: Peter Csermely

The heat shock, or cell stress, response was first identified in the polytene chromosomes of "Drosophila," This was later related to the appearance of novel proteins within stressed cells, and the key signal stimulating this appearance was identified as the presence of unfolded proteins within the cell. It is now known that this is a key mechanism enabling cells to survive a multitude of physical, chemical and biological stresses.

Since the promulgation of the 'molecular chaperone' concept as a general cellular function to control the process of correct protein folding, a large number of molecular chaperones and protein folding catalysts have been identified, and it has been recognized that not all molecular chaperones are stress proteins and vice versa. The discovery of molecular chaperones as folding proteins went hand-in-hand with their recognition as potent immunogens in microbial infection. It was subsequently shown that administration of molecular chaperones such as Hsp60, Hsp70 or Hsp90 could inhibit experimental autoimmune diseases and cancer.

More recently evidence has accumulated to show that certain molecular chaperones are also present on the surface of cells or in extracellular fluids. A new paradigm is emerging: at least some molecular chaperones are secreted proteins with pro- or anti-inflammatory actions, regulating the immune response in human diseases such as coronary heart disease, diabetes and rheumatoid arthritis. In addition to having direct effects on cells, molecular chaperones can bind peptides and present them to T cells to modulateimmune responses. This may be significant in the treatment of cancer.

This book brings researchers together to review and discuss: our current knowledge of cell stress response and molecular chaperones the changing paradigms of protein trafficking and function cell stress proteins as immunomodulators and pro- and anti-inflammatory signalling molecules the role of these proteins in various chronic diseases and their potential as preventative or therapeutic agents.

"The Biology of Extracellular Molecular Chaperones" will be of particular interest to immunologists, cell and molecular biologists, microbiologists and virologists, as well as clinical researchers working in cardiology, diabetes, rheumatoid arthritis and other inflammatory diseases.

With the recent renaissance in mitochondrial biology and increasing recognition of their role in many diseases, this book provides a timely summary of the current state-of-the-art in mitochondrial research. The book opens with the regulation of mitochondrial replication and biogenesis and reviews the mechanisms and functional consequences of mitochondrial fission and fusion. Further chapters address mitochondria and oxidative stress and their roles in cell signalling and cell death. The book includes extensive, fascinating discussion of the biochemistry of mitochondrial cell signalling (especially involving calcium) and of oxidative stress. The nature of the proteins engaged in these processes, many only recently discovered, is covered in detail.

Mitochondria have been strongly implicated in neurodegenerative diseases such as Parkinson's, Huntington's and amyotrophic lateral sclerosis. They are also affected in cancer, ageing and cardiovascular disease. The final section of the book reviews mitochondrial mutations and their consequences in ageing and other phenotypic manifestations. The authors discuss how mitochondrial proteins might constitute important therapeutic targets and describe initial attempts to develop compounds that can regulate their function.

Novartis Foundation Symposium 289

"Growth factors and psychiatric disorders"

Chair: Moses V. Chao

Psychiatric disorders such as depression, bipolar disease and schizophrenia are debilitating illnesses that are influenced by many genetic and environmental factors. While little is known about the neural circuits that underlie such disorders, the convergence of psychiatric, genetic and basic neuroscience research is providing new and exciting insights.

In recent years genetic studies have identified several growth factors as susceptibility genes for depression, schizophrenia, and learning and memory. This suggests that psychiatric disorders may be influenced by a small number of genes with multiple actions. These genes will provide clues to the biochemical mechanisms and pathways that underlie these complex disorders.

This is the first book to undertake a comprehensive investigation of this research. International leading experts are brought together to discuss the latest findings and look at future directions.

Topics addressed include Neuroplasticity and neurotrophic factors. Mechanisms of intracellular trafficking of growth factors. BDNF gene variants in affective disorders. Trophic factors and cognitive functions. Neurotrophins and depression. Schizophrenia genes and neuropathology. Pharmacological treatments of schizophrenia.

"Growth factors and psychiatric disorders" will be of particular interest to psychiatrists, neurologists and geneticists, as well as cell and molecular biologists, and neuroscientists.

Sepsis, the complex, systemic, clinical syndrome resulting from the innate host inflammatory response to infection, is an increasingly common condition, particularly in an ageing population with multiple comorbidities. The mortality rate remains high - about 30 0n the USA and Europe and much higher in the developing world. Indeed, the annual number of deaths from sepsis rivals those due to myocardial infarction and exceeds the mortality rate of virtually every common cancer, yet the syndrome has received relatively little attention as a modifiable disease process.

Most therapeutic strategies target pro-inflammatory mediators, but these have frequently not improved survival of patients when studied in large, multicentre clinical trials. Greater appreciation of the complex pathophysiology by which sepsis induces multiple organ failure has stimulated research into new therapeutic approaches. Depending on the phase of the septic syndrome, these could even involve stimulation of inflammatory, immune or other systems, so the timing of intervention is important. With advances in supportive care in the intensive care unit, the ability to titrate treatment individually is becoming both a reality and a necessity. This important book brings together contributions from an international group of experts in diverse fields, including adaptive immunity, inflammation, neuroendocrinology, bioenergetics and metabolism, to consider all aspects of sepsis and its treatment.

"The pattern of critical illness has changed, such that sepsis, multiple organ failure and impaired patient immunity now dominate clinical practice. Sadly, despite many therapeutic advances, the mortality of this complex syndromeremains high, posing a major challenge. This book highlights the complexity of the disorder and signals the directions for future therapeutic endeavour."

Dr Jack Tinker, Emeritus Dean The Royal Society of Medicine, London