Since the early times of the Greek philosophers Leucippus and Democritus, and later of the Roman philosopher Lucretius, a simple, fundamental idea emerged that brought the life sciences into the realm of the physical sciences. Atoms, after various interactions, were assumed to acquire stable configurations that corresponded either to the living or to the inanimate world. This simple and unitary theory, which has evolved in successive steps to our present time, remarkably maintained its validity despite several centuries of alternative vicissitudes, and is the foundation of modern biophysics. Some of the recent developments of this ancient idea are the discovery of the direct relationship between spatial structures and chemical activity of such molecules as methane and benzene, and the later discovery of the three-dimensional structure of double-helical DNA, and of its relationship with biological activity. The relationship between the structure of various macromolecules and the function of living cells was one of the most striking advancements of modern science, obtained by the cooperation of physicists, chemists, mathematicians, engineers, biologists, and physicians. This crossing of the life and physical sciences has given rise to new and exciting frontiers, and to a new synthesis where there is a frequent interconnection of expertise, and where there is an exchange of roles among traditionally separated soft and hard sciences. Even if knowledge is still transmitted to new generations within univer­ sities as separate disciplines, new knowledge is acquired today in the laboratory by truly interdisciplinary teams.

Inhalt

1. Normal Cells and Cancer Cells: Macromolecular Structures and Cellular Functions.- 1.1. Background.- 1.2. Native Chromatin-DNA Structure.- 1.2.1. What Is Chromatin?.- 1.2.2. Secondary Structure.- 1.2.3. Tertiary Structure.- 1.2.4. Quaternary Structure.- 1.2.5. Quinternary Structure.- 1.3. Nuclear Structure.- 1.3.1. Nuclear Pore Membrane and Chromosome Scaffold.- 1.3.2. Nuclear Matrix and Control of Nuclear Volume.- 1.3.3. Levels of DNA Organization in Situ.- 1.3.4. Active versus Inactive Genes: Euchromatin versus Heterochromatin.- 1.3.5. Structural Models.- 1.4. What Is a Gene?.- 1.5. Ribosomes.- 1.5.1. Protein Synthesis.- 1.5.2. Genetic Code.- 1.6. Modification in the Control of Cell Proliferation.- 1.6.1. Continuously Dividing Cells.- 1.6.2. DNA Synthesis Initiation.- 1.6.3. Induced Proliferation of Quiescent Cells.- 1.6.4. Water and Ions.- 1.6.5. Chromosomal Protein Modifications.- 1.7. Modifications in the Control of Cell Differentiation.- 1.8. Modifications in the Control of Cell Transformation.- 1.8.1. Cancer Genes.- 1.8.2. Virus and Spontaneous Neoplastic Transformation.- 1.8.3. Chemically Induced Neoplastic Transformation.- 1.8.4. Water.- 1.8.5. Negative Superhelical Turns and Z-DNA.- 1.9. Modifications in the Control of Cellular Aging.- 1.10. Membranes.- 1.10.1. Membrane Structure.- 1.10.2. Membrane Transport.- 1.10.3. Membrane and Neoplastic Transformation.- 1.11. Cytoskeleton.- 1.12. Control Mechanisms for Normal versus Abnormal Cell Growth.- 1.13. Molecular Mechanisms and Models for Gene Expression.- 1.14. Conclusions and Future Trends.- 2. Cancer Cause and Prevention.- 2.1. Background.- 2.2. Possible Causes of Cancer.- 2.2.1. Environment.- 2.2.2. Drugs.- 2.2.3. Viruses.- 2.2.4. Heredity and Spontaneous Induction.- 2.3. Cancer Prevention.- 2.3.1. Long-Term Tests.- 2.3.2. Short-Term Tests.- 3. Cancer Detection and Treatment.- 3.1. Background.- 3.2. Present Status of Human Cancer Detection and Treatment.- 3.2.1. Survival Data.- 3.2.2. Combination Chemotherapy and Radiotherapy.- 3.2.3. Immunotherapy.- 3.2.4. Phototherapy.- 3.3. Alternative Analytical Approaches.- 3.3.1. Pharmaco-Cell Kinetics.- 3.3.2. Pharmaco-Enzyme Kinetics.- 3.3.3. Pharmaco-Tissue Kinetics.- 3.4. New Observables.- 3.4.1. Cell Growth and Differentiation Parameters: G0-Q Cells and Metastatic Variants.- 3.4.2. Cell Heterogeneity, Reverse Transformation, and Macrophage Activation.- 3.4.3. Drug Sensitivity.- 3.4.4. Real-Time Response Monitoring.- 3.4.5. Biochemical Determination of Enzymatic Constants.- 3.5. Theoretical Simulation at the Cellular Level: Optimized Drug Metabolism Parameters in Animals.- 3.5.1. DRUGFIT Model.- 3.5.2. Mathematical Techniques for Fitting the DRUGFIT Model to Experimental Data.- 3.5.3. Animal Model.- 3.5.4. B-16 Tumors.- 3.5.5. Small Intestinal Crypt Cells.- 3.5.6. Differential Response.- 3.5.7. Regression Equations.- 3.6. Treatment Optimization in Animals.- 3.6.1. Synchronization versus Recruitment.- 3.6.2. SIVFIT and Optimal Control Theory.- 3.6.3. Suggested Strategies: Time Scale and Dosage.- 3.6.4. Actual Results: Survival and Selected Killing of Metastases.- 3.7. Drug Interaction and Molecular Perturbation in Animals.- 3.7.1. Experimental versus Theoretical Isobols.- 3.7.2. Time-Dependent Changes in Nucleotide Pools.- 3.8. Extrapolation to Human Cancer.- 3.8.1. Early Cancer Detection.- 3.8.2. Flow and Scanning Cytometry.- 3.8.3. Monoclonal Antibody Testing.- 3.8.4. DNA Probes.- 3.8.5. X Rays-Computerized Axial Tomography.- 3.8.6. NMR Imaging.- 3.8.7. Diagnostic Ultrasound.- 3.8.8. Modeling as a Useful Adjunct in Cancer Chemotherapy.- 3.8.9. Treatment Strategies Based on Cancer Cell Biology and on Analytical Modeling.- 3.8.10. Medical Artificial Intelligence.- 4. Experimental Probes.- 4.1. Background.- 4.2. Preparative Tools.- 4.2.1. Tissue Culture.- 4.2.2. Radioactive Labeling.- 4.2.3. Macromolecule Isolation, Size, and Shape.- 4.2.4. Chromophore Identification: Absorbance and Emission Photometry.- 4.2.5. Activation Analysis.- 4.3. Probes for Lower-Order Structures.- 4.3.1. Template Activity and Restriction Enzymes.- 4.3.2. Genetic Engineering and Protein Engineering.- 4.3.3. Circular Dichroism and Optical Rotatory Dispersion.- 4.3.4. Scattering of Unpolarized and Polarized Light.- 4.3.5. Dye Binding Studies.- 4.3.6. Thermal Denaturation.- 4.3.7. Linear Dichroism and Flow Birefringence.- 4.3.8. Scattering and Diffraction by Neutrons and X Rays.- 4.3.9. Nuclear Magnetic Resonance.- 4.4. Probes for Higher-Order Structures in Situ.- 4.4.1. Electron Microscopy.- 4.4.2. Premature Chromosome Condensation and Cell Fusion.- 4.4.3. Computer-Enhanced Image Analysis.- 4.4.4. Immunocytology.- 4.4.5. Microviscoelastometry.- 4.4.6. Microcalorimetry.- 4.4.7. Microfluorimetry.- 4.4.8. Fluorescence Staining of Macromolecules.- 4.4.9. Complex Dielectric Constants.- 4.4.10. Laser Spectroscopy.- 4.4.11. Biophysical Instrumentation for Electrical Phenomena.- 5. Theoretical Probes.- 5.1. Background.- 5.2. Enzyme Kinetics.- 5.2.1. Michaelis-Menten Equation.- 5.2.2. Lineweaver-Burk Plot.- 5.2.3. Competitive Inhibition.- 5.2.4. Noncompetitive Inhibition.- 5.2.5. Feedback Inhibition and Activation.- 5.3. Signal Processing and Analysis.- 5.3.1. Correlation Function and Fourier Transform.- 5.3.2. Application of Fourier Techniques to Discrete Measurements.- 5.3.3. The Fast Fourier Transform.- 5.3.4. Algorithm for Cross-Correlation Computation.- 5.3.5. Search for Periodicities of Macromolecular Distribution within an Intact Cell.- 5.4. Statistical Mechanics and Thermodynamics of Cell Structures.- 5.4.1. Entropy, Free Energy, and Enthalpy.- 5.4.2. Statistical Mechanics.- 5.4.3. Multiple Equilibria.- 5.4.4. Biopolymer Conformation at Equilibrium.- 5.5. Polyelectrolyte Theory of Interactions among Biopolymers.- 5.5.1. Counterion Condensation and Molecular Theory.- 5.5.2. Persistence Length.- 5.5.3. Model for Chromatin Structure, as Influenced by Ionic Strength and H1 Modification.- 5.5.4. Comparison with Experimental Findings.- 5.6. Physicochemical Model for Dye-Nucleic Acid Interaction in Situ.- 5.6.1. Experimental Evidence from Studies in Solution.- 5.6.2. Description of the Model for in Situ Staining.- 5.7. Electromagnetic Theory of Polarized Light Scattering by Large Biopolymers.- 5.7.1. Multiple Scattering of Dipoles.- 5.7.2. Dielect…