Genomics : applications in human biology

in medicine 1 Introduction 1 Recombinant DNA technology 2 The central importance of cloning 2 Identification and cloning of specific genes 5 Functional characterization of cloned genes 9 From recombinant DNA to molecular medicine 10 The use of DNA sequences as diagnostic tools 11 The production of therapeutic proteins 11 Gene medicine 14 Disease models 15 The impact of genomics on medicine 15 The new molecular medicine 17 Outline of this book 18 Further reading 19 CHAPTER TWO: An overview of genomics 20 Introduction 20 A review of progress: the Human Genome Project 21 Breakthroughs in genetic mapping 23 Breakthroughs in physical mapping 25 Sequencing strategies 28 Genome annotation 31 The future: functional genomics 35 Sequence comparison and comparative genomics 37 Transcriptomics: global analysis of mRNA 40 Proteomics: global analysis of proteins 45 Technology platforms for proteome separation 47 Protein characterization by mass spectrometry 49 Applications of expression proteomics 51 Technology platforms for interaction proteomics 51 Mutational genomics 55 Further reading 57 CHAPTER THREE: Genomics and the challenge of infectious disease 60 Microorganisms causing disease 60 Where do new diseases come from? 63 Identifying the causative agent of a disease 65 Molecular epidemiology 68 Host resistance to infection 70 Understanding bacterial pathogenicity 70 Pathogenicity islands 72 Comparative genomics and genome plasticity 73 Combating infectious disease 75 Novel routes to vaccines 76 Genomics and the development of new antibacterial agents 78 Combating fungal infections 81 Progress in tackling protozoan diseases 82 Developing antiviral drugs 86 Further reading 89 CHAPTER FOUR: Analyzing and treating genetic diseases 90 Genetic disease in context 90 Detecting single gene disorders 91 Treating single gene disorders 96 Finding genes for monogenic diseases and determining gene function 98 Positional cloning 99 The candidate gene approach 100 Analysis of polygenic disorders 102 Model-free linkage analysis 102 Linkage disequilibrium mapping 103 Haplotypes 105 The major histocompatibility complex 106 Individual responses to drugs (pharmacogenomics) 109 Further reading 110 CHAPTER FIVE: Diagnosis and treatment of cancer 112 Introduction 112 The molecular basis of cancer 112 The impact of genomics on cancer research 116 viii Full Contents New methods for the diagnosis of cancer 119 New approaches to cancer therapy 122 Radiotherapy 122 Chemotherapy 123 Biotherapy 127 New therapeutic targets 129 Further reading 129 CHAPTER SIX: The large scale production of biopharmaceuticals 131 Overview 131 The generation of monoclonal antibodies 132 Radioimmunotherapy and diagnostic imaging 135 Other modified antibodies 137 The large scale culture of microorganisms 137 The large scale culture of animal cells 140 Expression systems 144 Downstream processing 145 Using gene manipulation to facilitate downstream processing of biopharmaceuticals 148 The quality of biopharmaceuticals 149 Good manufacturing practice 153 Alternative production systems 154 Further reading 155 CHAPTER SEVEN: Genomics and the development of new chemical entities 157 Introduction: how drugs are developed 157 High-throughput screening 159 Target validation and animal models 163 Combinatorial chemistry 167 Dynamic combinatorial libraries 170 Virtual screening 171 Combinatorial biosynthesis and chemobiosynthesis 172 Drug metabolism 174 Toxicogenomics 175 Further reading 176 CHAPTER EIGHT: Gene and cell therapies 178 Introduction 178 Gene therapy 179 Gene delivery strategies 181 Gene delivery mechanisms 182 Case studies 186 Full Contents ix Nucleic acids as drugs 190 Antisense drugs 190 Ribozyme drugs 191 The potential of short interfering RNAs 191 Aptamer drugs 193 Gene medicine for infectious diseases: HIV 193 DNA vaccines 194 Disease models 195 Models of single gene disorders 195 Models of complex disorders 199 Cell therapy 199 Stem cells and cloning 200 Organ transplants 202 Further reading 203