Animal Biotechnology - Technologies, Markets and Companies

Table of Contents

0. Executive Summary 13

1. Introduction to Animal Biotechnology 15

• Introduction 15
• Historical evolution of animal biotechnology 15
• Basics of biotechnology 16
• DNA 16
• RNA 16
• Genes 17
• Single nucleotide polymorphisms 17
• Gene expression 17
• Gene regulation 18
• Proteins 18
• Functions of proteins 19
• Monoclonal antibodies 19
• Animal genetics 20
• Molecular genetics 20
• Twinning in cattle 20
• Pig genetics 20
• Genetic studies in dogs 20
• Animal genomics 21
• The mouse genome 21
• The dog genome 21
• Sequencing of the dog genome 22
• Comparison of genomes of healthy and diseased dogs 23
• Analysis of DNA copy number variation 23
• The cat genome 24
• Marsupial genomes 24
• Genomes of non-human primates 24
• Chimpanzee genome 24
• Genome of the rhesus macaque 25
• Livestock genomics 25
• Bovine genome 26
• Bovine SNP map 27
• Pig genome 27
• Horse genomics 28
• Sheep genome 28
• Chicken genome 28
• Turkey genome 29
• Priority genome list of the National Human Genome Research Institute 30
• Applications of animal genomics 30
• Genomics of disease resistance 31
• Statistical genomics to improve breeding 31
• Chicken breeding based on genomics 31
• Animal proteomics 32
• Applications of proteomics in animals 32
• Caseins in goat milk 33
• Lactic acid bacteria 33
• Applications of proteomics in animal healthcare 33
• Bioinformatics 33
• Application of nanobiotechnology for animal health 34
• Recombinant protein manufacture 35
• Animal biotechnology in relation to other technologies 36

2. Application of Biotechnology in Animals 37

• Introduction 37
• Genetic engineering 37
• Livestock improvement by genetic engineering 37
• Disease control by genetic engineering 37
• Limitations and precautions for genetic engineering 38
• Transgenic animal technology 38
• Cloning animals 39
• Nuclear transfer technology 39
• Nuclear bisection for cloning 41
• Zona-free cloning method 41
• Abnormalities in cloned animals 42
• Cloning from embyonic cells 43
• Cloning of rabbits 43
• Cloning the rat 44
• Cloning the horse 44
• Cloning the cow 44
• Cloning the dog 45
• Cloning in primates 45
• Retrovector-mediated production of transgenic animals 45
• Episomal vector-mediated gene delivery 46
• Sperm-mediated gene transfer 46
• Lentiviral transduction of male germ-line stem cells 47
• Lentiviral transgenesis 48
• Transgenic pharmaceuticals 48
• Proteins from the milk of transgenic animals 48
• Advantages of milk as source of transgenic proteins 49
• Therapeutic proteins from rabbit milk 50
• Recombinant human antibodies from cows 51
• Therapeutic proteins from goat milk 51
• Chicken transgenesis for the production of biopharmaceuticals 52
• Concluding remarks about production of recombinant proteins in animals 52
• Companies involved in production of transgenic pharmaceuticals 52
• Transgenic food products 53
• Milking genetically modified cows 53
• Transgenic fish 53
• Cloned animals as sources of milk and meat 54
• Animal feeds from transgenic plants 54
• Transgenic modification of plants to increase nutritional value of animal feeds 55
• Transgenic disease models 55
• Technologies to create transgenic disease models 55
• Gene manipulation techniques 55
• Embryonic stem cells for gene targeting 56
• Homologous recombination 56
• Animal models of human diseases 57
• Transgenic models for studying human drug metabolism and toxicity 57
• The Human Genome Project and the role of transgenics 58
• Genomic and proteomic analyses of transgenic animal models 58
• Concern about health and welfare of transgenic animals 59
• Safety of transgenic technology 59
• Concluding remarks about use of transgenic animals 60
• RNA interference technology 60
• RNAi versus antisense 60
• Applications of RNAi in animal biotechnology 60
• Xenotransplantation 61
• Pigs for xenotransplantation 61
• Genetically engineered pigs for transplants 62
• Risks of xenotransplantation 62
• World Health Organization and xenotransplantation 63
• Companies involved in xenotransplantation 63
• Ethical aspects of animal biotechnology 64

3. A Biotechnology Perspective of Animals Diseases 65

• Introduction 65
• Infections in animals 65
• Viral infections 66
• Avian influenza 66
• Animal surveillance of influenza 68
• Animal biotechnology implications of H1N1 influenza 69
• Animal corona viruses and human SARS 69
• Avian coronavirus 70
• Bluetongue virus 71
• Canine parvovirus 71
• Classical swine fever 71
• Developing new treatments against FMDV 71
• Equine infectious anemia 72
• Foot-and-mouth disease 72
• Porcine reproductive and respiratory syndrome virus 74
• Rabies 74
• Rinderpest 75
• Bacterial infections 75
• Bovine tuberculosis 75
• Mycoplasmal pneumonia 76
• Protozoal infections 76
• Neosporosis 76
• Toxoplasmosis 76
• Coccidiosis 77
• Nematodes 77
• Infections that cross the species barrier 77
• Complications of bacterial infections and antibiotic use in animals 78
• Transmissible spongiform encephalopathies (TSEs) 78
• Inter-species transfer of prions 78
• Scrapie 79
• Bovine spongiform encephalopathy 79
• Epidemiology of BSE 79
• Biomarkers in the urine of BSE infected cattle 81
• Human health implications of BSE 81
• Breeding animals protected against BSE 81
• TSE research 82
• Prion gene haplotyping 82
• Pharmacological approaches to TSE research 82
• Molecular diagnostic approach to TSE research 82
• RNAi for knockdown of the bovine prion gene 83
• Chronic wasting disease 83
• Chronic wasting disease in wildlife 83
• Chronic wasting disease of the cattle in Sudan 84
• Chronic wasting in dairy cows in the Netherlands 84
• Genetic disorders in farm animals 85
• Diseases of pet animals 85
• Canine anemia 85
• Cardiovascular disease 86
• Heart failure 86
• Cardiac complications of canine babesiosis 86
• Diabetes 87
• Role of biotechnology in management of diabetes 87
• Arthritis 87
• Cancer in cats and dogs 88
• Cancer clinical trials in dogs 88
• Canine Comparative Oncology Genomics Consortium 89
• Preventive veterinary medicine 89
• Prevention of introduction of foreign animal diseases 90
• Producing transgenic cattle resistant to BSE 90
• Zoonotic diseases 90
• Collaborative management of animal and human health 91
• Vaccines for zoonotic viral diseases 91

4. Molecular Diagnostics in Animals 93

• Introduction 93
• Nucleic acid technologies 93
• The polymerase chain reaction 93
• Basic Principles of PCR 93
• Target selection 94
• Detection of amplified DNA 94
• Real-time PCR systems 94
• LightCycler PCR system 95
• Molecular beacons 95
• Applications of PCR in veterinary medicine 95
• Fluorescent in situ hybridization 96
• Immunodiagnostics 98
• Enzyme-linked immunoassays 98
• Bovine Gamma Interferon Test 98
• Antigen diagnosis of trichinosis 99
• Parachek"! for the diagnosis of Johne' s disease 99
• Antibodies for differentiation between vaccinated and infected animals 100
• Biochip/microarray technology 100
• Applications of microarrays in animal biotechnology 101
• Cattlearray3800 for functional genomics 101
• eSensor"! electrochemical biochip 102
• Biosensors 102
• Immunosensors 103
• Biosensor for ovulation prediction in dairy cows 103
• Flow cytometry for animal diagnostics 104
• Molecular imaging in animals 104
• Veterinary cytogenetics 105
• Applications of molecular diagnostics in animals 105
• Canine DNA testing 105
• Diagnostic aids to selective breeding 106
• Selection of desirable traits 106
• Using genetic markers for improved milk production in dairy cattle 106
• Application of bovine genomics for improving milk yield 107
• Recognition of hereditary syndromes 107
• Genetic markers in animals 107
• SNP genotyping in animals 108
• SNP genotyping for selective breeding of chicken 108
• Animal identity and parentage analysis 108
• Animal species identification in food 109
• Diagnosis of infections 109
• Bacterial infections 109
• Diagnosis of viral infections 110
• Molecular diagnosis of avian influenza 112
• Diagnosis of parasitic infections 113
• Detection of natural or bioterror threats to livestock 113
• Molecular diagnosis of prion diseases 114
• Bovine spongiform encephalopathy 114
• Testing for BSE in living animals 115
• Prions in urine 116
• Diagnosis of chronic wasting disease in wildlife 116
• Developing new tests for prion diseases 117
• Differentiation among various types of TSEs 117
• Protein cyclic amplification 117
• Antibody tests for prion diseases 117
• Scrapie genotyping 118
• A real-time ultrasonic method for prion protein detection 118
• Companies involved in developing molecular diagnostics for TSEs 118
• Diagnosis of genetic disorders 119
• Genetic screening of companion animals 119
• Genes associated with exercise-induced collapse 120
• Preimplantation genetic diagnosis 120
• Diagnosis of cancer in animals 120
• Diagnosis of food-borne pathogens 120
• Introduction 120
• Molecular diagnostic methods used in food-borne infections 121
• Limitations of use of molecular probes in food analysis 122
• Companies with technologies for food pathogen detection 122
• Biotechnology-based novel diagnostics for aquatic animals 123
• Detection of chemicals in foods of animal origin 123

5. Biotechnology-based Veterinary Medicine 125

• Introduction 125
• Biotechnology versus pharmaceutical products 125
• Role of biotechnology in drug discovery and development 126
• Cost of veterinary vs. human drug discovery and development 126
• Advantages and disadvantages of testing biotech products in animal models 127
• Biotechnolgoy-based antiparasitic drugs 127
• Non-antibiotic strategies for control of infections in animals 127
• Probiotics 128
• Potential role for probiotics in the human gut 128
• Potential role for probiotics in animals 128
• Probiotic bacteria for control of pathogens in cattle 128
• Nonantibiotic drugs for infections in animals 129
• Immunomodulation as an alternative to antibiotics in infections 130
• Cathelicidins: effector molecules of mammalian innate immunity 130
• Bacteriophage therapy for antibiotic resistance 130
• Biotechnology for treating tendon injuries 131
• Use of growth factors to facilitate tendon injuries 131
• Productivity enhancers 131
• Bovine somatotropin for increasing milk production in dairy cows 132
• Use of growth factors 133
• Transgenic plant products for use in animals 133
• Biotechnology-based vaccines 134
• Modern vaccines without viral non-structural proteins 134
• Vaccines for tick control 134
• Plant-derived vaccines for use in animals 135
• Genetically engineered vaccines 136
• Application of nucleic acid vaccines in veterinary medicine 136
• DNA vaccines 136
• DNA vaccine for tuberculosis 138
• DNA vaccines for West Nile encephalitis 138
• Gene-based vaccine for Marek' s disease 139
• Genetic engineering of live rabies vaccines 139
• Genetically engineered vaccines for equine encephalitis 140
• Genetically engineered vaccines for Johne' s disease 140
• Vaccines against avian influenza 141
• Vaccines against parasitic infections 142
• Recombinant marker vaccines 142
• Marker vaccines for foot-and-mouth disease 142
• Marker vaccine for Newcastle disease 143
• Vaccines for classical swine fever 143
• Using RNAi to develop vaccines for viral infections in prawns 143
• Nano-bead vaccine adjuvant 144
• Companies developing biotechnology-based vaccines 144
• Biotechnology in treatment of parasitic infections 145
• Biotechnology in the treatment of CNS injuries in pet animals 145
• Paraplegia due to acute spinal cord injury in dogs 145
• RNAi for suppression prions in livestock 146
• Cell Therapy 146
• Umbilical cord blood stem cells 147
• Application of stem cells in veterinary medicine 147
• Use of stem cells to repair tendon injuries in horses 147
• Stem cells for spinal cord injury in dogs 148
• Gene therapy 148
• Gene therapy vectors 148
• Gene therapy by mitochondrial transfer 149
• In utero gene therapy 149
• Applications of gene therapy in veterinary medicine 150
• Gene therapy for mucopolysaccharidosis VII in dogs 150
• Gene therapy to increase disease resistance 150
• Gene therapy for infections 151
• Gene therapy for hematological disorders 151
• Gene therapy for cardiomyopathy in dogs 152
• Gene therapy for endocrine disorders 152
• Gene therapy for arthritis 152
• Gene therapy for renal failure 152
• Cancer gene therapy 153
• Antiangiogeneic cancer gene therapy in dogs 153
• Brain tumors in cats and dogs 154
• Breast cancer in dogs 154
• Canine hemangiosarcoma 155
• Canine melanoma 155
• Canine soft tissue sarcoma 156
• Melanoma in horses 156

6. Research in Animal Biotechnology 159

• Introduction 159
• Research institutes 159
• Ethical issues of research in animal biotechnology 167
• Future prospects 167
• Strategies for control of twining in cattle 168
• Future developments of molecular diagnostics 168
• Future of vaccine application in veterinary medicine 168
• Promotion of innate immunity in animals 169
• Identification of key parasite antigens for eliciting immune response 169
• Virus-like particle vaccines for lasting immune response 169
• Control of respiratory virus infections 170
• Control and prevention of bioterrorism diseases in animals 170
• Genetic control of disease resistance 170
• Production of cattle lacking prion protein 171
• Application of genetics and biotechnology to wildlife management 171
• Future of animal genomics 172
• Future prospects of in vitro meat production 172

7. Animal Biotechnology Markets 175

• Introduction 175
• Markets for biotechnology-based products for animal healthcare 176
• Markets for animal diagnostics 177
• Test for bovine spongiform encephalopathy 177
• Animal biotechnology markets according to therapeutic areas 178
• Markets for biotechnology-based animal products for humans 178
• Transgenic proteins 179
• Market for xenotransplantation 179
• Strategies for promoting use of animal biotechnology 180
• Financial losses from death and disease in animals 180
• Losses in farm animals 180
• Losses in poultry 180
• Losses in equine industry 180
• The emerging role of pet owners 181
• Improvement in cattle through application of biotechnology 181
• Pig market 181
• Cattle Market 181
• Poultry market 182
• Milk from genetically modified cows 182
• Transgenic fish 182
• Role of biotechnology in livestock performace enhancer market 183
• Gene transfer technologies 183
• In vitro meat production and animal biotechnology markets 183
• Cost-benefit aspects of transgenic proteins 183
• Lower costs of transgenic production 183
• Lower costs of treatment 183
• Unmet needs in animal biotechnology 184
• Future opportunities for biotechnology in animal healthcare 185
• Farm animals 185
• Companion animals 185

8. Regulatory issues 187

• Introduction 187
• Regulatory agencies for veterinary biotechnology in the US 187
• FDA regulatory issues in agricultural biotechnology 188
• Food safety evaluation of transgenic animals 189
• Food from cloned animals 190
• FDA investigation of drug transfer into eggs 191
• Animal feed safety 192
• Medicated feeds 193
• Regulatory issues for production of transgenic proteins 193
• Risks of animal biotechnology 193
• FDA regulation of bovine products 194
• Worldwide biotechnology regulatory and trade issues 194

9. Companies Involved in Animal Biotechnology 197

• Introduction 197
• Biotechnology at top veterinary pharmaceutical companies 197
• Profiles of selected companies 197
• Collaborations 317

10. References 321

Tables

• Table 1 1: Landmarks in the evolution of animal biotechnology in the 20th century 15
• Table 1 2: Applications of genomics in livestock industry and veterinary medicine 31
• Table 1 3: Applications of proteomics in livestock industry and veterinary medicine 32
• Table 1 4: Selected animal genomics and proteomics databases (DB) 34
• Table 1 5: Expression systems for production of recombinant biopharmaceuticals 35
• Table 2 1: Recombinant proteins obtained from milk of transgenic animals 50
• Table 2 2: Companies involved in the production of transgenic pharmaceuticals 53
• Table 2 3: A comparison of gene knockout and transgenic techniques 56
• Table 2 4: Examples of transgenic mouse models of non-neoplastic human diseases 57
• Table 2 5: Companies involved in xenotransplantation 64
• Table 3 1: Diseases of dairy cattle 65
• Table 3 2: Causes of chronic wasting disease in animals 83
• Table 4 1: Potential applications of microarrays in animal biotechnology 101
• Table 4 2: Biosensor technologies with potential applications in molecular diagnostics 102
• Table 4 3: Applications of molecular diagnostics in animals 105
• Table 4 4: Viruses that can be detected by molecular diagnostics 110
• Table 4 5: Testing for harmful prions in brain tissue from dead cattle 114
• Table 4 6: Companies involved in developing molecular diagnostics for TSEs 119
• Table 4 7: Pathogenic bacteria in food and targets for molecular diagnostic probes 121
• Table 4 8: Companies involved in molecular diagnostics for food-borne infections 122
• Table 5 1: Veterinary biotechnology products 125
• Table 5 2: Pharmaceutical versus biotechnology products 126
• Table 5 3: Nonantibiotic strategies for control of infections 127
• Table 5 4: Experimental DNA vaccines tested in animals 137
• Table 5 5: Companies developing biotechnology-based vaccines for animals 144
• Table 6 1: Areas for future research applications of animal biotechnologies 168
• Table 7 1: Worldwide markets for biotechnology-based products for farm animals: 2008-2018 176
• Table 7 2: Worldwide markets for biotechnology-based products for pet animals: 2008-2018 176
• Table 7 3: Biotechnology-based markets for animal healthcare according to regions: 2008-2018 177
• Table 7 4: Biotechnology markets for farm animals according to therapeutic areas: 2008-2018 178
• Table 7 5: Biotechnology markets for pet animals according to therapeutic areas: 2008-2018 178
• Table 7 6: Worldwide markets for biotechnology-based animal products for humans: 2008-2018 179
• Table 9 1: Ranking of top veterinary companies with biotechnology products 197
• Table 9 2: Selected collaborations of companies in animal biotechnology 317

Figures

• Figure 1 1: Relation of animal biotechnology to other technologies and human health 36
• Figure 2 1: Nuclear transfer technology 40
• Figure 2 2: Generation of transgenic animals by linker based sperm-mediated gene transfer 47
• Figure 2 3: Production of therapeutic proteins in the milk of transgenic animals 49
• Figure 7 1: Unmet needs in animal biotechnology 184