This book, based on published studies, takes a unique perspective on the 30-year collapse of pharmaceutical industry productivity in the search for small molecule "magic bullet" interventions. The relentless escalation of inflation-adjusted cost per approved medicine in the United States -- from $200 million in 1950 to $1.2 billion in 2010 -- has driven industry giants to, at best, slavish imitation in drug design, and at worst, abandonment of research and embracing of widespread fraud in consumer marketing.The book adapts formalism across a number of disciplines to the strategy for design of mutilevel interventions, focusing first on molecular, cellular, and larger scale examples, and then extending the argument to the simplifications provided by the dominant role of social and cultural structures and processes in individual and population patterns of health and illness.In place of "magic bullets", we must now apply "magic strategies" that act across both the scale and level of organization. This book provides an introductory roadmap to the new tools that will be needed for the design of such strategies.

Preface v

1. BEYOND MAGIC BULLETS 1

1.1 The Pharmaceutical Catastrophe 1

1.2 A New Perspective 6

1.3 Cognition as 'Language' 8

1.4 The Human Cognome 11

2. EXPANDING THE THEORY 19

2.1 No Free Lunch 19

2.2 Multiple Broadcasts, Punctuated Detection 22

2.3 Metabolic Constraints 25

2.4 Environmental Signals 27

3. DYNAMIC 'REGRESSION' MODELS 29

3.1 The Simplest Approach 29

3.2 A Rate Distortion Reformulation 35

3.3 Multiple Time Scales 38

3.4 Incoming Information 39

3.5 Pathologies 40

3.6 Refining the Model 42

4. AN EVOLUTIONARY EXCURSION 47

4.1 Introduction 47

4.2 Ecosystems as Information Sources 50

4.3 Genetic Heritage 53

4.4 Gene Expression 54

4.5 Interacting Information Sources 56

4.6 Conclusions 59

5. EXAMPLE: MENTAL DISORDERS 63

5.1 Introduction 63

5.2 Two Classes 67

5.3 Global Broadcast Models 70

5.4 Gene Expression 72

5.5 Summary 74

6. EXAMPLE: PROTEIN FOLDING 77

6.1 Introduction 77

6.2 Spontaneous Symmetry Breaking 81

6.3 A Formal Approach 83

6.4 The Energy Picture 86

6.5 The Developmental Picture 86

6.6 A Comprehensive Treatment 91

6.7 Aging and Protein Folding 95

6.8 Summary 97

7. EXAMPLE: GLYCOME DETERMINANTS 99

7.1 Introduction 99

7.2 Stochastic Topology 101

7.3 The Glycomic Conundrum 103

7.4 Another Cognitive Paradigm 104

7.5 Regulating Glycan Determinants 108

7.6 Glycan Spectra 109

7.7 Summary 111

8. EXAMPLE: GLYCAN/LECTIN LOGIC GATES 113

8.1 Introduction 113

8.2 The Critical Exponent 114

8.3 Two Examples 116

8.4 Information Catalysis 120

8.5 A Tiling Symmetry Model 122

8.6 Summary 126

9. EXAMPLE: IDP LOGIC GATES 127

9.1 Introduction 127

9.2 Symbolic Dynamics of Molecular Switching 130

9.3 Another Dual Information Source 131

9.4 Information Catalysis 133

9.5 Summary 134

10. TREATMENT 137

10.1 The Generalized Retina 137

10.2 Therapeutic Efficacy 141

10.3 Psychosocial Stress 144

10.4 Flight, Fight, and Helplessness 146

10.5 Institutions as Niche Construction 148

10.6 The Hall of Mirrors 150

10.7 Side Effects Reconsidered 152

11. HISTORY AND HEALTH 157

11.1 Malaria and the Fulani 157

11.2 The American Catastrophe 160

12. BEYOND GLASPERLENSPIEL 179

13. MATHEMATICAL APPENDIX 183

13.1 The Tuning Theorem 183

13.2 The Rate Distortion Theorem 187

13.3 Stochastic Differential Equations 189

13.4 Morse Theory 194

13.5 Groupoids 196

13.6 'Biological' Renormalization 199

13.7 Large Deviations 204

Bibliography 207

Index 223

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