Evidence-Based Evolutionary Medicine

John S. Torday is a Professor of Pediatrics at UCLA, USA.

Neil W. Blackstone is a Professor in the Department of Biological Sciences at Northern Illinois University, USA.

Virender K. Rehan is a Professor of Pediatrics at UCLA, USA.

Preface­ xiii

1 A Brief History of Evolutionary Thinking 1

­Summary 1

­Introduction 2

­Darwin 3

­Darwin’s Theory 6

­The Modern Synthesis 7

­The Darkest Chapter 9

­Conclusions 14

­References 14

2 Outlining the Major Transitions in the History of Life 17

­Summary 17

­Introduction 18

­The Major Transitions 20

­Conclusions 29

­References 30

3 One Central Mystery: Why Did Eukaryotes Only Evolve Once? 31

­Summary 31

­Introduction 32

­Conclusions 45

­References 45

4 A Levels‐of‐Selection View of Evolutionary Physiology 49

­Summary 49

­Conclusions 59

­References 59

5 The Cell as the Smallest Functional Unit of Biology/Physiology 63

­Summary 63

­In the Beginning 64

­The Advent of Multicellularity 65

­Evolution: Cellular Style 69

­The Water–Land Transition and Vertebrate Evolution 70

­The Cellular Approach to Evolution Is Predictive 74

­We Are Not Just in This Environment, We Are of It 77

­Bioethics Based on Evolutionary Ontology and Epistemology, Not Descriptive Phenotypes, and Genes 78

­The Theory of Everything (Toe) 79

­Coda 81

­References 81

6 Development of Tissues and Organs 83

­Summary 83

­Introduction 83

­Lung Alveolar Morphogenesis 85

­Parathyroid Hormone‐Related Protein 86

­Stretch‐Induced Cell–Cell Interactions 88

­References 89

7 When Homeostasis Fails 91

­Summary 91

­Introduction 91

­Peroxisome Proliferator Activated Receptor Gamma as a Connection to the Evolution of the LIF 93

­PPAR, Statins, and TOR as Mechanisms for Homeostasis 93

Homeostatic Control of What? 93

­Pleiotropy: The Deus ex Machina (Ghost in the Machine) 95

­Rubik’s Cube as a Metaphor for Pleiotropic Evolution 96

­The Lung as the Prototypical Pleiotropic Mechanism 99

­The Lung as an Interactive Barrier: Homolog of the Plasma Membrane, Skin, and Brain 102

­NKX2.1, Thyroid, Pituitary, and Lung Pleiotropy 104

­The Phylogeny of the Thyroid 105

­An Evolutionary Vertical Integration of the Phylogeny and Ontogeny of the Thyroid 105

­A Retrospective Understanding of Evolution 107

­Denouement 109

­Conclusions 111

­References 112

8 Wnt Signaling During Development 113

­Summary 113

­Introduction 113

­Role of Growth Factors in Alveolar Homeostasis 114

­The Kidney Glomerulus as a Homolog of the Lung Alveolus 116

­Pathologic Consequences of Failed Paracrine Signaling 117

­Reference 117

9 Integrated Regulation of Homeostasis – Vascular, Nervous, Endocrine, Neuroendocrine, Autonomic 119

­Summary 119

­Introduction 119

­Water–Land Transition as the Catalyst for Vertebrate Evolution 121

­Parathyroid Hormone‐Related Protein Signaling Is Key to Understanding the Evolution of the Lung 121

­The Physics of Lung Evolution 122

­Functional Homology between Membrane Lipids and Oxygenation 124

­Atmospheric Oxygen, Physiologic Stress, Gene Duplication, and Lung Evolution 125

­Duplication of the  Adrenergic Receptor and the Glucocorticoid Receptor Genes 127

­Evolution of Endothermy/Homeothermy as Evidence for the Effect of Stress on Vertebrate Physiologic Evolution 127

­Hibernation as Reverse Evolution 129

­Predictive Power of the Cellular–Molecular Approach to Evolution 131

­Conclusions 133

References 136

10 Endogenous and Exogenous Mechanisms for Healing 137

­Summary 137

­Introduction 138

­Endogenous Mechanisms for Healing 138

A Fine Homeostatic Balance between the

Differentiated Interstitial Fibroblast and the Myofibroblast 138

Universality of Wnt/‐catenin in Myofibroblast Proliferation and Scarring: DKK, Shh, Alphabet Soup 140

Prostanoids, Homeostasis, and Regeneration 140

PGJ(2) 141

ApoE4 143

Evolutionary versus Traditional Medicine 144

­Exogenous Mechanisms for Healing Using Evolutionary Principles 145

Summary 145

Cholesterol and Homeostasis 145

Pathophysiology of Hypercholesterolemia 145

Statins as Anti‐Inflammatory Agents 146

PPAR and Homeostasis 146

TOR and Homeostasis 148

­References 148

11 Systems Biology as Recapitulation of Ontogeny and Phylogeny 151

­Summary 151

­Introduction 151

­A Paradigm Shift in Evolution 152

­Endothermy as “Proof of Principle” for the Evolution of Serial Exaptations 154

­Endothermy Defies Physics, Fostering Migration 155

­Conclusions 157

­References 158

12 Terminal Addition as Physiologic Homeostasis and Regeneration, or Evolutionary Medicine 159

­Summary 159

­Introduction 160

­Conflicting Viewpoints 161

­Terminal Addition as a Perpetual Cellular Link with the Environment 163

­Terminal Addition as Layered Cell–Cell Signaling 164

­Epigenetic Impacts and Terminal Addition 167

­Physiologic Stress, Vascular Shear Stress, Radical Oxygen Species, and Mutation within Constraints = The Mechanism of Terminal Addition 168

­Homeobox Genes, Colinearity, and Terminal Addition 169

­The Alveolar Lipofibroblast as Terminal Addition 170

­The Participation of Glomerular Mesangial Cells 170

­PTHrP Effects on the Anterior Pituitary, Adrenal Cortex, and Adrenal Medulla 171

­Catecholamines, Lung, and Heart Biology 171

­Oxytocin, Endothermy, and the Retina 171

­Central Nervous System 172

­Terminal Addition, “Reverse Evolution,” and Evolutionary Medicine 172

­Discussion 173

­Terminal Addition: The Fundament of Haeckel’s Biogenetic Law 173

­Somewhere between Gene and Phenotype Lies the Process of Evolution 174

­Conclusions 178

­References 179

13 Phantom Limbs: Imagination and Epigenetics 181

­Summary 181

­Introduction 181

­Background to Phantom Limb Sensation 182

­Relevance of Phantom Limb Sensation to Terminal Addition 183

­Phantom Limb Sensation as Non‐Localization 183

­Limbs and Hearts 184

­Relationship of Limbs to Bipedalism and the Evolution of Birds and Mammals 185

­Of Limbs and Consciousness 186

­Life as Fractals 186

­Consciousness, the Epitome of the Continuum from Inanimate to Animate 188

­References 188

14 Man’s Place in the Universe 191

­Summary 191

­Introduction 192

­Anthropomorphisms Subvert the Biologic Imperative to Cooperate 193

­Euphysiology 193

­References 200

15 Evolution, Deception, and Public Health 203

­Summary 203

­Part I. Deception Is Deceiving: The Exception that Proves the Rule 203

Introduction 204

In the Beginning 204

Epigenetics and Niche Construction 205

The Deception Proves the Rule 205

Our Own Personal Heliocentrism 206

Deception and Social Pathology 207

Physiologic Stress 208

Ambiguities in Biology 211

­Part II. Resolution of the Ambiguities by Assimilating the Deception 214

Introduction 214

The Cell as the First Niche Construction –

Self‐Organization Overcomes the Ambiguity 214

The Evolution of Endothermy as Internal Niche Construction; or, Self‐Organization Overcomes Biologic Ambiguities 215

Stress‐Induced Evolution of Endothermy by Stepwise Changes in Physiology Predicts Bipedalism, Evolution of the Avian and Hominid Forelimbs, and Higher Consciousness 217

Cold Stress and DRD4–7: Did Risk‐Taking Drive Us Out of Africa? 218

How Androgens Act to Reduce Ambiguities of Life 220

How Art Seemingly Resolves the Deception of Life 221

How Music Resolves the Deception of Life 221

Literature (Deceptively) Resolves the Ambiguities of Life 222

Liturgy Resolves the Ambiguities of Life: Back to the Garden? 222

­Part III. Deception and Public Health 222

Cognitive Dissonance: Scientific Principles, Disease, and Health 223

­Part IV. Prediction: Bioethics Based on First Principles of Physiology 224

­References 226

Index