Allergic to Life: How the Human Body Rejects the Modern World [1st ed. 2023] 3031460251, 9783031460258

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Allergic to Life How the Human Body Rejects the Modern World Frank Lichtenberger

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Allergic to Life

Frank Lichtenberger

Allergic to Life How the Human Body Rejects the Modern World

Frank Lichtenberger Allergy and Immunology Piedmont Healthcare Statesville, NC, USA

ISBN 978-3-031-46025-8    ISBN 978-3-031-46026-5 (eBook) https://doi.org/10.1007/978-3-031-46026-5 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

Preface

Concerning Humans This book is completely concerned with the discussion of humans, meant to be read by humans, and it is the hope that there will be a better understanding of the species. This is definitely not the first book written on any of the many subjects concerning humans and most certainly will not be the last. There are many expert texts already written on human health, wellness, and disease, and this will not replace any of them. References for further reading are listed on many of the subjects presented; however, the attitude with which they are expressed is entirely that of the author, and not the publisher or any other professional affiliation. Humans live on planet Earth and inhabit nearly all of the surface of the planet. They have visited the bottom of the ocean, left the confines of the atmosphere, and sent probes far out into space. They come in all shapes and sizes and different colors and effect all different manners of occupation. Humans are a unique species, seemingly aware of the strangeness of life, and are able to communicate and record all resulting discoveries—in effect creating an enormous library of information and history. They have different languages, cultures, traditions, foods, and beliefs on nearly everything in day-to-day life. Humans are capable of extraordinary feats of artistry, beauty, and creation. On the contrary, humans have committed acts of heinous, ugly violence and destruction on an increasingly unimaginable scale throughout their history. This book does not pass any judgement on human history either good or bad, nor will it seek to explain any of them regardless of how much these have impacted the modern-day environment. Mentions of human history are presented here relative only to the modern-day subject matter and are not comprehensive reviews of any event or time. Humans are not the largest or tallest species on the planet, nor are they the smallest. They cannot fly without the use of advanced machinery, nor swim very far without it either. They can run and jump, crawl, walk, and imitate most other forms of life they share the planet with. Humans seem to define the individual by the

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Preface

differences from each other; however, when in large groups and packs, they can efficiently act as a single entity. It is not the purpose of this book to answer any of the metaphysical questions on the nature of humans, as the author has very little opinion and even less knowledge on the subject. There will be no answers to “What does it mean to be human?” or “Why are humans here?”. In fact, for the purpose of the reader, humans will be discussed like any other animal or topic in science, and there will be no greater context beyond a simple cause and effect. It is through the effects that humans feel, see, smell, and taste and try to interpret the cause to their own understanding. The origins of anything good or bad, beautiful or heinous, and sick or healthy can be traced back through cause/effect eventually until the “root” cause or the origin is found. It is very distracting to get caught up in the “why” of anything, and science is very distracting. Prior to the availability of scientific knowledge, humans answered these questions very creatively, using the power of imagination. Now with widely accessible and detailed records of nearly every scientific discovery, humans have continued to create new answers to questions that were previously unimaginable. Humans are truly fascinating. One can spend their entire life in the study of this species and still continue learning surprisingly new things on a daily basis. There is a gap in the understanding of the cause behind any new effect. That gap is the sum of the time it takes from the cause to reach an effect perceivable to humans and then the time it takes for humans to discover this new effect. Within only one or two human lifetimes, there has been an unprecedented explosion of changes to the environment and the ecosystem of humans. The speed at which these changes occurred has become faster than humans’ ability to perceive the long-term effects of what these changes cause. This, in effect, has caused considerable confusion amongst humans. There are many that are seeking answers on the basic function of the species, such as “what to eat,” “how to sleep,” or “whom to mate with and raise younger humans.” The advancement of scientific knowledge has given humans an environment that is manufactured and dispensed without concern for the resulting long-­ term effects. This author is making the case that these long-term effects happen to be the cause of many of the modern-day human health problems. Discovering the beginning or original “root” cause is not very difficult in many cases as many of these events were very well documented. It is the conglomeration of all of these causes together that now affects the environment, with the “environment” being everything else in the world that is not a human body. Understanding that if everything that is not human has radically changed, then what was “human” before no longer fits the environment for humans now. It would be a highly disorganized and overly complicated approach to any discussion concerning humans, or “human bodies” more specifically, if we sought to discuss everything that is the whole body. There is just too much to write about: too many organs, cells, systems, and conditions. It is overwhelming even for those silly humans (physicians/scientists) that have spent upwards of 20 years in the isolated study of the human body. Furthermore, we must consider that human bodies are not static or separable from their host environment. On the contrary, humans are the most adaptable species to any form of environmental change or stress. Thus, not

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only are humans made up of “complicated interconnected parts” inside the body, but also the body must be in constant change related to its environment. It must be realized that the study of the human body is a calculus of adaptations to environmental change. So, seeking to discuss the current state of the human body, we must be looking at not only the “ground state,” but also the response to “environmental change.” To simplify the explanation of the adaptive process, we will focus on the compartment of the body that responds most prominently to every environmental stress: the mast cell. Mast cells are known in the medical world as being the force behind allergic reactions. These cells are the author’s lens to view the modern environment and how it just does not seem to fit humans. No prior knowledge of these cells is needed. Mast cells are “environmental response mechanisms,” and their effects on the human body will hopefully be discussed in a way that every human can understand. The environmental stressors driving mast cells to exert these effects on the body will be made clear when we look back at the root cause of this change. The mast cell is a very defiant cell that can populate any terrain of the human body, like humans can populate any surface of the planet. Mast cells can be a force for healing or destruction; they defend from infections and tumors but can also trigger life-threatening changes in the body’s vital signs with little warning. Mast cells are different from person to person; like humans, they are adjustable from time to time, but their job is to react to changes. Through understanding the effects of mast cells on the human body, as well as the multiple causes of these effects from the environment, the hope is that humans will better understand how human they are.

Key Terms • Humans: Dominant species that evolved on planet Earth. Self-aware, most have ten fingers, ten toes, etc. • Environment: Everything else on and around planet Earth that is not a human. • Mast cells: The parts of humans that make adjustments because of the environment. Statesville, NC, USA

Frank Lichtenberger

Contents

1

Introduction: Allergic to Life������������������������������������������������������������������    1 1.1 We’re Not Supposed to Be Here ������������������������������������������������������    1 1.2 It Is Not a Weakness, It’s a Changed World��������������������������������������    2 1.3 How Did Humans Get Here?������������������������������������������������������������    3 1.4 Inflammation Is Felt When the Immune System Is Working More than Normal����������������������������������������������������������������������������    4 1.5 What Is “Normal” Anyways?������������������������������������������������������������    4 1.6 People Tend to Think they Are the Cause of Their Problems����������    5 1.7 Bad Habits Do Not Mean Bad Humans��������������������������������������������    6 1.8 Seriously, Humans Are Not Trying to Hurt Humans on Purpose ����    6 1.9 The Grand Experiment: Human Life������������������������������������������������    8 1.10 Responding to Long Term Stress: Hypertrophy Vs Atrophy������������   10 1.11 Too Much of a Good Thing Is Bad—What Does that Even Mean?   12 1.12 There Is No Understanding of an Ideal Environment for Humans����   14 1.13 Feeling Better Starts with…… Feeling Better About Oneself����������   15 1.14 This Is Not a Cure for Anything ������������������������������������������������������   16 1.15 Simplified Summary ������������������������������������������������������������������������   17 Reference ��������������������������������������������������������������������������������������������������   17

2

 Strange New World, Same Old Humans��������������������������������������������   19 A 2.1 Get Human Laws Off the Human Body��������������������������������������������   21 2.2 The Gift that Keeps on Giving Blisters��������������������������������������������   22 2.3 The World Current Humans Live in Is Excessively Unnatural��������   24 2.4 Different Is Different, Not Good or Bad������������������������������������������   26 2.5 The Immune System Is Not a Perfect Defense System��������������������   27 2.6 Born Ready to Fight: Innate Immunity��������������������������������������������   28 2.7 Remembering the Environmental Threats: Adaptive Immunity ������   28 2.8 When Adapting Doesn’t Go Perfectly����������������������������������������������   30 2.9 Modern Practice Still Not Perfect ����������������������������������������������������   31 2.10 Rheumatic Fever: Too Much Immunity��������������������������������������������   32 2.11 Efficiency: This Is the Name of the Game����������������������������������������   33 ix

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2.12 Allergies Are Completely Immune System Mistakes ����������������������   33 2.13 Summary ������������������������������������������������������������������������������������������   34 Bibliography����������������������������������������������������������������������������������������������   34 3

Mechanisms of Rejection������������������������������������������������������������������������   37 3.1 Everything Is Falling Apart, So Let’s Tie It All Together ����������������   37 3.2 Rejection Part 1: Immune System, It’s About Food��������������������������   39 3.3 Barrier Immunity: Borders of the Body��������������������������������������������   40 3.4 When Defense Becomes Offense������������������������������������������������������   41 3.5 Mast Cells Externally Respond to the Environment, But Internally Adapt the Human Body ��������������������������������������������   43 3.6 Rejection Part 2: Nervous System (Autonomic)—It’s Still About Food ��������������������������������������������������������������������������������������   43 3.7 Automatically for the People������������������������������������������������������������   44 3.8 Mast Cells Connect the Autonomic Nervous System to the Immune System����������������������������������������������������������������������   45 3.9 Turning It All Off������������������������������������������������������������������������������   46 3.10 The Immune System and the Autonomic System Are in Constant Communication ������������������������������������������������������������   46 3.11 Simplified Summary ������������������������������������������������������������������������   47 References��������������������������������������������������������������������������������������������������   48

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House Dust Mites ������������������������������������������������������������������������������������   49 4.1 The First Allergists and the Worst Allergy����������������������������������������   49 4.2 A Toxic Long-Term Relationship ����������������������������������������������������   50 4.3 Humans Are Food ����������������������������������������������������������������������������   51 4.4 Don’t Forget the Yeast Fixins’����������������������������������������������������������   53 4.5 Its All About Pumping Iron��������������������������������������������������������������   54 4.6 What Are House Dust Mites? ����������������������������������������������������������   55 4.7 The Inflammation Does Not Stop with Allergies������������������������������   55 4.8 100% of Clean Homes Have Dust Mites������������������������������������������   56 4.9 I Give Up, Feed My Worthless Human Body to the Mites ��������������   57 4.10 Sensitization Is a Two-Way Street����������������������������������������������������   58 4.11 Simplified Summary ������������������������������������������������������������������������   59 Further Reading ����������������������������������������������������������������������������������������   60

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The Human Ecosystem����������������������������������������������������������������������������   61 5.1 In the Time of Chimpanzees, I Was a Monkey ��������������������������������   61 5.2 Bacteria Have Evolved New Genes in the Past 50 Years, Lots and Lots of Them����������������������������������������������������������������������   62 5.3 Some of These New Bacteria Genes Are Specific for Humans��������   64 5.4 Many of These Changes Were Discovered Years or Decades After They Evolved in Bacteria������������������������������������������   64 5.5 This Steadily Increasing Use of High-Powered Antibiotics Could Only Lead to Good Things����������������������������������   65 5.6 Ecosystem, More Like Freak-O-System������������������������������������������   66

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5.7 Gut Environment Is Also Important for Other, Non-gut Related Disease������������������������������������������������������������������   67 5.8 But People Born Before 1976 Have to Fight These Bacteria Too, Right? ������������������������������������������������������������������������   67 5.9 Humans Killed the Water Too. Drinking Water Used to Be Alive ������������������������������������������������������������������������������   68 5.10 Adding Algae Back to the Diet Improves Immune System��������������   68 5.11 The Skin Is a Bacteria Party Too������������������������������������������������������   69 5.12 How Do Humans Kill Bacteria Anyways?���������������������������������������   69 5.13 “I Prefer the All-Natural Methods”��������������������������������������������������   70 5.14 The “Auto-Brewery Syndrome”��������������������������������������������������������   71 5.15 Summary ������������������������������������������������������������������������������������������   71 References��������������������������������������������������������������������������������������������������   72 6

 Humans Are What We Eat (Quantity vs Quality)��������������������������������   73 6.1 Its Starts with the Babies������������������������������������������������������������������   73 6.2 The Mouth Is a Mucosal Barrier, But More Like a Bouncer������������   75 6.3 Sugar, High Fructose Diets, Even Sugar-Free Sugar, Reduce the Sensitivity of the Vagus Nerve to Calories��������������������   76 6.4 There Is in Existence an “Anti-Inflammatory Diet”��������������������������   77 6.5 A Tale of Two Vitamins (Vitamin B12 and Vitamin C)��������������������   77 6.6 De Fish in C, Vitamin C Deficiency, Scurvy������������������������������������   79 6.7 The Second Managed Disease: Pernicious Anemia��������������������������   80 6.8 There Have Always Been Toxins in Human Diet ����������������������������   82 6.9 Dietary Proteins Should Only Be Purchased from the “The Leftorium”��������������������������������������������������������������������������������   83 6.10 “Round Up” the Wrong-Handed Aminos ����������������������������������������   85 6.11 Pile Hate on Glyphosate (GLEE-fo-sayt) ����������������������������������������   86 6.12 Simplified Summary ������������������������������������������������������������������������   87 References��������������������������������������������������������������������������������������������������   88

7

It’s About Time to Eat ����������������������������������������������������������������������������   91 7.1 Life = Finding Food Versus Not Becoming Food����������������������������   91 7.2 Food Always Stays Outside the Body Which Means It Is Part of Our Environment������������������������������������������������������������   92 7.3 Fasting Is Probably How the Body Should Be Most of the Time������   93 7.4 Explain Intermittent Fasting to a Sixteen-Year-Old��������������������������   94 7.5 Explain Intermittent Fasting to a Six-Year-Old��������������������������������   94 7.6 Food Shuts Down the Body, or Is Supposed to Shut Down the Body ��������������������������������������������������������������������������������   94 7.7 Swallowing Can Wait, Masticate������������������������������������������������������   95 7.8 What Happens in Vagus, Gets Sent to the Whole Body�������������������   96 7.9 It’s Only in Your Head. I.E. “Imaginary Symptoms”������������������������   97 7.10 Take a Walk Down the Vagus Nerve ������������������������������������������������   98 7.11 Digestive and Immune Systems Are One and the Same for About 2 Ft��������������������������������������������������������������������������   99

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7.12 Mixing Up “Fight or Flight” and/or “Rest and Digest”��������������������  100 7.13 Everything About How Humans Eat Has Changed in the Past 50 Years ��������������������������������������������������������������������������  101 7.14 Rushed Food Ingestion Leads to Improper Digestion����������������������  102 7.15 Simplified Summary ������������������������������������������������������������������������  102 Bibliography����������������������������������������������������������������������������������������������  103 8

Indoor/Outdoor Air Quality�������������������������������������������������������������������  105 8.1 It’s Human Nature����������������������������������������������������������������������������  105 8.2 By the Humans, for the Humans������������������������������������������������������  106 8.3 The United States (Healthcare System) Is Bad at Math ������������������  106 8.4 The Air Which Does Not Kill Us, Makes It Harder Us Breath Harder������������������������������������������������������������������������������������  107 8.5 Medication Induced Airway Change������������������������������������������������  107 8.6 What Exactly Is “Smoke” ����������������������������������������������������������������  108 8.7 Smoke Is Not the Only Thing That Hurts to Inhale��������������������������  108 8.8 Indoor Air Quality: Who’s Fault Is it Anyway����������������������������������  109 8.9 But How Does Breathing Tiny Pieces of Garbage Hurt Our Bodies?����������������������������������������������������������������������������������������������  110 8.10 The Size Matters, But Not in the Way Most People Think��������������  111 8.11 When the Air Is Clean, Less People Die������������������������������������������  112 8.12 High Efficiency Means Recycled Air������������������������������������������������  113 8.13 All Inhaled Forms of Garbage Trigger Mast Cells ��������������������������  113 8.14 This Generation Has Never Breathed Air without Plastic����������������  114 8.15 Plant Reproduction Is Getting to Be a Problem��������������������������������  115 8.16 Pollen Is Just Nature Doing Its Freaky Thing����������������������������������  115 8.17 There Are Gateway Allergens ����������������������������������������������������������  116 8.18 Get Out of the “Friend Zone” with Ozone����������������������������������������  116 8.19 There Is a Fungus Among Us������������������������������������������������������������  117 8.20 Simple Summary������������������������������������������������������������������������������  117 References��������������������������������������������������������������������������������������������������  118

9

Human Social Interactions����������������������������������������������������������������������  119 9.1 Despite All Human Rage, We Are Still Just Rats in a Cage ������������  119 9.2 Bring Your Friends, It’s Fun to Lose and to Pretend������������������������  120 9.3 Here We Are Now, Entertain Us ������������������������������������������������������  120 9.4 Over-Bored and Self Assured ����������������������������������������������������������  122 9.5 Where Do Emotions Come From?����������������������������������������������������  123 9.6 Laughter Is the Best Medicine (Please Don’t Tell the Drug Companies) ��������������������������������������������������������������������������������������  124 9.7 The DNA of a Human����������������������������������������������������������������������  124 9.8 The DNA of a Human-to-Human Healing: Apology������������������������  125 9.9 After Saying “I’m Sorry,” Don’t Forget “Please” and “Thank You”����  127 9.10 Get Mellow with Melatonin, Get Anxious with Histamine��������������  127 9.11 Social Sensitization, Social Hypersensitivity�����������������������������������  128 9.12 I Feel Stupid, and Contagious����������������������������������������������������������  129 9.13 A Little Tribe Has Always Been, and Always Will, Until the End ��  129

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9.14 Human Culture and Traditions Are a Way of Defining the Pack of Humans��������������������������������������������������������������������������  130 9.15 Simplified Summary ������������������������������������������������������������������������  131 Bibliography����������������������������������������������������������������������������������������������  132 10 The  Human Brain/Body Input/Output��������������������������������������������������  133 10.1 The Father of Stress������������������������������������������������������������������������  133 10.2 Seasonal Affect Disorder (SAD)����������������������������������������������������  134 10.3 Human Brains Have Functions That Exist in Addition to Emotions����������������������������������������������������������������������  136 10.4 The Importance of Body Heat��������������������������������������������������������  137 10.5 Life: Temperature Variance Outdoors ��������������������������������������������  138 10.6 In Experimental Models of Obesity, Mast Cells Are the Switch��������������������������������������������������������������������������������  139 10.7 Fatigue, Plasma Volume, Sauna������������������������������������������������������  141 10.8 Hibernation to Conserve Energy: Shivering to Warm the Body ������������������������������������������������������������������������������  141 10.9 Now I See the Light: Too Much Light Actually ����������������������������  143 10.10 With the Lights Out, Its Less Dangerous����������������������������������������  144 10.11 Methods of Measuring Autonomic Function(Ok to Try These At Home) ������������������������������������������������������������������  145 Bibliography����������������������������������������������������������������������������������������������  147 11 The  Adjustment Mechanism of the Body: Mast Cell����������������������������  149 11.1 Mast Cells and the Immune System������������������������������������������������  149 11.2 Mast Cells and the Autonomic (Fight/Flight or Rest/Digest) Nervous System ��������������������������������������������������������  151 11.3 Mast Cells Both Detect and Respond to Environmental Stress����������������������������������������������������������������������  151 11.4 The Mast Cell Compartment of the Body: Can Also Keep Its Cool������������������������������������������������������������������  152 11.5 The “Signal Molecules” Are Determined by the Need of the Tissue��������������������������������������������������������������������������  152 11.6 The Stress Molecule: CRH, Activates Mast Cells��������������������������  153 11.7 Mast Cells Program the Body for Allergies, Allergies Activate Mast Cells����������������������������������������������������������  153 11.8 Tryptase Might As Well Be a Dust Mite Parasite Digestive Enzyme ��������������������������������������������������������������������������  154 11.9 Large Quick Release Can Cause a Chain Reaction Shockwave Through the Body: Anaphylaxis����������������������������������  154 11.10 Too Many Mast Cells: Mastocytosis����������������������������������������������  155 11.11 Too Active Mast Cells: Mast Cell Activation Syndrome(MCAS)��������������������������������������������������������������������������  156 11.12 Remember, Humans Don’t Like Humans��������������������������������������  156 11.13 Why Does Anyone Need to Know About Mast Cells? ������������������  157 11.14 Summary ����������������������������������������������������������������������������������������  157

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12 Desensitize from the World ��������������������������������������������������������������������  159 12.1 Time to Find a New Planet?������������������������������������������������������������  159 12.2 Whose Fault Is It? ��������������������������������������������������������������������������  159 12.3 Drugs Are Not the Answer (Ok, Some of Them Might Be Part of the Answer) ��������������������������������������������������������  160 12.4 The Mast Cell Compartment of the Human Body Is “Expendable,” and “Trainable” ��������������������������������������������������  161 12.5 Developing a Healthy Relationship with Food ������������������������������  162 12.6 Elimination Diet, Antigenic/Allergenic and Adding Back Foods��������������������������������������������������������������������������������������  164 12.7 Two Weeks Only ����������������������������������������������������������������������������  164 12.8 After Elimination: Measured Food Inclusion ��������������������������������  165 12.9 Don’t Forget the Algae��������������������������������������������������������������������  166 12.10 Physical Contact with Pack������������������������������������������������������������  167 12.11 How Exactly Does Somebody Learn to Relax on Their Own?������  167 12.12 Try This At Home, and Try This on the Phone ������������������������������  168 Distracting the Search Strings��������������������������������������������������������������   168 Alternative Exercise ����������������������������������������������������������������������������   168 12.13 Social DePrograming: “A Clockwork Human”������������������������������  169 12.14 We Must Adapt to the Parasites that Have Adapted to Our Lifestyles����������������������������������������������������������������������������������������  169 12.15 Time to Reheat the Meat����������������������������������������������������������������  170 12.16 What About Cooling the Body?������������������������������������������������������  172 12.17 Taking Away the Blame������������������������������������������������������������������  173 Index����������������������������������������������������������������������������������������������������������������   175

Chapter 1

Introduction: Allergic to Life

1.1 We’re Not Supposed to Be Here I didn’t always want to be a Physician, in fact, for most of my childhood I wanted to be an astronaut. Like many other children I gravitated towards Science Fiction during playtime. I used to dream about exploring alien worlds in far off solar systems, with all of the bizarre forms of life that evolved on planets different that our little blue marble, Earth. I was born in the 1970s, right in the middle of the cold war between the East and West. In that decade space exploration had experienced a large expansion due to this aggressive but thankfully non-military conflict, and through this exploration the human race achieved incredible feats technologic advancement. While humans haven’t yet set foot on alien soil, and haven’t met or discovered any forms life from outside planet Earth, there happens to be quite a bit of other-worldly stuff happening down on Earth some 50 years later. Humans made several trips to Earth’s moon in the 1970s, and back then and even now most people believe that human boots will eventually step down on another planet. Whoever that person is, be them a Man, Woman, or Non-binary, that trailblazing human will not just be wearing boots. That far-traveling human will also wear some kind of spacesuit, helmet, and probably lots of other forms of barriers to protect their body from the harsh alien world. The concept that a human astronaut needs a spacesuit on a different planet seems obvious, I.E. it should not be hard to believe that a species from one planet might have a hard time breathing on a different planet. The astronauts that landed on the moon were wearing spacesuits the whole time, and taking them off would have resulted in a quick death due to the unnatural environment. One can envision a whole future field of medicine, dedicated to exploration of new worlds as well as the human ailments that will develop from these alien environments. I mean, humans are from Planet Earth, so human bodies belong on Planet Earth, right?

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5_1

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New Planetary Environmental health problems seem like a pretty decent Science Fiction concept. Unfortunately, these new health problems are not Science Fiction, it’s just Science. Our current planet is a vastly different environment from the Earth humans called home for the most recent 150,000 years. Most of these changes have occurred only within the past 50–70 years, and have had a profound effect on human health. The events or inventions that brought about these planetary changes occurred without much foresight for any potential negative impact on human health. Quite possibly there are other Earth changes in the near future that we haven’t figured out. I’m not a Space Doctor, my field is Allergy/Immunology. This specialty can be described as a study of how the body reacts to its environment. Professionally, I treat human conditions which vary from mild runny noses to profound Immunodeficiency or hypersensitivity syndromes. Most humans consider their health to be of great importance, and therefore it is a great privilege to be involved with such matters. Quite commonly I encounter questions along the lines of “what did I do to make this happen?” If I respond, “well, the reason you have a runny nose is because you haven’t been wearing your space suit when you’ve been outside planet Earth,” those patient encounters often end with both a confused look, and a poor online performance review. The farce is not far from the truth: Human bodies become unhealthy just by existing in today’s environment. Much of humans feel as symptoms of illness are natural human body process, but in response to an unnatural environment. These body responses can get bigger and stronger over time, eventually leading to body damage which we refer to as Disease. “The Boy in the Plastic Bubble,” was a made for Television movie released in 1976. The story was a fictionalized account of patients with Immune Deficiency syndromes. It has lived on in pop and real culture, and has been referenced in political speeches as well as comedy television. “Bubble Boy” as a reference seems to be gaining current attention, even though the conditions detailed in the movie have a near 100% complete cure rate these days. Many of my patients feel that they “need to live in a bubble,” due to frequent illnesses, allergies, or other conditions. This is an expression of the perceived incompatibility of the body and the environment, and it is nearly always viewed as a personal weakness. Like the patient in the bubble, people today seem to look to themselves as the cause of illness, like they are “missing something” that everyone else has which allows the others complete environmental freedom and health.

1.2 It Is Not a Weakness, It’s a Changed World In general, American Professional Football players are remarkably robust physical specimens. The strength, power, and agility of even an “average” professional player are far superior compared to the rest of us normal humans. Despite these remarkable human bodies, the frequency of physical injuries in professional football is very high. The rate of physical injury of NFL players is higher than any other

1.3  How Did Humans Get Here?

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profession, even Immunologist. However, it is nonsense to think that these frequent injuries are due to flaws in the bodies of those who are uninjured. No person in the right state of mind would blame bodily weakness as the cause of frequent injury in the National Football League. In this exaggerated example, it’s clear that the harsh environment of professional full contact sport is the “root cause” of the high frequency of physical injuries. Don’t blame the player, blame the game. Outside the arena of sport, it would be hard to imagine any of them having any type of workplace injury from lifting boxes, etc. In the same thinking, it would be ridiculous to consider placing an average human body on the same field as these players(smash!). So, it is with humans in our changed world, the body’s weakness is not the problem, the brutality of the modern environment is the problem.

1.3 How Did Humans Get Here? Life began on Planet Earth somehow. It was a long time ago, and I wasn’t there. Over time, life grew more complex and adapted as the environment changed. The environmental changed life, and life changed the environment. Eventually some forms of life became competitive with other life-forms, and that’s when evolution got interesting. Instead of life taking everything it needs from its environment, life began that focused on taking its needs from other living things. Life then became food for other forms of life. Lifeforms that did not wish to become food developed defensive systems. Those defensive systems originated close to 500 million years ago, about half-way from the start to the point we are now. The more complex the organism, the more complicated its defenses became. The Immune system is the modern-day endpoint of the original life defense system. One of its main jobs is to keep humans from becoming food for microscopic life forms such as viruses, bacteria, fungus, and parasites. The Immune System has allowed humans to gather in groups, trade goods and services, live in cities and travel to interact with other cultures to share ideas. Basically, with the human immune system there would be no civilization. However, I may have some professional bias in this regard. The most amazing thing about the immune system is that not only does it defend human bodies from millions of microscopic threats every single day; most of the time it completes this task without anybody noticing. That amazing feat occurs because of the second job of the immune system: protecting the host. While “protecting the host” might seem to be the exact same job as “defense,” there is a large difference. Protecting the host, or the “human body that made the Immune system,” requires an immune system have the ability to understand the difference between its specific host, and everything else in the entire universe. Fighting off the millions of potential invaders while simultaneously leaving the body unharmed is the goal of the perfect immune system, and most days this happens without any knowledge or concern for the average human. Occasionally some infections slip through the

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defenses, and other times the Immune system can’t tell the difference between host tissue and infection, that’s when the Immune system gets the body’s attention— through Inflammation.

1.4 Inflammation Is Felt When the Immune System Is Working More than Normal Describing inflammation as the symptomatic action of the immune system is a simplified truth. It certainly is an action of the Immune system, or reaction to the environment. Much of what is considered human illness today is strictly caused by too much Inflammation. Pain, swelling, fatigue, heart disease, all of these have their roots in an inflammatory process. Throughout history, infectious diseases caused by microorganisms were the major plagues of humanity. For the past 50 years or so many countries have felt the impact of “plagues” caused by our environment such as asthma, hypertension, diabetes, and obesity. When asked, 60% of American Adults report at least 1 chronic illness—Buttorff et al. (2017). A Multiple Chronic Conditions in the United States.

1.5 What Is “Normal” Anyways? Understanding of our bodies begins in childhood and is learned from the home environment as well as school. It is commonly assumed that the current human population is perfectly evolved and adapted to exist in the current environment. All other life forms on the planet are defined by their unique adaptive features for life: fish have bodies that are perfectly built for living in water, cacti that live in the desert can survive for long periods of time without water. A fish cannot live in the desert, nor can a cactus survive in the water. Simple. Obvious. A fish belongs in water; a cactus belongs in the desert. Therefore, we think we belong where we exist. Wrong. The environment in which a human body belongs is gone. I mention cacti and fish, as these are all very hardy organisms in their home environment. However, bringing either of them into a human home will, in most cases, drastically shorten their life expectancy. Personally, I have inadvertently caused the demise of both fish and cacti while I was in the process of trying to take care of them. Overfeeding, overwatering, under cleaning, too much humidity, it is a complicated endeavor to care for other forms of life. In the process of trying to keep these organisms comfortable, their bodies were stressed to the point of failure because of an artificial environment. Humans are 100% without question the sole responsible party for the changes to Planet Earth that are harmful for humans. However, I will hopefully make the strong

1.6  People Tend to Think they Are the Cause of Their Problems

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case that it was not done intentionally. In fact many of these changes are rooted from acts of discovery, and none of them occurred for the purpose of making humans sick.

1.6 People Tend to Think they Are the Cause of Their Problems After nearly 20 years of being a Physician, and twice that amount of time being a human myself, I’ve made a few observations about fellow humans. Most of these observations are simple, but only one seems to apply to almost everybody: People feel guilty for their own illness. I see it every single workday. I’ve coined the term “weaponized guilt,” and it may seem a bit overly dramatic, but the self-reinforcing belief that someone “deserves” to feel sick is directly harmful. A weapon is a tool that inflicts harm. Modern society seems to be structured around triggering guilt to control actions, and this is directly harming people. There is a unique vulnerability in seeking help from a healthcare provider, and turning this guilt back against the person seems to be becoming a vital part of the system. Weaponized guilt seems to be very prominent amongst humans who suffer with rare diseases. It generally takes longer to diagnose someone with a rare condition. The longer somebody goes through the system, the more possible touchpoints to reinforce the guilty feel. This sometimes leads to a sense of anger and further frustration, when telling someone that they don’t have a disease. It’s not that that individual wanted to have the bad diagnosis, it’s anger that they don’t have an answer and have to back through the patient-blaming gauntlet of modern heath systems. During the formal stages of my education, I became familiar with psychologic term “denial.” This is to expect that a patient will refuse to believe a diagnosis because it could be so shocking that the instinctual human brain can only respond by denying the reality of the findings. I have never, in my professional career, ever experienced one of my patients deny a medical finding or diagnosis. On the contrary, the diagnosis brought their feelings into reality, and then showed the opposite of denial: “relief,” that they were “not crazy.” Some of the patients that I was able to diagnose had suffered from symptoms of the rare disease for a decade, and occasionally even longer. Weaponized guilt is frequently difficult to address, and sometimes it hits me right in the face. This is not from rare conditions, but from increasingly common conditions such as asthma and food allergy. The bias that illness or sickness is the patient’s fault has become part of the healthcare identity. I have had sick, vulnerable people in my office apologize to me for their illness. In all fairness, I think that physicians perpetuate this belief due to the developed bedside mannerisms. Why shouldn’t we blame the sick person? Lifestyle habits are to blame for a very large portion of medical ailments, and these habits are all completely under the full control of healthy human decision making, right? No way. Smoking, drinking, poor dietary habits, all in some way harm the human body, but all of these “bad habits” are

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completely and perfectly normal in society. Not only normal and accepted, these bad habits all reinforce over-use behavior by chemically rewiring the brain. I don’t think that we should blame people for having behaviors that are legal, socially accepted, and addictive.

1.7 Bad Habits Do Not Mean Bad Humans Why would any self-aware brain support a habit that harms its body? Is that brain broken, or is it just weak willpower? Could it be genetic? Maybe some human was born without an enzyme that stabilized a portion of their brain? These bad habits are understood causes of human disease, and accepted and allowable in society that a human brain is willfully and habitually making a choice to hurt their body. We know that these harmful addictive substances destroy lives, but our society allows their use because we can blame the victims. The scope of my education and practice do not make me an expert on addiction psychiatry, therefore I don’t spend a whole lot of time in discussing these topics. The example here is only to highlight how conditioned we’ve become to shaming or guilting someone because they are not perfectly healthy as a result of chronic exposure to the environment. Nothing I’ve written down to this point is novel, new, or even minimally exciting information. I’m trying to drive a point so all can clearly see how our entire world has become altered beyond “normal.” The main effort here is to discuss the additive health consequences of this changed environment, and to give people some degree of freedom from the belief that they are just weak or willfully responsible for the health problems. While environmental conservation is critical to our long-term survival as a species, there are plenty of others with higher aptitude and are better suited for that cause. It should not be new information that unhealthy habits can make humans sick; in fact this knowledge has been around for longer than I’ve been alive, circa mid-1970s. It should also not be new information that most of these “bad habits” have impacts on the human brain that result in addiction or dependence on these bad habits. My point is that not only has human society allowed these harmful environmental habits to continue to exist, there is unprecedented access to an increasing number of this awful stuff in modern human life.

1.8 Seriously, Humans Are Not Trying to Hurt Humans on Purpose For example: I used to frequently recommend and prescribe a medication called ranitidine. This medication was pulled off the available market in the United States in 2019. The FDA found that under normal storage conditions the medication was prone to decay. When this particular medicine decays, it produces extremely small

1.8  Seriously, Humans Are Not Trying to Hurt Humans on Purpose

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amounts of a compound called “nitrosamine.” Nitrosamine exposure could possibly, at high enough levels and for long enough periods of time, cause cancer in humans. The FDA set safe limit on this compound is 96 nanograms ingested per DAY. The concern on pulling ranitidine was stated that if the medication were left on the shelf too long that the level of decay could potentially reach 96 nanograms of nitrosamines when ingested. Notice, there was no intervention to shorten the expiration date, which would have eliminated the concern related to spoilage. There was no exploration on any other option to keep this medication available for those that needed it, not even warning labels. The quantity of nitrosamines (same horrible chemical as above) in one cigarette range from 840 nanograms to 5500 nanograms, or roughly 10–50 times the amount that triggered complete outlawing of a medication. My country lost complete access to a drug that treated allergic reactions and prevented gastric ulcers, because of the possibility that taking stale drug might expose the consumer to 1–10% of the amount of nitrosamine contained in ONE cigarette. I don’t keep score, but I think most smokers go through more than one cigarette per day. At the time of this publication, cigarettes are still legal in the United States, but there are thousands of Americans organizing in online groups to bootleg Ranitidine from international pharmacies because it was the only drug that worked for their symptoms. I have yet to meet someone that does not understand harmful effects of alcohol, tobacco and junk food. These things flat out kill humans, continue to be completely legal, and people love them. If we allow these known agents to continue to cause misery in broad daylight, imagine what could be present in our current “natural” environment that contributes to inflammation in human bodies and minds. I found worrisome drivers of inflammation in every place that I looked. Not only the obvious aspects of global climate change but nearly all modern-day environmental habits add to the amount of inflammation a human body handles in today’s earth. The home environment, with increased indoor living, all the comforts of home such as air quality, light duration and intensity, and even the stable temperatures/humidity control do not represent a natural environment or habitat. While they may not cause an obvious amount of harm like tobacco smoking or chronic drinking, the long-term effects of temperature DE acclimation, and indoor living can be linked to root causes of many symptoms and even illnesses. The air humans breathe, the water humans drink, the food humans eat is all very different from what the evolved the human species. There has been a massive shift away from an appropriate environment, and much is brand-new to this generation or only the past few generations. My hope is that any human that reads this book will have a better understanding of why many people are sick. Because it is NOT their fault. I hope to remove any feelings of guilt or shame that frequently accompany sickness. Because these negative feelings do NOT help, and they do NOT belong.

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1.9 The Grand Experiment: Human Life Experimental design is simple algebra. While “simple algebra” may seem like an oxymoronic statement like “jumbo shrimp,” it is the use of math to discover an unknown variable. In other words, Solve for X. The key here, and the simplest form of this math uses the smallest number of variables. Numbers are great, 2 + 2 = 4 every minute of every single day that I’ve been alive, I can count on it. X + Y = Z? I have no clue, X + Y = 4, there are literally infinite possibilities. X + 2 = 4? Yeah, I can solve for X all day long (its 2, I think). However, in experiments instead of numbers, we use “controls.” Controls are things we can count on, that are the same every minute of every day. The basic formula for an experiment takes two controls, changes only one thing in one of the groups, which becomes the experiment. The result is the measured difference between the two groups (Fig. 1.1). This is a simple illustration that shows how scientists determine the effect of Something, using experiment. To determine the experimental effect, it must also be determined what takes place if Nothing is the effect. To compare Something versus Nothing, we need both. The world is changed, and we don’t have a spare one to compare it to. Now in health science we use experiments to determine how “something” will behave in a biologic system. What is a biologic system? Could be anything that contains a unit of life: bacteria, yeast, plant, cell, mouse or even a human. One problem that develops as the experiments become more complicated is that biologic systems are not nearly as reliable as numbers. Sometimes we use mice for experiments—these are mice that have 100% the exact same genetics, born nearly exactly the same time, fed exactly the same diet, and live in exactly the same conditions. These experimental mice have “everything” controlled, and still there is variability each time the same experiment is run. In fact, biologic systems are so complicated that by the time we get to human clinical trials there has never ever been any result that was 100% perfect or 100% reproducible. Thankfully, we still manage to approve hundreds of new drugs each year.

Fig. 1.1  An experiment with controls

1.9  The Grand Experiment: Human Life

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It may not be entirely accurate to describe our current civilization as a “Grand Experiment,” because quite simply we have changed innumerable variables in our environment over the past 100  years, but we did not establish any controls. All humans are actually subjects participating in an uncontrolled experiment. It may be worthwhile to mention that NONE of these experimental changes had the intention to make us healthier or better functioning human being. Neither were these changes made with the intention to make us less healthy. They were simply made without understanding the potential consequences. It should be comforting to know that everything that I recommend in clinic, or medication that I prescribe in clinic has been thoroughly evaluated for evidence and safety. This usually means there is a substantial body of evidence through rigorous scientific method validated by non-biased peer review to determine that “it” does the job with minimal harm or risk of adverse effects. Even so, despite our best efforts and the hundreds of millions of dollars of research and preparation, scientists still do not have a perfected mechanism for preventing allergic reactions or other adverse drug reactions from occurring to the people we give them. So science can make a medicine that treats humans, but still has yet to make one thing that works for every human—that’s how diverse humans are, and how difficult medicine can be to practice. Many of the topics that I address in the upcoming pages are the result of technological advances that are regarded as breakthroughs in modern human comfort and affluency. The use of central air-conditioning for example, which by most measurements only became commonly available in the United States in the 1970s. AC is greatly considered a modern marvel that has substantially reduced the number of deaths from heat related causes. AC was initially designed to keep us comfortable, cool in the summertime and warm in the wintertime, but the use of indoor climate control was never rigorously measured against open ventilation for the long-term effects on the human body. One can compare climate-controlled US population and chronic health issues to another population with less dependence on AC; however undoubtably there will be such substantial additional differences between the two populations that we could not get a reliable measurement of the long-term impact of just climate control. I should clarify that I personally rely on air conditioning, but think it necessary to discuss the impact that the chronic use of climate control can have on the human body. The long-term impacts were never considered before it was rolled out to the masses of humankind, but here we are.

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1.10 Responding to Long Term Stress: Hypertrophy Vs Atrophy Any living organism is in a state of constant adaptation to the environment; humans are no exception. The environment can cause stress, strain, or injury to which the body can adapt to become stronger, more efficient, or in the case of injury trigger swelling and pain to protect the body from further injury. While those are recognizable responses to excessive environmental stress, it should also be noted that because of the constant adaptation, there also is change when the body is understimulated for periods of time; this is called atrophy or weakening. Humans are quite adaptable organisms, and have started to use technology to adapt the environment itself our comfort and pleasure. The use of technology in this way has led to unforeseen atrophy of several of the systems responsible for changing the human body. The hypertrophic response is easily visualized by the skeletal muscle system. The figure of a monstrously large body builder is a commonly recognized human form. That human has purposely gone after muscle hypertrophy. These athletes stress/strain their muscles for hours each day, week after week, often for years to get to competition size/shape. While any human can go into the gym to perform bicep curls; consistency, repetition and duration are all necessary for the body to adapt to this stress/strain resulting in growing larger biceps. While this can result in improvement in physical appearance for self-confidence and muscle strength, this is an example of a normal response to an abnormal environmental stimuli. Humans of any vocation throughout all of recorded history have never shown muscular enlargement like some modern day body builders (Fig. 1.2). In contrast, consider the example of someone unfortunately in a coma for several months. While the heart, lungs, kidneys, liver, all continue to function, the skeletal muscle system begins to shrink in a few days. This is muscle atrophy. This means decrease in size due to decrease in use. This is also a normal response to an abnormal environment—chronic disuse- from coma. When our unfortunate comatose patient wakes up in 6 months, they will need extensive work to rebuild their muscles, balance, even to walk again. The effect of controlled activity versus inactivity. The human that trains their muscles will see development of increased size and strength, the human that is not able to use them, will see loss of ability, muscle size, and strength. While these examples are certainly on the extreme ends of the stressor spectrum to the skeletal muscle system, they should also be readily understandable. Consider the body builder that skips leg day, with huge hypertrophic arms and gangling awkward legs. This is also extreme, but then again many of our current daily activities and environmental stresses could be considered extreme. I personally had chronic headaches and neck pain until my chiropractor told me not to sit with my wallet in my back pocket. It seemed that the simple act of sitting at a slight angle of center caused upward alternating compensatory stress which led to the persistent muscle spasms in my neck. My body was acting normally, with my vertebral muscles

1.10  Responding to Long Term Stress: Hypertrophy Vs Atrophy

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Fig. 1.2  Normal physical response to an abnormal environment

overworked and trying to correct for the environment stress. Simple solution, but it was a really painful problem. We are only now beginning to learn how important the muscle compartment is in the control of inflammation, but also day/night cycles awake and sleep, and other body functions as well. Long term stress or conditioning can lead to long term changes to the human body. However the environmental stresses can lead to sickness or disease. Like the human that is working on muscle development, the stresses send signals to the body that don’t feel good. My old coaches used to call this “pushing outside your comfort zone,” or “feeling the burn.” As an athletic coach pushes any human outside the comfort zone, that body can adapt to that new zone (Fig. 1.3) and after awhile it became less uncomfortable. The same workout is easier to do over time, if its done the right way. If its done the wrong way, the body can be hurt. Astronauts begin to lose bone mass with only a few days in space. The change in their environment is abnormal, I.E. the loss of the force of gravity. Astronauts are some of the most physically fit people on the planet, even so, they cannot escape the constant adaptions of being alive. To prevent this relatively rapid skeletomuscular atrophy (normal response to abnormal environment) we have been sending exercise equipment into orbit with our astronauts. Somehow, the thought of astronauts hurtling through space while performing studies for all mankind, and still managing to hit the gym, is still not enough to motivate me to get down the street to my own gym sometimes.

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Fig 1.3  Enviromental Stress Leading to Adaption The red human body, is “feeling the burn” of being outside the biologic comfort zone. Leaving the comfort zone is uncomfortable, and it feels wrong. Over time, if done correctly the body can adapt to the change(yellow), and become more comfortable (green again)

1.11 Too Much of a Good Thing Is Bad—What Does that Even Mean? It is pretty well established that “Sugar is bad for health.” While this is a simplified statement, it is an idea we can build on top of—Is all sugar bad? No. Sugar, as it exists in nature is a form of stored energy, and energy is necessary for life. It is only with the last hundred years (out of ten’s of thousands) that the average human has

1.11  Too Much of a Good Thing Is Bad—What Does that Even Mean?

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had access to, and ability to purchase, nearly unlimited energy in the form of sugar. For 99.99% of the developmental process which led to modern day human bodies, the major factors driving evolution were lack of adequate food supply as well as competition for that food supply. To survive pre-industrial life, humans developed extremely powerful energy scavenging AND storage mechanisms, to thrive in an environment where food energy was scarce. It doesn’t need to be explained that sugar tastes great, I mean it’s fantastic! It tastes so good that the nerve impulse from the taste can cause the brain to release the good stuff (dopamine.) I won’t go into the complex importance of this connection: but good tasting stuff leads to happy brain, then the happy brain remembers and reinforces everything that led to it getting that thing that tasted good. In a world where energy is scarce, and the body finds a form of energy, not only is it a great idea to eat every last delicious bite it can get (remember, energy was scarce, competition was fierce) but also to enhance the process to remember to find and get this source of energy. Human brains add emotion and feeling as ways to prioritize memories. When sugar is added to food, humans eat more food. Adding sugar was started in order to sell more food to humans, not to hurt them. Sugar is a source of energy (life necessity) that tells our brain to feel good, amazing! Let’s go hit up the donut shop! Nope. This is where biology becomes a buzzkill. Remember that while the design pressure of our bodies focused on surviving scarcity of food energy, nothing evolved to account for abundance. There isn’t any cap to all this energy grabbing efficiency, but I want to focus on when it starts to harm the body. Long term hypertrophic/atrophic body adaptions lead to the harm caused from excess sugar intake. The initial dopamine (happy brain) signal associated with sugar intake becomes a tidal wave of awesomeness. We don’t know exactly what number of grams overloads the brain, but it is not available “naturally.” It is only logical for any brain that experiences a scrumptious storm of sucrose satisfaction to seek to repeat the experience. That leads to chronic stress and adaptive changes, both in attempt to handle the overwhelming sweetness the dopamine signal (happy brain) atrophies and energy storage mechanisms (body fat) becomes hypertrophic. The brain needs constantly larger amounts of sugar to become happy brain. These changes to behavior and metabolism have hit the point that we’ve run out of names to label all the diseases caused. Nothing I have written about sugar is new or exciting; there are literally dozens of books dedicated to the subject. There is strong evidence that some industrial strength sugars affect the brain like highly addictive life-destroying drugs (Lenoir et al. 2007). Placing a human brain in a functional MRI and stressing it with high fructose corn syrup is identical to stressing it with cocaine. All hail Science! If our police force catches one of our members in possession of cocaine, they get put in jail for a long time. Also we regularly allow high fructose corn syrup to be given to human children. There is universal recognition that human willpower is not strong enough to allow recreational use of cocaine, so it’s outlawed, and its users need rehab and/or jailtime to teach them the importance of better life habits. The widely available industrial strength sugar is as present in our modern environment as is drinking water (and sometimes cheaper.) The human brain is functionally designed

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to seek out energy substances, however modern overload/abundance then adapts the brain and body to this unnatural environmental excess. There are powerful instinctual survival forces at work getting human brains hooked on high doses of sugar, and by the time the health impact has manifested the adaption has set in. Too much of a good thing is bad for body and brain when it drives chronic maladaptive change. This is more than the food quality or the choice to smoke cigarettes or drink alcohol. The illnesses that subsequently develop from these adaptations are from NORMAL HEALTHY responses to an ABNORMAL UNHEALTHY environment. The powerful human brain developed over millions of years and became the apex determinant of our species. The Human species survived extinction events, comets, ice ages, wars, plagues, due to our brain’s ability to find and recognize food energy through the harshest extremes. These are some powerful, screaming caveman type impulses. To be “healthy” means to control impulses which were strengthened through millions of years and are permanently hard-wired for human survival. Otherwise, obeying these survival impulses leads to developing obesity and many other devastating metabolic consequences. The United States has recognized obesity as a health emergency, one of the many factors driving up excessive healthcare costs, yet we allow our environment to overwhelmingly harbor harmful types and amounts of sugar. As a society we allow this to continue because we can blame the victims for their own biology. There is no need to add sugar to food. There has never been a blanket statement from any health agency calling for the addition of unnecessary empty calories to any food product. There is very good science that excessive sugar causes long term problems to human brains and bodies. This environment stressor did not exist in 1976, neither did the health problems related to it.

1.12 There Is No Understanding of an Ideal Environment for Humans I find myself getting confused with comfort. I really like being comfortable, and as I get older it actually seems like it is harder to feel physically comfortable. I actually get mentally angry if the temperature in my office is off by a few degrees. To write that down seems surreal, but my temperature intolerance summarizes our situation. We have near complete control over the indoor environment, which never existed in the history of the development of the species. I do not think that 70 degrees F(21 C) 50% is the ideal environment for the human body, but I actually need it now, a few degrees up or down and I become impossible to deal with. Our species survived ice ages, sabre tooth tigers, and several world wars, we have toughness in our DNA. I have the DNA of cave people and plains hunters, but utterly fall apart if I have to watch TV at 74 F(23C.) I am not alone in my desire for strict climate control. There is a very good reason that our

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body’s adaptive systems are very limited to a thin range of comfort, those systems are overwhelmed and utterly confused. I work in suburban and rural America as a physician, I noticed that Farmers rarely even get mildly sick in their 80 s, while stockbrokers get hypertension in their 30 s. Obviously that is an over simplification, but the human bodies that are fully functional in advancing years are human bodies that are well taken care of, and that spend time outdoors(wearing sunscreen.) Our population is spending more of its time indoors and the detrimental health effects are becoming measurable. The modern-day indoor environment is crowded full with aggressively reproducing human-skin-eating eight-legged parasites: dust mites. These mites have only recently adapted to our species. With the widespread adoption of indoor climate control these ubiquitous parasites have exploded in impact and population. These parasites have co-evolved in the past 50 years with the changing microenvironment of the human skin. While the body surface “ecosystem” has adapted from the pressure of antibiotics, favoring yeast fungal commensals, this has supercharged the mites ability to digestive human skin. The human microbiome inside and outside our body has long since adapted beyond any measure, and in many cases we weren’t aware of what was happening until it was too late. The food, water, and air we consume daily are entirely unrecognizable to our ancestral environment. The in-grown mechanisms of inter-personal connections have been traded for shallow meaningless online “likes.” The impact of these alien environments has overwhelmed the natural adaptive brain. The modern-­ day human instinct recognizes that something is wrong, as our body does not belong in its current environment. The current human mind and body are not adapted to our environments, and the dysregulated responses are difficult to interpret.

1.13 Feeling Better Starts with…… Feeling Better About Oneself Self-blame prevents improvement. I don’t understand the psychologic implications here, but in my observation 95% of people specifically blame themselves for anything bad that happens to their health. That has to be human nature (has to be basic human programming language), it goes across gender, culture, ethos, religion and morality, there is no other cultural habit that all humans share more so than this self blame. A close second, would be shame—or blaming others for their own illness, misfortune, etc. Our species become the dominant organism on the planet because of our ability to work together and help one another. There is a natural and powerful instinct to help another in need, unless it’s too hard. If helping people gets difficult, we allow ourselves to excuse this instinct. Healthcare providers convince ourselves of it, and this starts by convincing the sick that sickness is fault of the sick. That way providers are allowed to fail inside a failing healthcare system on an alien planet. I

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mean we specifically allow people to kill themselves with smoking, but closed down a world-wide economy to keep a virus from doing a similar thing. COVID19 killed one million Americans in two years, which is exactly the same amount of time that tobacco takes to kill one million Americans. While world-wide COVID19 was double the death impact of tobacco for the first year, the two mass-­ killers were handled much differently. While this is an exaggerated example, I believe that if we had 25% of the COVID19 response devoted to fighting tobacco that we could rid the world of tobacco related illness once and for all. Tobacco is not the only example, but it is obvious and simple. There are many other examples of potently harmful environmental exposures right inside our modern environment. As a society, we are all hypnotized into blaming the sick as weak, faulty, otherwise human beings unworthy of being healthy. This has progressed to the point many people fear to take medicine as they associate it with sickness. When the brain believes that the body doesn’t deserve to feel good, it will keep it from feeling good. Individually and collectively we have to “Drop that Feeling, and get with the Healing.” T-shirts are available online (copyright Allergic to Life dot com.) This is not new information. The placebo effect is present in every drug trial, and it tends to mathematically represent a clinical improvement of about 30%. This placebo “control,” is then used to compare to the “experiment.” This 30% improvement is an invariable effect from the belief that participants are taking something that will make them better. Nothing but a human belief in the effect of a drug is responsible for 30% of the benefit of that drug. So quite simply, anyone, anywhere, anytime suffering from any kind of illness—can feel better by believing they will feel better. I believe: That by using sarcastic but simplistic explanations, that deeply programmed self-blame can be unwound, and it will register to humans that they deserve to feel better.

1.14 This Is Not a Cure for Anything I’m not trying to get down some manifesto on the evils of Capitalist society and how all people need to start hunting our own food. I would never take a public stand against the sugar industry, it’s the resultant guilt and shame that I hope to remove. My own industry, the United States Healthcare System, has enough problems to fix before we go pointing our sausage-like fingertips at Big Sugar. The science here is not new, and further reading outside can result in a better understanding. Nothing here will fix asthma, or end an autoimmune disease. However, understanding how the human body responds to an unknown, untested, and highly toxic environment, individually we can all feel a little bit better about our human bodies.

Reference

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1.15 Simplified Summary There is nothing new here. While the concept of an organism’s health being tied to its adaptive environment is well understood, not much is known about the original adaptive environment of humans. I believe that many of the modern-day health problems can be sourced due to the disparity between current human life and its ideal environment. Society is aware of the health problems caused by this warped environment, but finds it easier to blame those suffering from illness than to correct itself. The examples of this are plentiful and easily recognizable. By stating the obvious, humans can recognize that human biology does not fit well in the current human environment. Removing self-blame for illness may be the first step to recovery from illness caused from an ill-suited environment.

Reference Buttorff C, Teague R, Melissa B. Multiple Chronic Conditions in the United States. Santa Monica, CA: RAND Corporation, 2017. https://www.rand.org/pubs/tools/TL221.html. Lenoir M, Serre F, Cantin L, Ahmed SH. Intense sweetness surpasses cocaine reward. PLoS One. 2007;2(8):e698. https://doi.org/10.1371/journal.pone.0000698. PMID: 17668074; PMCID: PMC1931610

Chapter 2

A Strange New World, Same Old Humans: Allergic to Life

I remember learning about the discipline of Allergy/Immunology at the tender age of 6 years old. No, I wasn’t reading The New England Journal of Medicine, in fact I don’t think I was doing much reading at that age. While the 1980s was the greatest decade in the history of Hollywood, medicinal science of that decade still had not developed the Chicken Pox vaccine (early 90s). While there was no vaccine, there was substantial knowledge of the virus that causes the condition. It was common knowledge that the Chicken Pox virus varicella zoster seemed to cause worse health problems if people developed their first infection as an adult. In addition, it was understood that Chicken Pox infection in childhood conferred lifelong protection from the virus. My mother knew the math: Lifetime of freedom if infected in childhood, really bad stuff if infected as an adult. So, when another kid in the neighborhood became infected with the pox, the right thing to do in the 1980s was to spread the virus around to as many children as possible. I don’t remember getting sick from the virus, but 40+ years later my blood tests still show that I am making Antibodies. Now, this chicken pox was a special virus, a member of the Human Herpes Viruses, number 3 actually. Most people have heard of other famous herpesviruses, such as number 1 and number 2. I was told I’m not allowed to make any jokes about Suburban families in the 1980s having play date parties to spread herpes to their kids. However, this type of purposeful infection was actually a centuries old form of Immunology. Back in the good-old days, this type of “pox-party” was very common, and the infected neighbor usually didn’t even charge a co-pay. Before the modern practice of vaccination, purposeful but limited infection, or inoculation, was the main method for combating infectious diseases. Delivering a small and controlled amount of infection into a healthy host generally caused a limited infection. Surviving the limited infection, the inoculated host developed resistance to the virus and typically did not get sick again. I don’t think that this type of purposeful infection is still part of suburban culture, but I think that it is important how humans understood their

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5_2

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bodies, as these old-school Immunology practices were both intuitive and obvious. This is not a modern invention, this understanding goes way back in human history. Around 430 BC, prior to the birth of Alexander the great, humans that had survived the plague of smallpox were called upon to provide care to those actively infected (PMID: 9831677). The concepts of microbes, infections, sanitization, were thousands of years from being discovered, however Immunology was already being used to save lives. The term “Immunitas,” was first used by the Romans to describe resistance to snake venom, and was then adapted to describe freedom from taxes, military service, and imprisonment. Even today the term “Immunity” is still used in our courts to describe a state of exception. Unfortunately, while my antibodies are amazing, I do not have Immunity from taxes. The first known medical text addressing the process of “creating immunity” was from an Islamic/Arab Physician who wrote a treatise on infections with smallpox and measles. It was in this area that the practice of inoculation, or purposeful infection, was then developed over the following years. The taking of pus, or other leaking fluid from a sick patient, and injecting small amounts in healthy people was practiced by arab, Asian, and Indian physicians for hundreds of years at that time. The Country and Western Physicians did not initially accept the practice, until visiting European nobility saw inoculation in practice and realized the potential benefit for political prisoners and orphans back home. The centuries old practice of Inoculation was brought from the East, and tested on vulnerable westerners. After it was found safe and effective for the vulnerable, it was then offered successfully to the nobility. Once nobility was on board, then everybody wanted to get stuck. The Western Physician that was given credit for developing the smallpox vaccine, Dr. Edward Jenner, was actually inoculated with the smallpox virus when he was a small orphan. Later in his life, during his career in medicine the story is he was very observant listener. The Legend suggests that he has eavesdropping on milkmaids (women that squeezed milk out of cows) and overheard them talking out how their profession was high risk for catching cowpox, a similar but less directly harmful virus in humans compared to smallpox. Human intuition made it clear that after milkmaids had cowpox—those milkmaids never got smallpox. Dr. Jenner wasn’t the first physician that tried to use the cowpox infection to create Immunity against smallpox. He wasn’t the first, however he was the most dedicated. Much like the famous Jenner’s of today, he seemed really adept at bringing all sorts of attention to himself. Jenner spent much of his life dedicated to the distribution and administration of the vaccine, to the point that his personal practice began to suffer. He started his campaign in merry old England around 1800. Smallpox was officially declared “eradicated” from the world in 1979, just before I was invited to the Pox-party in the old neighborhood. The biggest problem that Dr. Jenner faced with his mission to rid the world of smallpox, was not the virus itself, but was from the inevitable afterbirth of innovation: the anti-vaccination movement (Wolfe and Sharp 2002). Keep in mind, Dr. Edward Jenner committed to his campaign around the of writing of the United States Constitution. Even that long ago humans organized massive resistance to the effort to vaccinate humans. Much of the resistance came from workers that were

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claiming that mandatory vaccination “violated their bodies.” Prior to creation of labor unions, child labor reform, a 5-day work week, disability coverage, and all the social safety nets in place to protect basic human civil rights, humans stood up to fight against the Medical Scientists that were using science to save human lives.

2.1 Get Human Laws Off the Human Body Almost 100 years after the initial promotion of the smallpox vaccine (circa 1905), in the United States a court case declared that it was in the U.S.  Government’s authority to mandate vaccination as a means to combat communicable diseases. Thankfully, 1905 was the very last time that controversy on vaccinations or policy regarding vaccinations entered into the national dialogue. Sarcasm aside, it is important to note that over 200 years ago and nearly immediately after the adoption of mandatory public health measures, humans showed both religious and philosophical skepticism in addition to rejection of the mandatory measures concerning human bodies. The first anti-vaccination protests were not mild demonstrations, these were crowds in the tens of thousands. Massive amounts of determined humans marching in the streets, burning Jenner in effigy. This was nasty pushback. Pushback on infections prevention that was based on a thousand-year-old concept, and technically stolen from the Turks. There was no internet back them, nor any media that we currently blame misinformation on, there was only human nature and emotion. Humans have had 200+ years to work on general acceptance of scientific breakthroughs, but we still haven’t yet moved the needle slightly when it comes to the emotional quotient. In this historical narrative we see and hear many familiar concepts, including Immunity, Resistance to disease, organized people that shun science, but the interesting message to which we grow our knowledge is that Cowpox and SmallPox: were not the same virus. How the heck is that supposed to work anyway? Big words like “molecular mimicry,” and “cross reactivity,” is just another way of describing “mistaken identity.” Jenner’s vaccine worked on SmallPox because the defense system of the body developed a memory of the Cowpox—but it wasn’t perfect, it was quite naturally imperfect. Not only does the Immune system make a specific memory of the cowpox virus, but it develops enough overlap to defend against things similar to cowpox. This slight imperfection is the key to developing better and more efficient protection from infections. Infecting a human with a weakened version of an infection still creates the Immune memory, which is good but not perfect. When the actual infection occurs, the body has a running start and a better chance to fight it off.

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2.2 The Gift that Keeps on Giving Blisters Pretty much everyone reading this has some level of knowledge about the chicken pox. What might not be understood is that the body never clears itself of the virus, the Immune system only controls the inflammation. Once any human is infected— the herpesvirus continues to replicate until it is controlled by the immune system. Immunity keeps the virus under control, but it still exists as DNA in many of the nerve cells of the body. The virus is usually kept under control (dormant) for decades, or until the environment comes along to distract or greatly weaken the immune system. Environmental inputs that reduce the Immune systems effectiveness are stress, medications, other infections, aging, and all the other stuff that makes life interesting. In my own body, if this herpesvirus that my mother purposefully infected me with erupts again, it could really cause problems. This “reactivation” happens to humans as they get older, and the frequency is about 1 in 6 people over the age of 60, and 1 in 2 people over the age of 80. As of today—all of the currently aged 60 to 80 likely contracted the viral infection at some point in their life because of the herpes-­ parties. Previously infected humans will be at risk—not of new infection, but an outbreak from their original infection due to weakened memory Immunity. To combat the outbreak vulnerability, science has developed a “booster vaccination,” which helps re-stimulate the immune system to infection control. So, many of the people aged 30 and younger have never had the virus because of the campaign to vaccinate against varicella in early childhood, and then shouldn’t ever have an outbreak. So we are in the middle of another viral eradication, another victory for science! Within mere moments of the push to “vaccinate” humanity to smallpox, there was substantial community resistance. This polarizing phenomenon is still present today—and I’m human enough to admit that when I didn’t understand it, the anti-­ vaccination movement upset me emotionally. It seemed like a challenge to my authority, as for all the schooling and testing had given me some kind of power that people should just believe everything I say. In 1800 Smallpox had been around for over 2000 years, was responsible for hundreds of thousands of deaths, and blindness annually, and the preventative treatment–which won by the way(Smallpox is gone)—was immediately rejected by a large number of the population. People that rallied in the streets back then almost certainly had family, friends, or other people close to them that had suffered or died from the infection—and still humans fought against it. This mistrust of the medical profession, government, authority, whatever it was happened long before Physicians started getting people hooked on morphine or heroin, and was still during times when patients got holes drilled into their head to “let out the demons.” The anti-vaccination movement developed prior to evidence based medicine. The first public health action that is considered “evidence based,” in medicine was based on a study on vaccination side effects in children. Probably the caveman that invented the wheel got runover by it, likely the woman that invented fire got burned. Something somewhere in these rejectionists is an impenetrable desire to keep things “the way they were.” Somehow bringing a 6-year-old

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child to a neighbor’s house to purposefully transmit a viral infection is easier for many people to accept when compared to having a strange man in a white coat inject the child with a gooey needle. I still don’t necessarily agree with the anti-­ vaccination movement, but I understand and mildly respect where its coming from. Where vaccination does not exist, the practice of inoculation continues to this day. For example, in Afghanistan, there is still a practice of purposeful infection of children with the parasite Leishmaniasis. This is a parasitic infection that is transmitted by a fly bite. Professionally I’ve only seen it in one patient, on a serviceman that had returned from overseas. The infection leaves a very large sore-like scar in the area of initial infection. If this happens on exposed skin such as the face—the disfigurement can be substantial. When the person(parent) can choose the site of infection, say the hip or the lower back, the scar produced is not plainly visible and diminishes over time. This is a pretty significant and intelligent adaption to the environment, and its effective. It is also accepted. My colleagues, if they ever read this book, will likely give me some negative feedback because I don’t limit myself to any stance of being “Pro-Vax,” or “Anti-­ Vax.” Twenty five years of studying Immunology and I don’t think there is an easy answer, certainly not one that can be constrained to two syllables. If I could pick a label it would be “Pro-Human,” and “Anti-Death.” It’s a very tough subject, but breaking it down to the fundamentals everyone would agree: we all want to give the human Immune System the best chance to develop Immunity to these infectious diseases so that humans may live the best lives possible. This is problematic, because the immune responses of the human body is not entirely predictable. The immune system is one of the most unpredictable of human organs, and it is home to numerous “unmeasurable differences,” between humans. A measurable difference would be the difference in body habitus between myself, and NBA legend Shaquille O’Neil. I am a larger than average human, but next to a specimen like Shaq, I would look like a small child. It would be a very simple and measurable difference between our physical proportions and know “the good looking one is going to need a different size shirt than the other one.” What about caloric intake? The bigger the body, the more calories, right? How about medicine? Do two bodies of different size and metabolism need different amounts of medicine? These are overly obvious examples of “measurable differences.” Immunologists do not have the ability to determine between different humans and the variability in their potential Immune response to infection or vaccination. Some humans can get sick with influenza virus, but barely feel anything, while others can develop life threatening symptoms and many die each year. Some humans get sick from an influenza vaccination, it is extraordinarily rare that any die as a consequence of vaccination. The difference between the two populations? Most, but not all of the people that die from influenza each year did not get vaccinated. While Immunologists lack the ability to accurately predict human immune responses, it remains an obvious statistical fact that the more people vaccinated results in less people dying. Many modern medical advances are passionately avoided by millions of people. The impulse to avoid medicine, fear vaccines, hate pills, and look for “natural alternatives” seems to be proportional to how far from the realm of “natural” we push the

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surrounding human environment. As far as I know, there are no skull-drilling clinics left in the USA. Most of the other health practices in addition to skull drilling from 200 years have been debunked or greatly improved upon. Vaccination has undeniable scientific credibility. The fight against the first vaccine was brutal and lasted nearly 200  years. Smallpox was a clear and present danger in society, and still humans fought against it. Until the exact inflammatory response from any new technology can be predicted and guaranteed, it will be a natural human choice to try to do things “the old fashioned way.”

2.3 The World Current Humans Live in Is Excessively Unnatural I don’t fault anyone for looking for “natural” alternatives to current available treatments. Personally, if I got sick the last people I would call are some of the jokers I work with. The society’s burden of disease, sickness, and overall “unwellness” is a moving and expanding target. This is something that many people feel, but can’t necessarily articulate into words. There mathematically seems to be way too much illness and sickness prevalent in our society to actually be real. When I look at someone’s immune system, I am nearly 100% reliant on lab testing. The diagnostic approach certainly begins with a medical history, I.E. “Doc, I get MRSA infections in my skin every month, they require drainage, sometime surgery, but always antibiotics. What’s going on?” Well, with a history like that, it is clearly “recurrent staphylococcal skin infections,” as a diagnosis. Simple, elegant phrasing, however we’re not done yet. I need to measure in some way the patient’s natural and acquired defenses to the infection. This typically means a bunch of labs, then more labs based on those results. To explain some of the things I test for, like the “innate immunity” could take me an hour, and only maybe could I successfully explain this complicated topic—that personally took 7 years to learn. However, the conversation on some of these labs results boils down to basics, which ends up being the question: “Is this lab test result a good thing or a bad thing.” That minimalist approach seems like a simple way of discussing a result—but brother it is not simple. The concepts of “good and bad,” may seem like an easy topic in human health, and certainly there is the occasional problem that can be easily defined: The patient has lost all of their blood due to this cut.—This would be Bad. The patient will heal perfectly, and suffer no consequence due to this cut.—This is Good.

So, these shaving examples are obviously exaggerated to set up a point, that Bad outcomes usually refer to impending pain, disability, or death. While a Good outcome usually means no impending death. Some sometimes different is Bad, but other times different does not mean impending awfulness, it just means different. As much as I try to avoid committing to statements such as “good and Bad,” I usually try to explain results in the context of “information.”

2.3  The World Current Humans Live in Is Excessively Unnatural

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An easy to understanding, and not exaggerated example of “Neither Good or Bad,” is the frequently diagnosed gluten allergy, or Celiac Disease. This is a very common condition, that has only recently been discovered in a handful of decades. It is also highly variable—I have seen thousands of patients that had inflammatory reactions from food, and these reactions have varied from “mild indigestion” to “earth-shaking pain and swelling.” So being diagnosed with gluten allergy is not good or bad, however what happens NEXT—avoid the bad food = Good, continue to eat bad food  =  Bad. So an understanding of WHY the body is unwell is just knowledge; what someone does with that knowledge is what matters. This arching concept: “The world is different, human bodies don’t like it,” is a simple one that I don’t think can be summarized as “good or bad.” The world is changed. Its not going back. There are LOTS of reasons that this new alien planet is better for the human species, however we are trying to invoke understanding of the differences (Fig. 2.1). What someone does with the understanding is what matters; that is empowerment. The easy first step would be to understand, “My body isn’t healthy, and its not my fault.” Because self-blame will trap someone, and it has a strong tendency to keep someone unhealthy. We hope to bring an understanding of “My body isn’t healthy, but it’s doing an amazing job in a complex and strange environment, now I know what I can better for my body.” While the number of continents and the distance from the sun haven’t changed, much of the other planetary attributes have. Note: Figure is not drawn to scale. One of the main reasons that we live in much a better world: I have never seen a human with smallpox. That is pretty darn awesome. This plague that devastated

Fig. 2.1  Changing environment on earth—from 1975 to 2025

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humanity for thousands of years is gone. It took a long time, and there was striking resistance to the process of global eradication of smallpox, but humanity won. Both sides: Pro-vaccination and Anti-vaccination won as there are no more smallpox devastations, and there are no more mandatory smallpox vaccine campaigns. The list of ailments no longer problematic in the new world is a long one: vitamin deficiency, starvation, cholera, Network TV, all horridly devastating things that were once common in all pockets of humanity. Now those horrors are much better controlled. Our civilization hasn’t chosen to eradicate these things—because we could—they are much better controlled than they were previously. The list of medical maladies that were common 100 years ago is very different than it is today. I think that we are all better off in this strange new world, but that doesn’t mean its good for us. Now, it would be tough to discuss the topic of smallpox, government involvement, and population resistance without discussing the weaponization of the virus. I’m not saying that the current “anti-vax” movement has scientific basis for their claims, nor am I saying that they have an original idea, just they are entitled to their emotion fear because of human history: Humans have a long-standing history of hurting other humans. The past 50 years has not proven that the governments and ruling classes of many countries have their populations “best interests” at heart. Resistance to government mandated health policies is a natural population response given the historical actions of most humans. Its also nothing new. The very first vaccine, or “unnatural inoculation” was met with substantial population resistance. This resistance, this psychologic response to others forcing change on our bodies, is very much a part of human nature because humans are aware of human history. For example: My own mother purposefully infected me with a human herpesvirus for crying out loud.

2.4 Different Is Different, Not Good or Bad Humans are extraordinarily adaptive organisms, when we feel like it. There is a feedback system in place in our bodies to keep our functions regulated with our environment. On our planet there are members of our species that can survive at an altitude so high that there is barely any oxygen. There are whole villages where humans have spent their entire lives on the water, and they can hold their breath for nearly 10 minutes. There is even a guy that can eat 100 hotdogs in under an hour and not die immediately. These people are…..different. Some people may be born different; however all humans are capable of drastic physical adaptation through stressing and challenging the body. The key issue here is that human made adaptions are not natural, and to push the body to these limits feels unnatural. People aren’t born able to unassisted climb Mt. Everest, they develop that ability with time and effort. This practice may not feel healthy, but the results allow for human life to throve in some very unnatural places.

2.5  The Immune System Is Not a Perfect Defense System

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I do not advocate for competition eating, or chronic deprivation of oxygen, but those humans have different bodies than most. Because they adapted to the environment that surrounds their body. In fact, while there are training techniques for these adaptations, most of these changes are unconscious. As in the body’s responses to the stresses happen because of the stress, not because the humans want them. In fact, an astronaut’s body’s starts to adapt to the lack of gravity within only a few days. This loss of bone density (because it stopped being necessary) was noted with the first long term space dwellers. Now it is commonplace for astronauts that spend substantial time out of gravity to perform daily exercises to combat the effects of their unconscious adaption, and it is modestly successful. This was a thoughtful way to prevent maladaptation. Obvious examples are listed here to make the obvious points: Living without gravity is different, and if difference is understood, the human can change behaviors to adapt to the difference. If the astronaut was unaware of the sudden absence of gravity, then it would be nearly impossible to figure out what could be done to adapt to the changes. Physical exercise in zero gravity seems to be a relatively easy fix— however maybe it could have been possible to decrease bone loss through the use of medications? In the United States we have millions of people that develop thin and weakened bones. We use the medical term “osteoporosis,” which basically translates to “porous bones.” When this happens on planet earth, its not due to lack of gravity, however the changes are is still modifiable once the cause is known.

2.5 The Immune System Is Not a Perfect Defense System The Science of Immunology can be intimidating and complicated; to keep my mind right I try to keep things simple. In other words, this work cannot be expected to be a comprehensive encyclopedia regarding all current understanding of Immunology. It’s not even close. This simplified view of the major Immune system points which respond to environmental stress is hopefully enough to explain some of the topics later discussed. For example, it may seem obvious that fighting off 4 infections at once is harder than fighting one at a time. What is not obvious is that instead of 1, fighting off 3 different infections at once decreases the specificity of the immune memory, I.E. confuses the defenses and this can lead to unexpected results. Explaining the complexity of the Immune System is like trying to describe a symphony with words. The singular notes and instruments are obvious and explainable, but the arrangement has to be heard or even felt to be understood. Likewise, as we break down the individual components and list the role in defense, keep in mind these components are always interacting and balancing each other. While we talk about parts like Immunoglobulin or T-cells individually, but never do they act alone, those small parts are always part of a much bigger and balanced system.

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2.6 Born Ready to Fight: Innate Immunity The “environment” being labeled as everything outside of the body, and environmental threats are those things outside the body that can cause harm to the body. There are many daily threats to the body, and the human immune system can learn to remember the threats it encounters, to get better at defending and healing from the injury caused. The human body is born into the world with its Immune System already able to recognize, quantify, and respond to microbial threats. This “inborn” part of the Immune System is also called the “Innate Immunity.” As time progresses and the body encounters an increasing quantity and diversity of microbial threats, it develops a memory. Having a “memory” is beneficial for many reasons, but to simplify: memory Immunity is efficient. The Innate ability to fight off infection is based on the natural patterns of the bad guys. There are some fundamental natural molecular differences between Virus, Bacteria, Fungus, Parasite, and Human. The Immune System does not need to learn these, every animal alive is born with some form of innate Immune system. Not getting into the specifics—but the molecules that are unique to these bad guys are recognized by this Innate response. Virus’s unique molecules trigger an Innate Immune response which increases the human’s ability to fight off viruses—not a specific virus, just viruses in general. Likewise there are different patterns in bacteria that trigger and Innate response specific for fighting bacteria, fungal specific patterns in fungus, parasite patterns in parasites. Innate responses are driven by the Kingdom (virus, bacteria, fungus, parasite) and by the amount of the signal. The more Kingdom specific molecules, the larger the Kingdom specific response.

2.7 Remembering the Environmental Threats: Adaptive Immunity The effort to fighting off an infection can be very costly to a human body. Could be days with a high fever, inability to work or find food due to illness, vomiting, diarrhea, or even result in a rash. Regardless of the inflammation the body pays to fight off infection, resources are scarce, and to save resources adaptive responses make repeat infections less costly to clear. The more times the body is exposed to any specific infection, the better it’s supposed to get at recognizing and defeating that infection—specifically. Repetition means that specific threat is present in the environment and will likely be encountered repeatedly. It would make sense to somehow prepare for the next time that infection is encountered, right? Adaptive Immunity is the defenses that are specifically coded to an infection. This increases the efficiency of the defense. Less time and less energy required means less possible collateral damage to the rest of the body.

2.7  Remembering the Environmental Threats: Adaptive Immunity

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I think that this is one of the coolest parts of the Immune system. When its working ideally, humans have no idea its even there. When the body is in its ideal environment, the immune system can adequately handle almost everything. With the current environment, the messages are clear: The Human Immune System is working overtime (Fig. 2.2).

Fig. 2.2  Normal immune reaction to immune trigger. A single trigger to the immune system results in a predictable, but imperfect response. Multiple triggers can occasionally lead to less predictable, or less accurate responses. Adding extra inflammation can amplify the reaction, and lead to unpredictable responses (green)

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2.8 When Adapting Doesn’t Go Perfectly An overworked Immune system can sometime confuse signals and codes, and could lead to the wrong memory. A lot of wrong memories can sometimes lead to long term immune confusion. Having an unclear memory about what and where the Immune system needs to attack microorganisms is one of the major causes of “autoimmunity”—or when the immune system mistakes a part of its own body for an external threat. The American College of Rheumatology estimates that 23 million Americans, 7% of the population, suffers from an autoimmune condition and that number is rising. What absolute shenanigans is this? More people, year after year, are being attacked by their own body and this trend has been noticed for decades. The more innate signal, infections, or immunizations that trigger memories, the more specific antibodies are made. It’s not a perfect system. I mean its like 99.9% perfect, but still with that 0.1% chance of error adds up if it gets hit frequently enough. Error can mean that instead of only coding to the infection, it might code to and recognize/attack the host. This specific imperfection was very helpful in the case of the original Smallpox vaccination, which was actually a similar, but different virus. Cowpox was similar enough to Smallpox to give the Immune system enough working knowledge to effectively prevent the initial infection. This was an example of imperfection being a really good thing in the scope of developing a protective immunity. There are only 20 amino-acids that make up the “alphabet” of proteins (Fig. 2.3). There are 26 letters in the English alphabet, which is more than 20, and miscommunication in the English language is quite common. Sometimes one little letter can make the difference between attacking an invader or attacking the host. Friendly fire on a molecular scale.

Fig. 2.3  The amino acid “alphabet” of proteins. All living proteins are put together out of smaller pieces called Amino Acids. There are 20 amino acids to chose from, and in the English language there are 26 letters to make up words. The immune system reads proteins like humans read words (3–8 letters at a time.) Some English words look and sound alike but are different, likewise, some different proteins can look the same to the immune system

2.9  Modern Practice Still Not Perfect

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2.9 Modern Practice Still Not Perfect I do not think that I can discuss additive or multiplicative inflammatory events without mentioning modern day vaccination. The design of vaccines is such that they are factored to take advantage of human inflammatory mechanisms. Viral vaccinations: Measles, Mumps, Rubella, are combined into one inoculation and the innate and memory response gained is effectively viral. Bacterial vaccinations: Tetanus, Diphtheria, Pertussis likewise are combined into one inoculation. This minimizes the different signaling involved in the response and generation of long-lasting protection. The data on the effectiveness is indisputable. Personally, in 20 years I have never seen a single case of Measles, Mumps, Rubella, Tetanus, or diphtheria. Those infections used to be horrific, and now not. The data on how people “feel” about vaccinations is all over the place. As of 2023, it is common practice to give multiple vaccinations simultaneously. There are many reasons for this practice, but in the context of cross-reactivity, no human gets a vaccination if they have an active inflammatory response (example: fever.) The label on vaccinations list the expectation that injecting the contents of the vial will cause an inflammatory response (example: fever.) If a human body is fighting an infection like Strep Throat, it is globally understood as unwise to simultaneously give an influenza vaccination. Even if a human has active influenza, it’s not recommended that they get the influenza vaccination. Modern influenza vaccinations treat 4 different strains of influenza, usually the two most common forms of Influenza A and Influenza B going around from human to human that year. Inherent in modern day practice is concern and regard for Immune cross-reactivity, but it is not yet entirely in policy. Drugs and vaccines go through an extremely expensive and rigorous process to ensure that they are safe and effective for humans. I would argue that these topics are scrutinized more heavily than anything else currently produced for modern day consumption. I would never suggest that they under too much regulation. Neither am I trying to evoke emotions of pity for physicians. These common examples that invoke passionate arguments are contrast to discuss all the other stuff that has happened in human environment. These massive alterations in human-environmental interaction cause much more human harm than the stuff that doctors do to save lives. There is no perfect science or medicine, and vaccination is not perfect. Socially, modern medicine seems to be a favorite topic for blame for many modern-day health issues. This can be rationalized because in 2023 there are lots of human health problems that weren’t around in 1973. I think that it is human nature to suspect any industry which profits from a situation, to potentially be the source of the situation. For the entirety of human history there have been examples of humans taking advantage of other vulnerable humans. Occasionally this has resulted in measurable human-to-human harm. It is important to consider that in context, 100% of all the changes in our environment have been caused by humans.

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2.10 Rheumatic Fever: Too Much Immunity Antibiotics have been a miracle of modern scientific progress. Not only have they saved countless lives, but also have saved people from the consequences of long-­ term untreated bacterial infection. The children’s story, The Velveteen Rabbit, was set in a time when humans did not have antibiotics. The major plot point was a young child’s long illness followed by eventual recovery from a strep infection. While children’s fiction, the extend of the illness discussed is historically very accurate. This book was written in 1911, a few decades before the discovery of antibiotics. Rheumatic Fever—or joint fever, is a prolonged immune reaction from a common bacterial infection: Strep. Strep throat, if left untreated for weeks or longer, continuously triggers innate responses of the immune system. This high-level and prolonged response over time increases the amount of adaptive Immunity, too much and it can get some mixed signals. If this infection lasts long enough, the immune system’s imperfections start to add up leading to widespread inflammation all over the body. This widespread whole-body inflammation is called Rheumatic Fever. If strep is treated with antibiotics, the chances of developing the streptococcal related Rheumatic fever is essentially zero. However, if the infection is not treated quickly enough, and rheumatic fever develops, the immune system can cause damage the heart or even the brain. Antibiotics can prevent the long-term inflammation; however antibiotics also treat the long-term inflammation. In the case of post-­ streptococcal rheumatic fever, even though the major infection has passed, the remaining small amounts of strep left in the throat or other places can trigger enough remain memory to push the Immune system to attack the body. If Rheumatic Fever occurs as a complication of strep infection, doctors usually give anti-strep antibiotics for 6  months to a couple years. 100  years ago, in the United states, acute Rheumatic fever was the leading cause of death in people aged 5–20 years of age (Bland 1987). Currently there are several millions of cases of strep in the United States each year, but thanks to antibiotics, very few cases are fatal. This treatment is actually prevention. The daily antibiotics are not actively killing any infection, but are preventing any new immune response to strep that could happen. Preventing any new immune response—not waiting until infection symptoms—allows the adaptive response to cool down and the joints and other stuff get better. Even the smallest engagement with the strep bacteria will result in a response from the Immune system. In this case that engagement could wake up the process that attacks the heart or brain. Humans are constantly being engaged by the bacterial community, and one of the amazing things that our immune system does is eliminate these “micro-infections” without humans feeling sick or even noticing at all.

2.12  Allergies Are Completely Immune System Mistakes

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2.11 Efficiency: This Is the Name of the Game The innate immune system hits the body very hard when activated. When there is a lot of energy expenditure and even possible damage to the body, this can make a big mess. Each time the immune becomes engaged to a specific pathogen, it should be more efficient—less mess. The more times a specific pathogen infects the body, the more the response is developed. This allows these frequently encountered infections to be taken out quicker, with less sickness and damage. These memory cells last a long time, like 10–20  years, even if they never see the pathogen they were programmed against. When there is persistent inflammation, like strep infections before antibiotics, the strength of the learned adaptation can be problematic. Vaccination works by confusing the body to think it has been infected by whatever organism the vaccine supposedly replaces. However, there is no organism that multiples and keeps the inflammation going. This should result in a very short lived, but highly specific immune memory response which allows for a rapid and efficient clearance of the infection should the human every encounter it in the environment.

2.12 Allergies Are Completely Immune System Mistakes Allergens are environmental triggers but they are not threats to the human. Immune system fights this aggressively but Allergens will never invade or otherwise use the human for food. Allergens however, show the immune system molecules that are very similar to parasite molecules as far as human immune system is concerned. Parasites are very complex compared to a virus or bacteria. Parasites usually have different organs, complicated reproduction and life cycles, and definitely require a host. The similarities between parasite digestive enzymes and pollen enzymes is enough to trigger an innate immune response. Plants are supposed to be only food, but our imperfect Immune system will occasionally make a mistake and consider plants a threat. Everything that we consider an allergen, is an environmental trigger that is not a threat, but is regarded as a threat by the human immune system. Allergies are HYPER-sensitive reactions. “Hypersensitive” easily translate into “small little bits cause big problems.” We usually don’t see or feel the allergens that trigger sneezes, but we know they are there. Because of all the sneezing. The body senses the reaction, and the engagement of the response very quick after encountering an allergy. This quick and exaggerated inflammatory response, to small amounts of stuff, is also called “Immediate Type hypersensitivity.” Immediate Type Hypersensitivity affects humans immediately. Body detects pollen, body immediately sneezes. Human Environmental Allergies are a Human Immune defense mechanism gone wrong. It is attacking targets that are in no way bodily threats but have similar underlying natural codes. There may have been a time when parasites were likely the biggest threat to human survival, perhaps when food resources were scarce? It

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doesn’t take much environmental pressure to unlock allergies in those people that are susceptible.

2.13 Summary It took 100 million years to develop and cohesively gel the various layers of the human Immune system. It took us just over 50 years to completely screw things up. The patterns present in the major infectious kingdoms are recognized at birth and continues throughout the duration of life. In an ideal environment the Immune system learns to efficiently control the responses to infections, sometimes to the point that small infections aren’t even noticed. The environmental change we are burdened by has not been matched by humankind evolution—in fact humans as a species haven’t changed much in the past several hundred years, including our attitudes towards government and science. There is an overload caused from the capability of the human immune system to clear environmental triggers compared to the number of triggers in our current environment. The current human environment is strange to human immune systems, and the volume of that difference causes confusion which ends up triggering immune attacks against the human body. I am not suggesting anybody go back to “simpler time,” we’re on a one-way forward progress train and nobody’s getting off. Once we learn that our Immune Systems aren’t supposed to be in this environment, we can stop all of the shame, blame, and victimizing of those suffering from illness. Even those people whose Immune Systems are actively betraying them, those elegant and sophisticated systems aren’t hurting the host on purpose, they are just confused by a cruel and maladaptive world. Lastly, Allergies are a small portion of our immune resources, and this makes them a great target to reverse. Key Terms • Innate Immunity: Powerful part of the Immune System, humans are born with it. Can tell the difference between Bacteria, Fungus, Virus, and Parasites. • Adaptive Immunity: The part of the Immune System that learns from the environmental threats it encounters. • Autoimmunity: A complex condition that the Immune system mistakes part of the host for the environmental threat. • Allergen: An Environmental Trigger to the Immune System, not a threat, similar molecules to parasites.

Bibliography Bland EF.  Rheumatic fever: the way it was. Circulation. 1987;76(6):1190–5. https://doi. org/10.1161/01.cir.76.6.1190.

Bibliography

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Gross CP, Sepkowitz KA.  The myth of the medical breakthrough: smallpox, vaccination, and Jenner reconsidered. Int J Infect Dis. 1998;3(1):54–60. https://doi.org/10.1016/ s1201-­9712(98)90096-­0. Hung IFN, Yuen KY. Immunogenicity, safety and tolerability of intradermal influenza vaccines. Hum Vaccin Immunother. 2018;14(3):565–70. https://doi.org/10.1080/21645515.2017.132833 2. Epub 2017 Jul 6. PMID: 28604266; PMCID: PMC5861844 Wolfe RM, Sharp LK. Anti-vaccinationists past and present. BMJ. 2002;325(7361):430–2. https:// doi.org/10.1136/bmj.325.7361.430. PMID: 12193361; PMCID: PMC1123944

Chapter 3

Mechanisms of Rejection

3.1 Everything Is Falling Apart, So Let’s Tie It All Together I became a Medical Intern (first year out of medical school)—at the tender young age of 30. I spent my first day, night, then half day as a licensed physician in a state of continuous work. It seemed highly unnatural to me, however to all the other trainees it seemed just the way that things were done. I started my workday at 7:00 am, which meant I showed up at 7:00 am and was considered “late.” I began working as part of team that included one other physician and a handful of medical students. This team of trainees initiated the care of a dozen or so of the most substantially sick humans I had ever seen. Until that moment I did not realize how sick a human can be but also still be alive. While I was in a state of shock, the rest of the team went about their alien day/night/day as if everything was completely normal. There was no lunch break, no naps, no peace from the pager. After a solid 30 h, I was somewhat dazed. Time seemed to move differently, I was both sweaty from poor ventilation, constant high stress decision making, but also shivering from fatigue. After 30  h I could barely form thoughts to words as it looked like they moved on paper. Late in the day, one of elder statesmen-type professors was randomly roaming the halls and saw me attempting to finish my first work days(s). “Welp, looks like Dr. Lichtenberger has got that ‘Deer in the headlights’ look about him.” There was some soft chuckling had by all. That mid-Texas accent carrying the phrase seemed to both humiliate and educate at the same time. To this day, I am thankful for my “Humiliate-Education,” however also very thankful I am working relatively “normal” hours. But to think about it, “deer in the headlights” was an accurate analogy for the physiologic overload I was experiencing. Deer, by their nature are highly sensitive to their surrounding environment. Their eyesight, hearing, vibration, smell, all far better and more sensitive than what humans have. Deer are docile creatures by © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5_3

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nature, with little adaptation to physically defend themselves—so they run at the first signal that a potential threat is approaching. North American deer have not developed a method to teach their offspring to stay off of roads. Also, deer genetics haven’t changed since the invention of the automobile, so they only have those heightened senses which evolved over the past few million years. I can imagine a deer, in the middle of the dark night, walking on a road which is harder on their hooves than anything natural, when their ears pick up the sound of a car engine louder and faster than anything natural that could have preyed upon them. Turning their head to face this auditory and vibratory motorized monstrosity, when their eyes dilated to enhance any slight sliver of moonlight turn to focus on two beams of white light brighter than the sun zooming towards them at a rate faster than any animal. These graceful animals match their environment by being able to detect approaching threats and out run them, but they become frozen in the light and sound of an oncoming car. Some of the time, deer do not survive this unnatural encounter. None of the parties involved: the car, driver, or the deer mean for this interaction to go badly. After processing the fact that one of our most distinguished Cardiology professors had just referred to me as “frozen animal idiot roadkill,” I reflected on that lesson quite a bit longer than I was probably supposed. The feeling of being shocked and frozen in the moment of complete overload of my primitive mind has never been forgotten. I think that analogy sums up where we are as a civilization. Frozen and overloaded, stuck in a moment where the outside world is simply too much for our bodies to handle. A deer, frozen in the headlights of an oncoming car, is doing absolutely the best it can do in that moment. That deer was born into a world that it is not fully evolved to process, and it gets hit because it lacks the functional ability to react to the badness barreling towards it at unnatural speed. The driver—who somehow expects the deer to understand what about to happen, likely believes that the deer is going to move. An animal whose entire evolutionary existence is defined by having both highly sensitive threat detection and remarkable agility, losses its life when put into a situation that it simply can’t process. While stretching the boundaries of metaphors beyond good taste, the comparison actually makes good sense. Human bodies are nearly identical to the same bodies humanity had before the modern of evils of farming, electricity, and western medicine. Instead of a crash of puffy white tails and twisted metal, the traffic accident in our bodies is INFLAMMATION. Every day on a scale from molecules to mouthfuls our neuroimmune system is overwhelmed by the amount of noxious stimuli. The modern human inflammatory response does not “freeze us in the middle of the street,” but is a growing mixture of malfunctions in the basic operations of the body. There are so many sick people these days that it mathematically does not make sense that humans should be the dominant species on the planet. Wellness is now an industry. I do not intend to criticize the Wellness industry, I actually know very little about it. I have enough trouble keeping up with all the stuff going wrong with people’s bodies to learn an entirely new trade. I bring this up to

3.2  Rejection Part 1: Immune System, It’s About Food

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highlight that there is a recognition that things are not right, and that the current day-to-day actions in our lives do not keep us well and in fact are making us sick. Pointing out roots of health problems in modern life is actually quite easy; even my chiropractor can do it. Motivating change is very difficult. We are never going back to stone age living, and it would be idiotic to contemplate such nonsense. Technology will continue to move forward at a rate that exceeds natural selection, or even morality. However, the first step to healing any human body is removing the shackles of guilt. If a person believes that they deserve to be sick, no physician can really make much difference. In understanding that most illness is actually normal responses to an increasingly unhealthy environment, we can start to see that our bodies are strong. The state of modern illness is not because humans are weak as a species, but it is because our bodies are fighting for survival from threats and environmental forces that we do not have the appropriate tools to handle.

3.2 Rejection Part 1: Immune System, It’s About Food Scientists think that life on Earth began as simplistic single strings of protein over a billion years ago. The first forms of life from the “primordial soup” ultimately developed into organisms complex enough to contemplate the meaning of a process that started a long while back. What exactly is life? I never had the grades for Philosophy, so for the sake of brevity—life is defined as: things that eat food. Obviously, the definition of life is probably more complicated than that simplification. However, the process that led to millions of different species is directly related to how the organism adapted to find food. Photosynthesis—the process of turning sunlight into food, that was a pretty neat thing. The entire planet turned green, and the atmosphere changed. This is the food-­ finding process that led to the vast diversity of —different species. Once photosynthesis was figured out (please don’t ask me how this happened) there was plenty of food to go around the entire planet. Fast forward a couple hundred million years: eventually other organisms evolved that didn’t make food from sunlight, but the new organisms ate the plants as food. These hungry but mobile creatures became larger and needed more and more food, so they started to eat other creatures. That level of understanding is all we’re going for, in regards to the process of natural selection, evolution, and species development. If Eating Food is life, then life that was better at finding and eating food outlived the life that was not as good at finding and eating food. Right around 550 million years ago, this was during the Cambrian explosion, I remember it like it was yesterday—this was when carbon dioxide was decreasing and oxygen was increasing. There was so much photosynthesis that Oxygen became a very substantial portion of Earth’s atmosphere. Oxygen is also the key ingredient needed efficiently turn plants into food. With all this food, and oxygen to turn the food into life-energy, an interesting development occurred. Adaptation developed

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that enabled one organism to obtain all of its food from a different organism, but slowly, so as not kill it. The development of symbiosis, or more specifically parasitism, was a turning point for life because “not becoming food,” was no longer about running, hiding, or fighting, but developing a way for the larger life to micromanage its body to prevent parts of it from becoming food. Survival became less about longer horns, or sharper teeth, but also about defense from smaller parasitic forms of life. The adaptation of larger forms of life protecting themselves from smaller forms of life, and all consequential expansion, resulted in what we currently call our Immune system. Humans are the end point titration of evolution, and have evidence of primordial defenses against all forms of microorganisms—virus, bacteria, fungus, protozoa/parasites. While human beings may not look like much, our immune system is an absolute history lesson on the ability to adapt and survive to various threats. More than “defense” against invasive or parasitic threats, the immune system as we understand it also heals the body from injury, protects injured parts from further injury, clears away waste, prevents cancer, and the whole time is able to nearly perfectly recognize the difference between all other organisms and itself. The brain gets a lot of credit for the success of the human species; however the immune system is the pinnacle of >500 million years of evolution and competition for food resources. Immunity is a continuously active process which is highly successful in keeping our bodies from becoming food for other species.

3.3 Barrier Immunity: Borders of the Body Human barriers are the parts of the of the body that make contact to the environment. Human skin, credited as being the largest organ in the body, is a necessary barrier that prevents outsiders invading and water leaving(dehydration). It is not a stretch of the imagination that if a human body somehow lost 50% of its skin, it would be in serious trouble. The skin has many parts, but for the purposes of framing its a necessary barrier that must be maintained. Disruption or breakdown of this barrier has serious consequences. Other than the skin, all other barriers are collectively called “mucous membranes,” these are body parts that are exposed to the external environment, but also have a higher degree of chemical sensitivity. Eyes, lips, stomach, bladder, all technically contact the external environment. The flow of urine outward is considered part of the human “barrier,” as the faster the body makes urine, the harder it is for bacteria to infect the urinary tract. Mucous production is important in the nasal membranes, and in the lungs for trapping airborne particles. Mucous membranes as a barrier are much more sensitive that skin, and can inflame more severely compared to skin. Mucous membranes tend to have specialized functions associated with them, sight, smell, taste, digestion, reproduction; and also tend to be the major entry points for infections.

3.4  When Defense Becomes Offense

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Overcoming barriers is the deciding factor that determines to the success of an infection. We can see the “evolutionary tango” between microorganisms and their individual adaptions to break through human barriers. Evolution is not finished, it is active in every living species, everywhere, all at once. Human barriers are defense from becoming food, and there is evidence of recent evolution of microorganisms developing toxins which are highly specific for humans-only (Fries and Varshney 2013). There are bacterial toxins that have specific action to Human Immune systems only—which means the molecules were made for humans, not mice. Yes, this time its personal. Bacteria that have specifically evolved to hurt humans, should not be such a problem because this has been a million years process. However, the selection pressures due to recent changes in human healthcare environment have pushed microorganism evolution into overdrive. These microorganism adaptations seem able to outmaneuver all of our natural defenses. Barriers are major entry points of infection, it would make efficient use if they had a large capacity to recognize molecule patterns in nature. Recognizing the molecule patterns of environmental threats is the role of the innate Immune system. Remember, the innate immune system is ancient, and is able to detect the natural shape of threats. Barriers are the main response area due to allergies and allergic inflammation. Barriers are the first, but not the only places we will find mast cells. Actively present in the barriers, mast cells make humans itch, swell, turn red, produce mucous, wheeze, cough, sneeze, vomit, and many other awkward bodily processes. Mast cells are the “first responders” to any threat on human barriers, and they’ve been getting a lot of extra work in recent decades. Mast cells are the hero and the villain of this story, they are not good or bad.

3.4 When Defense Becomes Offense The first infectious form of life, or “small things trying to eat large things,” scientists think started simply in the form of a worm. A simple structure: tube like, outside barrier, inside digestion. When these fossilized organisms were found attached to other fossils, those other fossils were smaller than others of the same type. In other words, the fossilized-life with tube-worms lost their food energy to the worms. This ancient interaction, of one lifeform using another form of life as food, was technically the first “infection.” The organisms (host and infection) were nearly the same size as each other, so basically a worm that lived off of another slightly larger worm. Life has grown up a great deal from the worm-eating-worm Earth of 500 million years ago, unless we include Washington D.C. The ancestor of the modern Immune System sprung from the worm v worm interaction, likely by making it more difficult for the infectious worm to contact the host worm. This first purely defensive adaption was a controlled but specific release of toxin (we think). The first development of a specialized compartment that could

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Fig. 3.1  Primordial mast cell. The earliest defense against predators than were smaller than prey. As multicellular life became more complex, some individual cells developed specialized jobs. The first “Immune” defenses were stored toxins, that were released all at once when threatened. This initial containment, and rapid release does not kill either organism, but it does separate them

be used selectively to defend against being food for smaller forms of life was what we now refer to as a “Mast Cell.” These two life forms were actually pretty similar, so the same toxin would have hurt both, therefore compartmentalizing and storing the toxins was necessary. The purpose of this compartment was to store, but release it all at once to repel the environmental threat. While this release of toxins inevitably harmed the host to some degree, the focused release would free the host from the infection. The origin of the immune system predates warm blooded mammals, and has developed substantial improvements since the original “Primordial Mast Cell.” In fact, the evolutionary descendants of the original mast cells are still with humans, and are the major rejection method of the current environment (Fig. 3.1). What we have is “best guesses,” from fossilized records, not a play-by-play guide book for the development of the modern Immune System. With the constant of evolution and adaption, as organisms began to increase in size and complexity, mast cells have been co-evolving with host and threat organisms. Now the initial defense mechanism has different functions in different tissues. When they were first discovered, scientists believed that Mast cells were just defense against modern day worms and parasites; however now we know that mast cells are responsible for dozens of other functions related to the environment. Interestingly in a perfect environment, the host would never be aware of the existence of mast cells, because when things are perfect—mast cells don’t do anything. When activated, or “triggered,” mast cells coordinate and amplify the connection between the innate and the adaptive Immunity. Science has shown that the committed step to the development of some autoimmune conditions are the direct result of unnecessary activation and programming by the mast cells in the barrier (Dudeck et al. 2011). The role of mast cells as the sensor of the environment, and also programmer of the body’s adaptations is the take-away message of this chapter. Mast cells sit in the parts of the human body that interact with the environment, and were also the first defense against infection or parasitism. While environmental changes have been observed for decades, the role of the Mast Cell in influencing long term Immune responses is only about 10–15 years old at this point. The complete importance of

3.6  Rejection Part 2: Nervous System (Autonomic)—It’s Still About Food

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the human mast cell compartment is still not understood, but up until very recently nearly every scientist thought that mast cells were a “useless” part of the Immune system that caused runny noses from pollen. Human bodies in the 2020s are being directly engaged by a lot more infections than our ancestors, but these are not the only environmental threat that triggers mast cell responses. Within a generation we have learned that air pollution, food pollution, social pollution, all directly engage the mast cell compartment. Modern humans are swimming in a sea of inflammatory mast cells signals. Immune responses to the environmental triggers of Mast cells lead to a host of problems other than “allergy,” and I refer to as rejection of the modern world.

3.5 Mast Cells Externally Respond to the Environment, But Internally Adapt the Human Body The very same type of human cell can actually have very different jobs, depending where it ends up. While the barriers of the body have the most attention and research regarding mast cells, they can be found in nearly every organ of the human body. All mast cells begin their lives in the bone marrow, before being sent to areas of the body that are in distress. If mast cells end up in the Lung, they look and act differently than if they ended up in the skin. Both of those types of mast cells are different than mast cells that move into the gut. This differentiation makes efficient use of resources, because each barrier tends to be subjected to different types of threats. Adjusting the sentinels to match the associated threats saves time and energy. Mast Cell’s job in the barrier is mostly defense, and if they are over triggered, the accumulation of imperfect responses can eventually start the programming for autoimmunity. When mast cells end up in the deeper tissue such as muscle or fat, they change how the local systems work. The deep tissue mast cells in fat stores are the main controllers of metabolism. The mast cells in the heart help regulate how power in the heart functions. In the human brain, we are starting to find the role for mast cells and the histamine in response to psychologic trauma, sleep-wake cycle, and mental illness.

3.6 Rejection Part 2: Nervous System (Autonomic)—It’s Still About Food I was the victim of an anti-human toxin before, and it was terrible. I remember the summer night in the late 1990s like it was yesterday, hanging out with some friends in a suburban bar/restaurant in Ohio. I don’t remember the amount of food I ate, I do not remember which game was on the television, but I do remember how sick I got because of that food. I swear I felt some kind of poison coursing through my

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system. My body shivered and shook, sweating profusely, and burning and freezing at the same time. I have had only a handful of truly heroic moments in my life, and what my body did in that bathroom rivaled Hercules, Beowulf, and Luke Skywalker’s best moments. The pain left quickly after I heroically tossed the cookies, and everything got better. My heart rate slowed, and the sweating began to subside. The tidal wave of nausea was quickly receding. Little did I realize at that moment of vulnerability; my autonomic nervous system and my immune system were responding in a coordinated effort to protect me from food poisoning. I believe that I ingested staph toxin called “enterotoxin B.” This was the second toxin that staph bacteria were found to make, the first one being called “A.” The B-toxin is specific for humans, which means it doesn’t do that type of sickness in other species. It is able to directly activate the most powerful part of the immune system—the CD4+ cells. While the CD4+ cells have some ability to recognize molecular patterns in bacteria, these bacteria developed molecules that recognize human molecules and trigger them. As it turns out, barrier defense needs some backup. There is a connecting mechanism between the body and all its barriers called the autonomic nervous system. The autonomic nervous system goes to and from every part of the body. The human body’s day to day function is highly coordinated and organized, and if everything goes perfectly, no human would even realize they had one. While everybody knows that nerves travel from the brain to move muscles, there is actually more body not muscle (by weight) than is muscle. All those digestive and cardiovascular organs, skin, fat, bone, they also need to be told what to do. There are some humans out there that are capable of controlling their heart rate with their conscious mind, however none of those people have ever been to my clinic. When I rejected my dinner of chicken wings in the 1990s, my conscious human brain did not tell my body to do those things, it did them automatically. With Immune recognition, and autonomic coordination, I conquered the enemy and lived happily ever after.

3.7 Automatically for the People Almost everyone has had a fever before they’ve learned how to read. Seems very common, natural, body heats itself to help it fight off infection. Then there is shivering—rapid shaking of the muscles to generate heat, the autonomic nervous system goes to muscle as well, that’s 100% of the body. Immune system—tells the body it needs to be hot, Autonomic system makes it hot. The defense system against microorganisms is the Immune System. The Autonomic system is our defense for things much bigger, all the way up to lions, tigers, bears, etc. Like the Immune defenses, the Autonomic defense follows the forces of efficiency. A properly run human body doesn’t fight off a sabre tooth tiger at the same time as they sleep, or eat, or reproduce. When a human body needs to

3.8  Mast Cells Connect the Autonomic Nervous System to the Immune System

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fight, it fights (or runs away.) Shifting from a fight and/or flight mode to a rest and digest mode conserves energy, and maximizes the ability to survive. This management system helps humans do everything better. Think of it as “energy budgeting,” and it is balanced automatically. Any type of environmental change, activity change, mood change, comes with a response. How humans budget energy to the immediate environment is very much driven by what that human body needs to survive in that environment. Humans have an ability to adapt and survive wide ranges in in temperature, as well as changes in the lack or abundance in food and water. However, the modern environment is one of abundance but also absence. There is an over-abundance of food, but hardly any time to properly eat. The human brain does not consciously tell the heart to beat, the stomach to digest, or the skin to sweat. This system controls how the body responds to its environment, automatically. “Fight or Flight?” That is the body’s autonomic neurologic response to acute stress. “Rest and Digest?” That this the body calming down from the aforementioned fighting and flighting. The autonomic nervous system is also bordered on those interfaces of the body and the environment, is closely linked to defense, and the internal system is linked to adaptive body changes. Infection driven Fever responses, vomiting, shivering, salivating, and even some behavioral responses to infection are all “automatically” controlled by the autonomic nervous system.

3.8 Mast Cells Connect the Autonomic Nervous System to the Immune System The wiring of the body is pretty difficult to understand, and I can’t say that scientists have it all figured out. Most humans have some form of functional brain as the “central processor,” but instead of only electric messages, brains also use “neurotransmitters” to communicate with the body. Acetylcholine is one such neurotransmitter that carries the signals from brain to muscle, and autonomic nerve to organ. Also, all the wires that travel back to the brain use Acetylcholine as well. Also: norepinephrine, dopamine, serotonin, glutamate, GABA, are all chemicals that are involved in message transmission back and forth in the human brain/body. The autonomic nervous system interacts with the immune system using neurotransmitters, mainly “fight/flight” messaging leads to shutting down Immune responses. People will frequently recall a period of illness following a stressful period. The stress signals which include norepinephrine, adrenaline, and cortisol all contribute to the reduction in the activity of the Immune System typically leading to the illness. Mast cells do lots of stuff, not only do they have specialized defenses, they also bridge the gap between Immunity and Neurology. Mast cells are the producers of nearly all of the body’s histamine. Histamine gets it reputation by making skin itch and turn red, but it is also neurotransmitter in the brain. Mast cells also have

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receptors (they can be influenced by) adrenaline, norepinephrine, acetylcholine (autonomic nerve transmission). Mast cells also can produce serotonin and melatonin, meaning that they produce at least three different neurotransmitters (there are more…) and this nerve-immune junction is the foundation of the stress traffic-­ control mechanism. Mast cells are the first responders to infection in addition to healing wound. Mast cells help humans wake up, feel nauseated, produce mucous and constrict lungs to make them wheeze. They are also very important in the autonomic nervous system, as they control and amplify temperature responses in deep tissue, drive shaking muscles to increase temp, increase heart rate, and more is being discovered every year about their role in body changes. Mast cells can be thought of a “volume switch” to the human environmental response, including Immune activity. The science here is that Mast cells are the essential illness causing mechanism responding to the modern environmental.

3.9 Turning It All Off Vomiting is great for getting rid of toxins in the stomach. I am thankful for the human body and its ability to vomit. I am also thankful that the human body is able to STOP vomiting at some point. Fever, sweating, everything autonomic is a great ability to have, as long as it can be controlled. This control should fit perfectly to the environmental stress. The autonomic system has a very finely tuned on/off mechanism, which works well as long as the environment makes sense. Cooling and heating the body is nearly a full-time job, and for the most part the human body has a very narrow body temperature throughout the day. The autonomic nervous system is supposed to manage body temperature, not the HVAC system. Mast cells, when activated, are not easy to deactivate. While most of the response mechanisms of the body are outfitted with automatic “shut off” switches, Mast cell activation in turn causes more Mast cell activity. This activation cycle continues to build bigger and larger responses to environmental stresses. This leads to more pronounced changes in the human body.

3.10 The Immune System and the Autonomic System Are in Constant Communication The intricate layers of the immune system, and the interconnected wiring of all the organs probably deserves a lot more detail and attention. I have included what I think is relevant to the main theme of mast cell compartment is an ancient system that is up fully upgraded to the Earth of 2020. The rate at which the environment has recently changed outpaced the human species ability to evolve. This environmental

3.11  Simplified Summary

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gap is also increasing stress triggered illnesses from imperfect adaptations. While there is overload of some stress in modern environment, other areas cause adaptation from the lack of stress. The human body evolved overlapping and multipurpose systems as a mechanism to conserve energy and resources. At the crossroads between the Nervous system and the Immune system is the Mast cell compartment. When the environment pushes the human body, Mast cells push the body right back into the environment. Understanding the entire immune system is not necessary. But most people should understand that every part has a purpose, actually several purposes. As an Allergist/Immunologist I was taught that the purpose of Mast cells was to make humans itch or sneeze in response to allergens. That may be what Mast cells are best known for, but seasonal allergies are not why humans have Mast cells. Mast cells also cause unnecessary swelling and can erode joint spaces. Also, not in their main job description. Mast cells are the major adjustable component that is sensitive to the environment. This concludes the background information for the examples that follow. The central idea has been that the human body does not fit in its current environment. One major part of the body that senses the external environment, and also manifests changes of the body from environmental stress. This background is necessary as we will be migrating to discuss different major changes to the human environment, and not only how the environment changed but how we responded. Hope of being healthy is not lost to time, as humans are capable of conquering the environment, we are also capable of changing ourselves.

3.11 Simplified Summary The Immune system was born out of necessity, and it was also a very long time ago. The Earth has greatly changed in the past 500 million years, and life has changed with it. The relationship between life forms and other life form is a major environmental stress, and can be detrimental to life. Every human body is equipped with an Immune system and autonomic nervous system, and they are amazing but suited for a different world. Like a deer frozen from sensory overload in the headlights of an oncoming car, the mechanisms that were necessary for human survival are becoming dysfunctional. Key Terms • Barrier Immunity: The Physical borders of the body and the environment. Consisting of skin, and mucous membranes. • Mucous Membrane: A diverse number of specialized barriers, such as mouth, nasal passages, lungs, and digestive and reproductive surfaces. Not as thick as skin, and usually contains more nerves and Immune parts as these tend to be where infection happens.

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• Mast Cells: The main character of this story. An Immune cell. A Nerve Booster. The major sentinel of the body connections to the environment, and the effector of the body’s adaptations to the environment. Kind of a big deal. • Symbiosis : When two forms of life co-exist for the benefit of both. • Parasitosis: When two forms of life co-exist, with benefit to one, and harm to the other. • Evolutionary Tango: A dance with two partners. Throughout time life has evolved through the interaction with different forms of life. The co-evolution of parasites and symbiotes with specific host leads to interdependency of those in the hosts environment. I made this up, so its not actually in any science books.

References Dudeck A, Suender CA, Kostka SL, von Stebut E, Maurer M.  Mast cells promote Th1 and Th17 responses by modulating dendritic cell maturation and function. Eur J Immunol. 2011;41(7):1883–93. https://doi.org/10.1002/eji.201040994. Epub 2011 Jun 6. PMID: 21491417 Fries BC, Varshney AK.  Bacterial toxins-staphylococcal enterotoxin B.  Microbiol Spectr. 2013;1(2) https://doi.org/10.1128/microbiolspec.AID-­0002-­2012. PMID: 26184960; PMCID: PMC5086421

Chapter 4

House Dust Mites

4.1 The First Allergists and the Worst Allergy For most of the History of Medicine (up until 1900 or so), it is important to keep in mind that many of the concepts of modern-day science, like the Immune System, where not yet discovered. Despite lack of scientific knowledge about the mechanisms, infectious and allergic diseases still affected many humans throughout all the ages of history. While Arabic Physicians were actively inoculating their patients to small pox and other infectious disease, most of the European Physicians were in a difficult situation—their findings had to agree with the all-powerful Roman Catholic Church. In the 1553 (470 years ago), one of these very powerful humans, John Hamilton the Archbishop of St. Andrews in Scotland, was recorded to suffer from a disease of the lungs for several years. He enlisted the assistance of Italian Physician Gerolamo Cardano, to help him breath. The accounts of this tale are variable, however Bishop Hamilton was reportedly wheezing to the point he had difficulty speaking. Cardano, an Italian of many talents, was a contemporary of Leonardo Da Vinci. Cardano observed the Archbishop for several weeks, to diagnose his breathing condition. He made recommendations to cover the mattress with very tightly woven silk, remove cloth pillows and use leather coverings in furniture. Aside from silk and leather having absolutely no place in any Catholic Archbishop’s bedroom, the bishop made a recovery. Because of the bedroom renovation, the Archbishop went on to father at least 6 illegitimate children before he was executed for treason. While the allergen could have been dust mites, fomites, or catamites, encasing the bedding let the Bishop breathe better. Gerolamo Cardano’s documentation is generally considered the first account of the use of “allergy avoidance” as a means to control symptoms. This physician was also a mathematician, scientist, and astrologer. His presumption was that the feather mattress that the Archbishop was sleeping on was “heating up the spine.” While this may seem like a dated hypothesis, there is a very high likelihood that his mattress © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5_4

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was infested with dust mites, as well as the airborne particles that we now describe as “Allergens.” Not to be outdone by the Italians, about 50 years later, Flemish Physician Jean Baptist van Helmont recorded that asthma was a condition that originated in the lungs, and represented a “spasm of the tubes that carried air.” These observations were not published or credited to him until after his death, as they contradicted the Church’s beliefs at that time. A Full 150 years after Gerolamo Cardano first improved an allergic condition by removing an allergen, English Scientist John Floyer was working on the concepts of inhaled particles, specifically allergens such as dust, as the cause of asthma. The year that this is credited to him is 1698, and this is nearly 100 years before Edward Jenner was pushing the first vaccination. Interesting, Floyer may have also been the first to record food(fish) to be a source of asthma. While these historical examples are widely known and accepted, they don’t necessarily have much to do with the modern world, or the changes that have occurred to how humans live. However, it is very clear that house dust mites are a major cause of allergic disease. In 1987 the World Health Organization declared House Dust Mites a cause of allergic asthma, and eczema (The Journal of Allergy and Clinical Immunology, 1989, 83, pages 416–427). The obvious next step after noticing this alarming trend would be to take steps to enforce building standards to result in the decreased exposure to dust mites. Despite the historical significance, as well as the prevailing opinion of the world’s allergists for over 40 years, there are a lot more dust mites in today’s human homes than ever before.

4.2 A Toxic Long-Term Relationship I try not to limit my jokes about 2020s reality TV when I discuss the modern-day definition of a parasite. But a parasitic relationship is something that almost everyone can understand. A relationship requires at least two members, and a parasitic relationship is qualified by one of those members living off the other and causing harm. Dust mites are parasites; however, they are best known as a major cause of allergies and asthma for hundreds of years (Fig. 4.1). Pollen, pet dander, and even mold spores are the other major allergen groups, but not considered parasites.

Fig. 4.1  Dust mite timeline. As far as historians can detail, dust mite as indoor allergens have been a trigger of respiratory illness for hundreds of years. However, shortly after the widespread use of air conditioning, futurist Dr. Thomas Platts-Mills declared the threat of dust mite triggered asthma as a world-wide issue in 1988

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House Dust Mites have been linked to asthma and allergies, but more interestingly is that simple exposure of any human to the particles will cause allergy symptoms. Prolonged exposure in many cases will lead to worse symptoms, and the humans that are exposed to them will go from allergy symptoms to allergic disease. Dust mite allergens can be considered a “gateway allergen,” in that exposure to these parasite particles alone can cause any human to develop allergic diseases. Humans are very special to these parasites, frankly they belong to human lifestyle. These parasites can survive in very harsh environments, but they thrive inside modern human homes. Dust mites need three things to live: 1. Moisture or humidity of 35–40% or higher 2. Human Skin scales—the more the better 3. Mold/Yeast to help them digest #2. The changes to how humans live in the past 50 years has made our environment an environment that has led to the planet Earth becoming a gigantic House Dust Mite House party. Unfortunately, we’re all invited. The warming climate, increased air recirculation, decreased ventilation, humidified air, and increasing population density have all been suggested as contributing to the dust mite population boom. Also, likely the widespread use of antibiotics (see microbiome) has also directly contributed to making this already recognized pathogen as popular and as toxic as American Reality Television.

4.3 Humans Are Food Becoming food for another life form is not the best way to stay alive, for any organism. Humans are referred to and widely considered to be the dominant species on the planet, and are at the tippy top of the Earth food chain. This is not entirely true—as house dust mites prefer human skin to almost all other type of food. Obviously, no human actually feels these mites chomping on their skin, the skin scales that they eat are shed into the environment. While some may argue that shed skin is just waste product, as we learn about the dust mite interaction which human mast cells, we discover that they have hacked human Immunity for their benefit (Fig. 4.2). Dust mites eat human skin, and they produce an enzyme that digests human skin. This enzyme is called many names, but Allergist call this “Der p 1,” but it is also known as cysteine protease C1. This is very similar to common Human kitchen enzyme papain, which is a meat tenderizer. Gross, but the analogy is actually a very important part of the evolved adaption to human indoor living. This protease is released into the air, and when humans inhale it—the mucous membranes(barrier) become inflamed and also start to lose water vapor. When the skin(barrier) is activated by these enzymes, it becomes itchy. Most people scratch their skin when they

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Fig. 4.2  The Author’s Interpretation of Immune “Hacking”. Similar to computer hackers that are able to use computer code to get the computer to do what they want, Dust Mites are able to stimulate the human immune system to get more moisture and more skin. Note, not drawn to scale, and is an allegorical representation of “hacking”

itch, thus removing skin scales to feed the hungry waiting dust mites. So is these two ways, dust mites get moisture and food from humans through direct stimulation of the human Immune system. Mast cells are the immediate defense to dust mites; however they get taken advantage of by these toxic roommates of ours. The digestive enzymes released by dust mites are directly able to bind to, and activate, mast cells. Mast cells are the first line defense, then direct traffic, and also communicate with nerves and other parts of the immune system. The original purpose of the mast cell compartment is very much along the lines of parasite defense, and house dust mites are parasites. House dust mites directly activate mast cells—in other words Mast cells are the receiver for this environmental parasite. But the human house dust mite relationship gets much more toxic, as activated mast cells call in the rest of the immune system to form memory responses. This are the beginning of Th2, or Allergic-polarization. Once Immune system in at the barriers

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of the body start becoming programmed to make allergy memories specific to dust mite, all the machinery is there for not only imperfect memory, but also to make allergy memory to anything else that comes around the barrier(dander, pollen, etc.) So not only does exposure to house dust mites greatly increase the risk of allergy to dust mites, but this parasite increases the risk of developing allergies to everything else.

4.4 Don’t Forget the Yeast Fixins’ House dust mites have an interesting digestive system, in that much of breaking down its food is completed outside mite’s body. Like the human gut, which is dependent on microbes to assist digestion, the mite digestive process depends on yeasts and molds to break down human skin to become food energy. Mold can be found anywhere there is humidity and food. Some of the molds that are functionally the best for dust mite growth, candida and trichophyton, are increasingly being recognized as being important allergens in skin disease (Fig. 4.3). It is not known how

Fig. 4.3  Molds that are needed for house dust mite growth. The key to digesting meat is to make it tender, or easier to digest. While the dust mite digestive system lives outside much of its body, it also heavily relies on yeasts that thrive in indoor climates to assist in digestion. These common mold/yeasts: Alternaria, Candida, and Trichophyton all greatly improve dust mite growth and multiplication. These molds are also allergens themselves

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long that these yeasts have been used to supercharge dust mite digestion, but we do know that when those specific yeasts are absent the environment, there are generally fewer dust mites as well. While there has been no direct study to correlate, microbiome disruption likely contributed to the loss of protective bacteria from the skin. Activity such as increasing usage of “antibacterial” soaps and washes, as well as heavy use of oral antibiotics in the past few decades probably reduced the “good bacteria” that used to cover and protect human skin. Either way, killing bacteria makes room for yeast. When a space for organism gets vacated, nature fills that space pretty quickly. So, it seems that as the amount of human microbiome related digestive issues have exploded since the 1980s, that the likelihood of microbiome driven skin issues has also increased. Thus the additive yeasts helped make the food(human skin) easily digestible for dust mite multiplication.

4.5 Its All About Pumping Iron Human bodies shed several dozen grams of skin scales per day. This can really add up over time. That’s a lot of food for house dust mites, however there is slightly more gross scientific facts to this story. House Dust mites are very dependent on iron, and the human body is usually really good about not wasting iron. Typical shed skin scale contains virtually no iron. How then, do dust mites get the iron that is necessary for their life cycle? Itchy skin, or more specifically flakes of skin from itchy people, actually contains iron. This is a mind-numbing realization of nature’s ability to adapt to changes in the environment. Unfortunately, this change has been to make humans a better source of food for house dust mites. Allergy patients have a high tendency to have iron deficiency anemia. At this point is not proven that the increased skin turnover is a major loss of iron in atopic patients. However, an iron deficient body primes mast cells for itchy action. It has been proven that skin from patients with atopic dermatitis has dramatically increased amounts of iron. There is very disgusting circle of life, that humans are being farmed for moisture, skin, and iron. Allergy is bad disease, many additional bad things come with it. Mast cells are the key connection in this adaptation, and much of what is felt by humans effected by house dust mite allergy is because of the human mast cell activity. The inescapable cycle of stressor, inflammation, then chronic hypertrophic response—follows humans all the way home, where we sleep, where we eat, and do other stuff. Like it or not, human beings are food for these little critters and mites have perfectly evolved to human modern lifestyle comforts.

4.7  The Inflammation Does Not Stop with Allergies

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4.6 What Are House Dust Mites? What exactly is a house dust mite? Scientists think human houses have only been around for a little over 10,000 years, plenty of time for evolution of a smaller species. More importantly, modern houses which include temperature control, humidity control, I.E all the comforts of energy efficient climate control at our fingertips, have only been widely available for the past 40–50 years. This modern house-style has led to accumulation of house dust, there can’t be house dust mites without house dust. These mites are not going anywhere, they’ve been around as long as humans have lived indoors, and this includes areas such as ancient Egypt, and even early Mesopotamian cultures. We know this, or believe this, not because they had microscopes back then, but because archeologist attribute the first culture to have cloth and bedding to be the ancient Egyptians. House dust mites are exactly that, tiny microscopic bugs that are in dust. Yes, the dust in every human’s house is alive, and a part of the environment. These mites inhabit nearly every home in modern civilization. There is a direct correlation with the total amount of house dust mite particles inside of the building to the extent of human suffering of the residents. What is interesting is that the progression of modern science and medicine as well as climate control has directly led to the overwhelming infestation of house dust mites, despite the long-held knowledge that this might not be good for humans.

4.7 The Inflammation Does Not Stop with Allergies There are molecular patterns in nature, and all humans are born with the innate ability to recognize and response to these patterns. The things on the Immune System that recognize these patterns are called “Pattern Recognition Receptors.” In the case of dust mites, the pattern that is recognized is also the major allergen—their digestive enzyme, the meat tenderizer. There are over 20 recognized allergens that come from dust mites, and scientists have figured out the function of most of them. Most of the allergens are crucial to the process of turning small bits of human into food for the mites. The more dust mite enzymes in the air, the more these patterns to be recognized by nasal and skin mast cells. Mast cells are site of the major recognition of dust mite enzymes. Keep in mind this molecule recognition is innate, and every human alive has this recognition. This means 100% of every human on planet earth has some level of Immune response(inflammation) when exposed to dust mite particles. Now, depending on variables including volume and duration of the exposure, the continued innate recognition of dust mite particles eventually leads to a memory response. This memory response results in MORE mast cells into the area affected, and more local mast cell activation the stronger the long-term response.

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The major result of this inflammatory cycle is called “Sensitization,” in that if someone is “sensitive” to house dust mite, they will have a larger immune response when they are exposed to the particles. When the WHO organization first made the statement on 1987 the estimated number of people sensitized to dust mites was between 5% up to 30%. In 2018 it has been documented that dust mite sensitivity is >50% in many places. Repeated exposure to Allergy sensitizers increases the amount of Allergy the human develops. Dust mite sensitivity is the major allergic contributor to Asthma, and technically this was recognized 500 years ago in Scotland. Between 1980 and 1987 the CDC estimated that the prevalence of asthma increased from 3% to 4.1%. That year in 1987, dust mite sensitization was considered a health threat on a world-wide scale. In the years most recently, the incidence of asthma in the United States was 7.2% (2018), with a predicted 500,000 emergency room visits for the disease in 2024. (PMID: 34529643) The CDC reported that 8% of the USA had active asthma and a whopping 14% of the population reported a diagnosis of asthma at some point in their lives. In the past 10 years, scientists have unfortunately been learning that the total burden of inflammation does not stop at Allergy and Asthma. Asthma was found to increase the risk of heart disease by a huge number, close to 50% (PMID: 28433577) This is a higher rate of cardiovascular disease compared to being exposed to second hand smoke, which is 25–30% relative risk of heart disease. Second hand smoke being outlawed in many public buildings. A study looking at over 100,000 humans showed a greater than 60% risk of developing Rheumatoid arthritis (PMID: 26314811) And a country wide study from Sweden showed that asthma in children is highly associated with non-inflammatory conditions such as anxiety, depression, and sleep disorders (PMID: 35861116). This study also found a connection between asthma and autoimmune conditions. Cross-wired pathways of inflammation can lead to a confused memory response, and memory responses are never perfect. Dust Mite triggered inflammation is being found in conditions that are outside the normal range of allergic disease. That means that there is a direct correlation between what dust mites can do to a human, in addition to causing asthma and other allergic diseases. I personally believe that the large prevalence of iron deficiency in the United States and developing countries is related to the unmeasured losses from skin turnover. Clearly this will not be the entire cause of this deficiency, but this is a modern medical problem that has yet to be adequately explained.

4.8 100% of Clean Homes Have Dust Mites A common response I hear from patients when the have a dust mite sensitivity is that “they have a clean house.” That is likely true, and there does not need to be visible dust on Furniture to be an exposure. There just has to be people living in the home. There have been many studies on different methods of killing dust mites, and very few of them are better than the methods used in the 1700s, such as using

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nutmeg oil to repel dust mites. Avoidance measures, which are also very helpful, have not been remarkably improved in the past 500 years. Humans cannot run or hide to get away from the house dust mites. Dust Mites are everywhere and the more any human is exposed, the better source of food that human becomes. The higher the level of allergic disease, the more inflammation, leading to more skin and moisture for the mites. The recommendations on cleaning and avoidance have been stable for nearly 40 years, and these also mirror the environmental changes of the last 40 years. 1. Keep indoor Humidity Levels below 40% 2. Wash bedding in very hot water 3. Use of Dust mites approved coverings for bedding

4.9 I Give Up, Feed My Worthless Human Body to the Mites To recap: the human species is losing the war for dominance of Planet Earth to dust. There is more of these mites than ever before in human homes, directly correlating with the explosion of asthma and allergy related conditions. There has never been a proven way to safely rid the home by killing them off. Worse than that, the innate defenses of the body are automatically triggered by these mites, and repeated exposure leads to allergic sensitization, then disease, then death by heart or autoimmune disease. Basically, the best advice the Allergists of the twenty-first century have been able to offer are methods of avoidance that were first popularized 500 years ago. Humans are unsuccessful with cleaning or killing them off; this in an unavoidable Immune trigger. Medicine can be effective for some of the symptoms of triggered mast cell activation (Itching/mucous), allergic sensitization, and even allergic diseases such as asthma and eczema. Symptomatic management is what our medicine can deliver, which basically just makes the humans more comfortable when they get farmed to be food for dust mites. The long-term inflammatory changes that lead to disease are not improved by these medications, and much of the time there is side effects from medications such and antihistamines and steroids. Humans are able to run away from the invasive species, and it makes a very clear health improvement. A German study showed that there is a dramatic resolution of childhood eczema simply by having the children live at an altitude above the survival radius of dust mites. This study was a near repeat of the initial studies performed in 1923 which demonstrated that asthma could be fixed at altitude, but then triggered by dust from the patient’s homes. While it is very encouraging that the subjects skin improved dramatically, we can’t really send 8–14% of the population to the top of a Mountain for 6 months.

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4.10 Sensitization Is a Two-Way Street There is no available option to eradicate this invasion. While 100% of humans will be triggered by the dust mite, the number that are affected to the point of disease has increased dramatically in the past few generations. The modern world belongs to the dust mites, and the human race has handed it to them. However, there is a very important step between exposure and disease—sensitization. Sensitization is an increased Immune Response; in other words the Immune system has started to put more force behind the response to dust mite exposure. As stated before, the rate of sensitization is as high as 50% in some places of the USA. There is a very valid and evidenced based method to control, and prevent, the diseases that develop from dust mite sensitization. We call that process “Desensitization.” This may be one of those long medical terms, but this one actually makes sense. Stopping the disease process starts with changing the immune message. There is a natural pattern associated with dust mites that triggers activation leading to sensitization. This very much involves the mast cells. However, the proven process of desensitization presents the signals to the human immune system in a different way. Over time, the continued desensitization to environmental triggers can turn off the memory immune responses from building up and turning into disease. This process is powerful, and currently it is the only method available that is considered able to reverse the process of asthma. There are at least two different methods currently proven to be able to desensitize the human body. Allergists have been calling this process “Immunotherapy” but it should probably be rephrased to “Allergotherapy,” or “desensitization.” Injection Immunotherapy takes purified proteins that have been extracted from the dust mites themselves, and injects them through the skin(barrier.) This process starts out with low amounts of the protein being injected and then increasing doses over time. The evidence of the dosing that is effective is only a few milligrams of the actual protein to be injected every 2–4 weeks. The longer a human is given Immunotherapy, the longer the therapy lasts, and the more effective it is. The other form, sublingual Immunotherapy, uses the exact same types of extracts, but has the human place them under the tongue for absorption through the barrier. There is currently debate amongst allergists about which is better, more effective, etc. But I look at the question as “one of these is WAY better than no desensitization.” Desensitization does not make it “safe” to be inhaling dust mite proteases; however it can stop and reverse the progressive Immunologic responses that lead to development disease. That is such a powerful statement. This is a proven weapon in the war, one that just might give the human race a chance to survive this invasion. Think of the dust mite invasion/epidemic as a futuristic Science Fiction story, in which the human race is trying to colonize a faraway planet, but there are these invisible microscopic eight-legged organisms that have started to make some of them sick. The humans that become sick seem to be better at becoming food for these organisms. What then would the Astronaut Doctor hero of our story do for these colonists? Keep them comfortable as they became sensitized, until they

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develop trouble breathing? I think that after seeing the number that are sick more than double within one human generation that there would be widespread monitoring of sensitization, and then immediate desensitization to prevent actual sickness affecting the population. It makes a great story, but also sounds very expensive. Asthma is expensive, CDC estimates that $50 billion dollars each year are spent on asthma in the United States, and nearly 4000 dead. With 26 million Americans affected, that budgets out to around $2000 per person per year. That is close to the recent statement of the American Thoracic Society which estimated in 2018 that the annual cost of asthma was $3266 per person. That does not begin to include the additional disease conditions that are being found to associate with asthma. It very much seems that asthma is already a very expensive condition. In a way all modern humans are like colonists on an alien world—that is full of environmental stimuli to which humans are not adapted. The humans need to not give in to the hordes of mites whose digestive secretions make them sick. The human race needs to take back our planet, but the first thing we need to do is keep our snot in our nose, air in our lungs, skin on our bodies, and iron in our bloodstream. To do that, humans need to stop the biologic process of sensitization.

4.11 Simplified Summary The molecules that house dust mites release into the air are able to engage and activate the Immune system of 100% of humans born on Planet Earth. While we cannot make a verified statement that dust mites have completely evolved to hack human biology for survival, it is happening all over the world. Avoidance, when possible, has been a therapeutic treatment long before the invention of the microscope. In addition, there has yet to be an effective method for eliminating these parasites from human homes. Mast Cell Activation from this parasite causes symptoms immediately, but also directly leads to more mast cells, and then leads to Immune memory for Allergy. The development is called sensitization, and over time sensitization leads to larger and larger Immune responses resulting in human disease. The Immune responses here do nothing to help the body fight off the parasite, but actually help the parasite gets its food and water. Key Terms • Allergy Avoidance: Removing a human from an allergic trigger, or removing an allergic trigger from the environment of the human. Works every time. • Sensitization: The process of engaging, and then progressing, building a larger Immune Response (usually Allergy) to something in the environment. • Der p 1: An particle released into the atmosphere that “hacks” human biology into providing more skin and moisture for dust mites. • Desensitization: Using the ability to adjust Immune memories, this process is able to reduce sensitization and avoid development of disease. Works most of the time.

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Further Reading Asano M, Yamasaki K, Yamauchi T, Terui T, Aiba S.  Epidermal iron metabolism for iron salvage. J Dermatol Sci. 2017;87(2):101–9. https://doi.org/10.1016/j.jdermsci.2017.04.003. Epub 2017 Apr 14 Forslind B, Werner-Linde Y, Lindberg M, Pallon J. Elemental analysis mirrors epidermal differentiation. Acta Derm Venereol. 1999;79(1):12–7. https://doi.org/10.1080/000155599750011624. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL.  Prevalence of iron deficiency in the United States. JAMA. 1997;277(12):973–6. https://doi.org/10.1001/ jama.1997.03540360041028. Molva V, Nesvorna M, Hubert J. Feeding interactions between microorganisms and the house dust mites Dermatophagoides pteronyssinus and Dermatophagoides farinae (astigmata: pyroglyphidae). J Med Entomol. 2019;56(6):1669–77. https://doi.org/10.1093/jme/tjz089. Nesvorna M, Pekar S, Shcherbachenko E, Molva V, Erban T, Green SJ, Klimov PB, Hubert J.  Microbiome variation during culture growth of the European house dust mite, Dermatophagoides pteronyssinus. FEMS Microbiol Ecol. 2021;97(4):fiab039. https://doi. org/10.1093/femsec/fiab039.

Chapter 5

The Human Ecosystem

5.1 In the Time of Chimpanzees, I Was a Monkey When my grandparents were my current age, Mid 40s, it was sometime after World War 2 but before color TV. At that in U.S. History, there were some pretty substantial “growing pains” happening in the Public School system. A few of these arguments eventually made it to the U.S.  Supreme Court. Not teaching an American History lesson here (personally, it ruined 11th grade) but US States ended up being forced to allow the teaching of evolution in school. Not only did this enlightened judgement end all prejudice and bigotry in the USA, but was instrumental to the subsequent explosion of human health research which followed in the next few decades. For the most part every single bit of modern medical advancement has been built or discovered due to the shared physiology of all life on earth. Understanding the similarity between species, this meant scientists could test their theories on animals, instead of humans. Every drug, therapy, procedure we currently use in human Medicine was first used in an animal model. Humans share about 98% of our genes with chimpanzees, and 90% with mice. Humans share much more than just genetics with the animal world. The sharing continues through to the products of these genes, how these products bind together and interact with each other, AND how these complex systems interact with the environment. Turns out, humans can test out lots of different ideas on the animals of the Earth. This landmark time in our history was not too long ago, only a few generations. Genetically speaking 100% of the genes I have come from my 4 grandparents. There has been no substantial pressure, or need for any type of DNA change, and this trend continues. All humans are very much a genetic amalgam of our immediate ancestors, especially those about 50 years ago. While this turbulent time changed much of our government, culture, and science there has been no change to human genetics. Likewise, there has not been much natural modification in Earth’s animal © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5_5

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genome. The same cannot be said for the bacteria that colonize or infect us, those microbes have evolved into nightmare versions of the species the grandparents of modern day humans dealt with. Right about the same time as the “greatest generation” was battling for the integrity of collective soul of the country, the use of antibiotics for infections became commonplace. While this was great for physicians and drug companies, it was an enormous evolutionary pressure for the super-distant genetic relative—bacteria. The widespread killing of bacteria began a pressure cooker for survival in which only the strongest bacteria survived. So, while only 2 generations of humans have come through in the past 50 years, there have been MILLIONS upon MILLIONS of generations of bacteria. The kinder, gentler sore throats of pre-1960s no longer exists.

5.2 Bacteria Have Evolved New Genes in the Past 50 Years, Lots and Lots of Them Penicillin was a big deal before television. The legendary discovery and subsequent manufacture into a drug initially came about by accident. Sir Arthur Fleming, the scientist credited with discovering the drug, was growing a bacteria called Staph Aureus in his lab when the unexpected occurred. His laboratory technique was a little messy, resulting in mold contaminating his experimental Staph growing. While moldy growth may look like raging hot garbage, Dr. Fleming noticed that the bacteria on the plate were kept in check by the mold. The name of that mold was “Penicillium notum,” and until that moment in history, Penicillium was only known to be good for making stinky cheese. Fleming initially did very little with the discovery. But another group of scientists reviewed the paper nearly 10  years later. Over the decade from discovery to utilization, scientists extracted the molecule responsible for killing Staph Aureus and named it Penicillin, after the original mold that produced the molecule. In the second world war Penicillin was utilized on the battlefield. Since its initial use, Penicillin has been estimated to have directly saved 200 million human lives. I mention this historical anecdote whenever my wife points out that my desk is covered in hot garbage, however she never lets me figure out if any accidental stuff growing could someday save millions of lives. The discovery of the antibiotic penicillin was solely due to its ability to kill Staph Aureus, which even 100 years ago was a major human infectious pathogen. Doctors had a solid decade of time that penicillin was able to kill Staph Aureus. The first strains of penicillin resistance emerged in Staph Aureus in the 1950s, less than a generation from the discovery. In the 2020s, there are no forms of staph Aureus that can be killed by old fashioned Penicillin. Penicillin resistant Staph Aureus traveled the Earth as the first bacterial pandemic, until Methicillin was invented in 1960. Staph Aureus was found with

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resistance to Methicillin in 1961. That was quicker than the first developed antibiotic resistance. Methicillin Resistant Staph Aureus (MRSA) had to develop or acquire a brand-new gene to resist this new antibiotic. Currently there are numerous bacteria with multiple antibiotic resistances, even some that are considered completely resistant to all known antibiotics. Yeast, which has a more complex basis for its DNA, has also started to evolve into a resistant species. Infectious bacteria multiply, mutate, and share their DNA with other species of bacteria. When one bacterium mutates and develops a better faster way of hurting a human than the other bacteria, that mutant becomes dominant. Dominant Until one of those mutants develops an additional better/faster mutation then becomes dominant. The cycle of growth and change continues to this day. We are tracking dozens of new pathogens, superbugs, and struggling to come up with new antibiotics to kill them. More than just MRSA, there is pseudomonas, Acinetobacter, Klebsiella, e. coli all now developing or acquiring new genetics to survive against our medicines to kill them. It may come off as Science Fiction that drugs that kill bacteria actually are responsible for making bacteria unkillable. What doesn’t kill bacteria (nature) makes them stronger. If a patient with a bacterial infection takes an antibiotic that kills 99.99% of the bacteria causing the infection, that still leaves 0.01% alive and able to infect. Most of the time the Immune system finishes the job and clears out the survivors. Sometimes people have impaired Immune Systems from chronic illness, and this gives a little boost to bacterial survival. Hospitals, nursing homes, and other healthcare facilities tend to be breeding grounds for “superbugs” as these are the places where Immunocompromised people like to hang out. Penicillin, in the 1940s and 1950s used to be dosed at 100–200 mg per dose, in 2023 the effective doses are much higher. The first recorded public use of penicillin was on a woman named Ann Miller. The hospital record of this is in the Smithsonian institute. She had developed a blood infection that had kept her sick for weeks. Her temperature was reported to be as high as 107 Fahrenheit. After a dose of nearly 200 mg Penicillin, her fever broke for the first time in weeks. She started to make a recovery with routine injections about every 2–3 h. Current upgraded “penicillins” used for Hospitalized patients, we use 2000–3000 mg every 4–6 h, and often times this is combined with an additional drug to make the form a penicillin more stable against bacteria. This increased amount of drug required for treatment is NOT entirely because of developing resistance. Along with developing resistance, there have been many other factors that have developed in the past 50  years that make current infectious bacteria a very different enemy. This constant nearly annual evolutionary upgrading of bacteria has not only confused Immune systems, but made humans much sicker than they every did previously. Sir Arthur Fleming, when accepting the Noble Prize for his dirty desk in 1945, made a statement that urged caution in the use of this wonder drug, as he was concerned about bacterial resistance. The bacteria he was culturing, Staph Aureus, has been resistant to penicillin for the entire time I have been alive.

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5.3 Some of These New Bacteria Genes Are Specific for Humans Antibiotic resistance of some type can be found in almost all infectious bacteria these days. There are more classes of antibiotics than just penicillins, and certainly more bacteria than MRSA. Resisting antibiotics is not the only trick bacteria have figured out in the past 50 years. Positive genetic mutation pressures have resulted in some strains of staph aureus have developed “superantigens,” which cause enormous action on the memory system. This action inflames a large host of very different innate and memory cells— causing a huge response from the entire Immune system. This is a distracting trick, because the Immune system doesn’t program to correct Kingdom (virus, bacteria, Mold, or Parasite) so the immune response is a misdirected attack. This allows that Staph to do its dirty work unheeded by an immune system looking to efficiently kill some staph Aureus. It is not completely understood when or where these anti-human genetics came from, but some of them were characterized before the 1970s. Some of the Immune-evasion tactics are actually “response-specific.” MRSA is found on the majority of affected skin in humans with eczema. This led to evidence that certain proteins produced by MRSA can re-program the Immune system. This is the ultimate in crossed signals and mixed imperfect memory. MRSA toxins can switch the Kingdom of Immune memory formed in response to infection, and shift it to more of a “parasitic or allergy type response.” The main defense that the human Immune system has against bacteria like MRSA is a highly energized form of Oxygen call “SuperOxide.” By diverting the Kingdom response from bacteria to Parasite/Allergy, the Immune system does not generate this SuperOxide, allowing the MRSA to survive. Pretty neat trick, if it didn’t make people itch so badly. Mast cells, living in the barriers of the human body, are capable of recognizing bacteria. Mast cells have detection methods especially for bacteria like MRSA, and other “gram positive” types of bacteria. In 2008 it was discovered that some strains of MRSA have developed the ability to directly block the mast cells bacterial recognition equipment. This is another example of the specialization that bacteria have developed in order to survive. So not only can MRSA outmaneuver the human body’s innate defenses, it hijacks them, and redirects them to produce a response that allows it to survive.

5.4 Many of These Changes Were Discovered Years or Decades After They Evolved in Bacteria We don’t know what human bacterial pathogens or symbiotes were like before the 1970s. Undoubtably species of bacteria that humanity hosts have become more aggressive, more virulent, and generally more hurtful year after year. Likely it has been a steady progression as the years went by due to increasing available options

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to fight bacteria, further increasing the pressure on the bacteria to change its DNA. Bacteria have greatly changed. Antibiotics have changed. Humans have not changed in that time frame. I am personally grateful for antibiotics, and have prescribed them tens of thousands of times. I have even personally used antibiotics a few times in my life, and completed the entire course almost twice. Human medicine will never kill every single bacterium, it only kills the weakest, selectively breeding the strongest, making it more and more difficult for the human Immune system every year. Antibiotics work by exploiting the difference between how humans and bacteria copy DNA. The faster the bacteria copy their DNA, the safer targets for antibiotics. The better our scientists and engineers get at antibiotics, the better the bacterial enemies become at reproducing and hiding from these changes.

5.5 This Steadily Increasing Use of High-Powered Antibiotics Could Only Lead to Good Things The need to continuously build stronger antibiotics definitely had some unintended consequences. The kind of consequences that give people lethal diarrhea. A kind of bacteria called Clostridium difficile (c dif.) started making people very sick with diarrhea in the 1990s and this trend continued through the next few decades. This specific bacterium makes toxins that directly cause damage to the lining of the colon. Over time, this bacterium developed its own antibiotic resistances and became better at infecting humans. The higher the number of different antibiotics someone took correspondingly meant a worse case of c. dif. From 1998 to 2009, the number of cases of c dif. Requiring hospitalization in the United States went from 25,200 to 110,600—an increase of over 400%. The reason these severe cases plateaued and have decreased since 2009 was not from new kinds of antibiotics, but because of the increasing adoptive usage of other bacteria. So, it was only this millennium that the collective community of Physicians and Scientists discovered that good bacteria are good because they don’t make room for bad bacteria. The best way to keep the human gut healthy, was to have non-toxic bacteria taking up most of the space in the gut. I think we can call them “good” bacteria, but let’s just say that that there is only so much room in the human digestive system. Bacteria in the gut that don’t produce toxins, that don’t try to break through the intestinal walls, and kind of just hang out and not provoke an Immune Response, that sounds “good.” Names are important, and humans tend to think of things as “good” and “bad.” Obviously, bad bacteria make people very sick. However, to what extent can we call bacteria “good?” IT is difficult to know what the optimal “good” bacteria were for the human gut, because humans started killing off bacteria before understanding that some of them should have been kept around. While calling bacteria “good,” might seem a little nicer than saying “less-toxic” the type of bacteria in human digestive tracts have been linked to obesity,

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autoimmunity, and even allergy. Some types of digestive bacteria contribute to human obesity, or other forms of human disease, that sounds “bad,” but the secret sauce for the “best” gut microbiome is still being sought. In the past decade scientists have been making hundreds of discoveries between the gut microbiome and human inflammation, this was completely unpredictable. While Humans were warned of the potential for bacterial resistance in 1945, and started to see evidence of this in 1950, it was only within one generation of humans that there has been an understanding of the long-term human consequences of antibiotic caused negative selection of bacteria. Having a healthy number of “good” bacteria is important for any part of the body that potentially has room for bad bacteria. Nature does not like empty spaces. There are products on the market for the skin microbiome, nasal microbiome, and genital microbiome. There is no plan to review any of these product here, however in the time that I have been a physician I have gone from not understanding probiotics to adding them to nearly every prescription for antibiotics. The human body is actually not a single organism but a veritable ecosystem of microscopic life.

5.6 Ecosystem, More Like Freak-O-System The phrase that “tall fences make good neighbors” is pretty well known. Rephrase to say that “good neighbors are the ones that exist but would never be known.” In other words, no loud noises, no excess waste products, no bad smells, and most importantly—they don’t invade personal space. The exact same thing can be said for the neighborhoods of the human body, like the skin, airway and digestive tract. These are also well known as the physical barriers of the body with the environment. This is also the very common place for the environmental sensor, the mast cell. Human bodies were never alone in existence, and have always required some level of quiet assistance from microbes. Unfortunately, there were at least two generations of aggressive bacteria killing before any human took notice. Immune pattern recognition is online at birth, and then Immune memory begin. Much of the Immune memory is from early childhood. The gut is a very important barrier, and is becoming an understood site of both pattern recognition and Immune programming. The gut mast cell compartment is believed to be largely responsible for the inflammation triggered from gut infections like “bad” E. coli, and quieted by “good” bacteria like lactobacillus (Song et al. 2021) and also a site that the protective bacteria can keep under control. In addition, the pattern recognition for diarrhea causing bacteria proteins is recognized and then stabilized through actions on gut mast cells (Feng et al. 2007). Now the whole concept of this book, is that environmental changes of the past half century or so have led to a lot of new levels of human misery. What does all of this discussion on the gut microbiome have to do with the “environment.” Just like the skin, and the airway, the gut is a barrier. It is important to realize that food never actually goes inside a human, it flows through a tube and comes out very different than when it came in, but it never directly enters the human body. The food that is consumed is broken down into various smaller particles (mouth), and then

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submitted to a series of acids, bases, detergents and other enzymes to separate all the important stuff out. Much of the immune system actually sits right at this border— called gut mucosal associated lymphatic tissue. This has more of the immune system localized to it than the rest of the body combined. So the entire process of digestion should commence without unnecessary inflammation or other actions from the immune system of the gut. There is building evidence that the gut barrier mast cells, the key receptor and signaling compartment are very important for the perception of pain in that area, and also the cause of motility disorders De Winter et al. 2012). Many of the bacterial adaptations found in the human digestive system specifically target the human immune system, including the mast cell compartment.

5.7 Gut Environment Is Also Important for Other, Non-gut Related Disease Aggressively dividing bacteria need to eat, and they can become a competitor for necessary micro and macronutrients. For example, nutrients such as choline and Carnitine are found in numerous foods, these are necessary for energy production, and also a healthy nervous system. “Good” bacteria don’t steal these nutrients, while some “bad” bacteria will actually use these micronutrients as an energy source, changing the compound from something useful to humans into a harmful chemical. In one example “pathogenic” gut bacteria will take choline and carnitine and turn them into “trimethylamine,’ or TMA. TMA is poison to humans, it reverses cholesterol transport and substantially increases the risk of developing heart disease. While not causing diarrhea, or direct inflammation, this in effect slowly poisons the human due to the type of bacteria in the gut.

5.8 But People Born Before 1976 Have to Fight These Bacteria Too, Right? Immunologic traumatic memory that occurs at an early age can have a lifetime of effects. Being infected with an involved pathogen as a child has substantial long-­term effects that do not occur if one become infected after middle age. The timing of infections is becoming very important as well, not only for bacteria, but for viruses as well. In 2021, amazing research was completed looking at the development of Multiple Sclerosis in the United States Military. The most interesting thing to me was that to be included in the study, the samples had to come from people that DID NOT have the EBV virus. Most of the samples were from people before the 20th birthday, but then developed the EBV infection years later. This linked infection with the virus to development of Multiple Sclerosis, only in people that were not infected in early childhood. This virus affects the developing world in the first few years of life, and they have less than 20% of the incidence of MS that is found in the United States.

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We know from the recent studies of the microbiome, that the Immune system is “educated” by the microbiome, and that tendency to develop autoimmunity can directly stem from more aggressive bacteria in tandem with the human.

5.9 Humans Killed the Water Too. Drinking Water Used to Be Alive That’s right, this planet is teeming with life to the point that all-natural water sources had bunches of living organisms. While these were never likely a significant source of calories or nutrients, it had life, so it was probably interacting with our bodies. Now keep in mind that water borne infections leading to diarrhea are still the number one cause of death in the world. However, this has developed from contamination of much of the earths water. Growing plants with fertilizer is commonplace now, and growing animals for food is also commonplace. This has changed our environment by changing the water. Freshwater quickly became full of angry, competitive organism once excess nutrients and animal feces got into it. The resulting idea was to sterilize the supply, which also killed off the algae and other non-harmful microorganisms.

5.10 Adding Algae Back to the Diet Improves Immune System Plants don’t usually hurt humans. The case of pollen is excused from this discussion; however the human Immune system does not recognize patterns from plants as alarm signals. There has been emerging evidence that many compounds that are found in algae, have a protective effect on the inflammation responses (Florez et al. 2017), and also can improve physical exercise performance (Gurney et al. 2022) and while the mechanism in humans has not been completed proven or unraveled, in the animal models of disease the protective effect of algae on the development of allergies was through the gut mast cells (Bae et al. 2013). It is difficult to find out when and where the water supply has had algae removed from it, however the event has occurred because of the adulteration of the water supply. Currently access to fresh water is limited in many places of the world, and there is no evidence that adding algae back to the water supply will prevent deaths from diarrhea. However, we know that algae were a part of every drop of drinkable water for 99.9% of human development, and not only is it a healthy food if consumed in quantity, it very well have some built-in calming effect to the human body that we have been unaware of until the most recent couple of years.

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5.11 The Skin Is a Bacteria Party Too While the gut microbiome has caused very noticeable problems, especially following the use of very strong antibiotics, the skin has also been found to be a unique ecosystem. There is a balance in the skin between different strains of bacteria, including bacteria that live on the oily secretions and those that exist in the barren wasteland of the dry skin of the arm. These bacteria also associate with some common yeasts, and we know that dust mites love to consume flakes of human skin that have yeast helping to digest them. There is very good information that the “commensals” or the bacterial microbiome of healthy skin is generally not very aggressive bacteria. However, the genetics of antibiotic resistance and for increased ability to attack humans (virulence factors) have been found in bacteria from very healthy skin. MRSA and the skin mast cell are very important contacts that activate diseases like eczema. It is very interesting to note that the Immune system will tolerate many bacteria on the skin, but if they become invasive, then the immune system will recognize their pattern and mount a defense. This may not sound like much, but it shows the level of developmental co-­ existence between human skin and the human skin microbiome.

5.12 How Do Humans Kill Bacteria Anyways? Antibiotics and antibiotic dosing have not changed much in the past 20 to 30 years, and I do maintain that it is completely the fault of the bacteria themselves for the changes to the human microbiome. Most of the antibiotics prescribed and dispensed in the United States are in the form that is taken orally. This should be obvious to anyone that has attended any form of school or daycare in the past 30 years. Antibiotics have clearly saved countless lives, and are true masterpieces of biochemistry and medicine. These are molecules that have been selected for their toxicity to bacteria, but lack of toxicity to human cells. The diversity of mechanisms and selectively are well beyond my scope, and certainly the time to prepare any type of meaningful explanation. I do not wish to point out one antibiotic being better/worse, more/less toxic than any other, as those data are highly complex. To keep things simple: Antibiotics stop the growth of bacteria. To measure the amount of antibiotic needed to stop the growth of bacteria, the clinical term “Minimal Inhibitory Concentration” or MIC is used. This is the amount(milligrams) of antibiotic per the volume of the target(human.) Most humans can be considered to have a “volume” of 60 to 70 Liters, I looked it up. Most of the MIC of the antibiotics used are 4 milligram per liter, or lower. Many of these bacteria/antibiotic combinations are below 0.5 milligram/Liter. This means to stop the growth of bacteria, the antibiotic going into the mouth should reach at least between 0.5 to 4 milligrams per liter. Looking at my own prescribing, the antibiotic which I prescribed the most of in 2021 was oral Cefdinir. The standard adult dose is 300 mg twice daily. Here is the data: 300 mg Cefdinir orally reaches a maximum concentration of 1.6 mg/L. 600 mg Cefdinir orally reaches a maximum concentration of 2.9 mg/L.

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Doubling the dose, does not double the body concentration. There is no deceitful math here, this drug is not completely absorbed, and results in pretty significant concentrations remaining in the gut through digestion. This is also data from very healthy people, not people that are actively sick, or that have slow moving guts, or malabsorption, or any other reason for inefficient absorption of the medication. Less than 100% of the common bacteria can be effectively controlled with these concentrations, looking at s. pneumoniae, the susceptibility was 74% of bacteria. Therefore because of the delivery mechanisms, there are bacterial resistance because only of ineffective amounts of the antibiotic reaching the target. Taking a pill by mouth, some of the antibiotic will remain in the gut. It is very common these days to recommend probiotics (good, neighborly bacteria) with the use of these antibiotics. Unfortunately, urine and stool are not the comprehensive final destinations of these antibiotics. Several of the commonly prescribed oral antibiotics will be found at concentrations higher than 4 mg/L in human sweat, after a single dose of these antibiotics (Hoiby et al. 2000). This is good, for treating skin infections. This may not be so good for keeping good bacteria happy and healthy on the skin. I was unable to find a comprehensive list of antibiotic concentrations in sweat, but I think that there is more to be learned here.

5.13 “I Prefer the All-Natural Methods” Great. Awesome. If the stuff that was infecting us was all natural. The bacteria that are currently infecting us, living inside us, etc. are anything but natural. This world that we are allergic to is the product of our scientific success. Using the gifts of nature to fight off nature seems like a nice harmonically balanced zen-like dream. Unfortunately, human versus bacteria fights are now only unnatural. There are absolutely no original bacteria that co-evolved with humans, the 1940s started the processes that got rid of them. The pressure that humans have put on bacteria has caused them to push back in ways that could have never been predicted. It would be impossible to weigh the astronomical number of lives saved from the use of antibiotics against the amount of problems the use of antibiotics has unintentionally caused. The human race is not able to escape from this new microscopic world that is now the new human ecosystem.

5.14 The “Auto-Brewery Syndrome” I recommend probiotics for almost all of my patients that go on antibiotics; however there does not seem to be any that are “the best.” This is a very exciting area of research and medical advancement that will eventually one day lead to improvements. Probiotics, I.E. lactobacillus and other like this are not generally considered harmful, and there have been very few complaints about side effects from the use of

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these “good” bacteria. A paper published in 2019 very much opened my eyes to the enormous amount of human ignorance that we have regarding our very own internal microbiome (Malik et al. 2019). In this case the human was under great duress from the legal enforcement body due to frequent ethanol intoxications. This was despite his repeated statements that he was not drinking. He continued to develop alcohol intoxication—enough to prevent him from legally driving. The trigger for this reaction was the ingestion carbohydrates, which the yeasts in his gut were able to ferment into alcohol. It took severe measures to clear him of this condition, but we would not call it an infection. There was no known Immune response. In reading this, it is important to know that the human body has absolutely no known mechanism for the creation of ethanol, and that it can only come from outside the body. This patient was affected enough that he could become legally intoxicated due to the production of alcohol from carbohydrates. While this is an extreme case, this clearly must be an underrecognized condition. With the sweeping alteration of the human microbiome from the use of antibiotics, and then the need for some microorganism to fill the gap, it is difficult to believe that there aren’t potentially millions of people affected by this condition—not to the point of intoxication, but possibly to the level of liver fibrosis, or other types of metabolic disturbances from chronic ethanol intoxication.

5.15 Summary There are no historical accounts of what bacteria that should live in the human gut or on the human skin. However, there is clear evidence that all human environmental barriers are affected by the changing aggressive genetics of these bacteria. There are patterns of active communication between the different micro-organisms that populate each niche, and also active communication with the human immune system. There clearly is a pattern or combination of bacteria that can keep the Immune system well controlled, and the one that is in current circulation is capable of not only turning nutrients into poison, but programming, or reprogramming, human immune responses to become allergic or even autoimmune. The interaction between the human microbiome and the human Immune system is only a piece of the importance of this relationship. I don’t think that there is any reliable data on which probiotics are “good” or “bad.” The generations of humans born into the era of antibiotics do not have the same ecosystems of previous generations. The infectious bacteria are more aggressive and harder to defend against, and the neighborly bacteria seem to have been deleted. In terms of going forward, the ability to identify specific bacteria or viruses as the cause of infection are becoming commonplace in walk-in clinics. Administration of antibiotics as injection, sparing the burden on the gut, has no evidence to be less intrusive on the human microbiome. Hopefully, the full implication of human microbiome changes will be understood soon, and with that will come better decisions on antimicrobial treatments.

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Key Terms • Microbiome: The combination of all microscopic life that live on or in a human body Like biomes on Planet Earth, microbiomes are interdependent on the local environment. • MRSA: Merr-Sa,” or “M. R. S. A.” Methicillin Resistant Staph Aureus—now highly dominant “bad” bacteria in human microbiomes. Byproduct of human scientific success. • Clostridium difficile: c. dif or “Sea Diff” A bacteria that is a frequent cause of life-threatening diarrhea that follows the use of antibiotics. • Trimethylamine: A chemical toxin that is produced in polluted human gut microbiomes. This is made from a vitamin-like amino acid “choline.” Choline is good for humans, this chemical is hurtful. There are others. • Algae: Microscopic plant life, no longer in human consumption, might actually be good for humans. • Antibiotics: Chemicals which are poisonous to bacteria, but not poisonous to humans. Usually cannot tell good from bad bacteria, or toxic from less toxic bacteria.

References Bae MJ, Shin HS, Chai OH, Han JG, Shon DH. Inhibitory effect of unicellular green algae (Chlorella vulgaris) water extract on allergic immune response. J Sci Food Agric. 2013;93(12):3133–6. https://doi.org/10.1002/jsfa.6114. Epub 2013 Apr 5. PMID: 23426977. De Winter BY, van den Wijngaard RM, de Jonge WJ. Intestinal mast cells in gut inflammation and motility disturbances. Biochim Biophys Acta. 2012;1822(1):66–73. https://doi.org/10.1016/j. bbadis.2011.03.016. Epub 2011 Apr 8 Feng BS, He SH, Zheng PY, Wu L, Yang PC. Mast cells play a crucial role in Staphylococcus aureus peptidoglycan-induced diarrhea. Am J Pathol. 2007;171(2):537–47. https://doi.org/10.2353/ ajpath.2007.061274. Epub 2007 Jun 28. PMID: 17600127; PMCID: PMC1934528 Florez N, Gonzalez-Munoz MJ, Ribeiro D, Fernandes E, Dominguez H, Freitas M. Algae Polysaccharides’ Chemical Characterization and their Role in the Inflammatory Process. Curr Med Chem. 2017;24(2):149–175. https://doi.org/10.2174/0929867323666161028160416. PMID: 27804878. Gurney T, Spendiff O. Algae Supplementation for Exercise Performance: Current Perspectives and Future Directions for Spirulina and Chlorella. Front Nutr. 2022;7;9:865741. https://doi. org/10.3389/fnut.2022.865741. PMID: 35321288; PMCID: PMC8937016. Hoiby N, Pers C, Johansen HK, Hansen H. Excretion of beta-lactam antibiotics in sweat—a neglected mechanism for development of antibiotic resistance? Antimicrob Agents Chemother. 2000;44(10):2855–7. https://doi.org/10.1128/AAC.44.10.2855-2857.2000. PMID: 10991872; PMCID: PMC90163. Malik F, Wickremesinghe P, Saverimuttu J. Case report and literature review of auto-brewery syndrome: probably an underdiagnosed medical condition. BMJ Open Gastroenterol. 2019;6(1):000325. https://doi.org/10.1136/bmjgast-2019-000325. PMID: 31423320; PMCID: PMC6688673. Song X, Pi S, Gao Y, Zhou F, Yan S, Chen Y, Qiao L, Dou X, Shao D, Xu C. The role of vasoactive intestinal peptide and mast cells in the regulatory effect of Lactobacillus casei ATCC 393 on intestinal mucosal immune barrier. Front Immunol. 2021;12:723173. https://doi.org/10.3389/ fimmu.2021.723173. PMID: 34899686; PMCID: PMC8657605

Chapter 6

Humans Are What We Eat (Quantity vs Quality)

6.1 Its Starts with the Babies As early as the 1920s, scientists were working on infant formula made from soy. Even 100 years ago there were youngsters were dairy or milk allergic at that time. Human babies are entirely dependent on other humans for their food supply. While human babies are adorable, they also need nearly everything else done for them in addition to finding food. As a father, I can vouch for being “udderly useless” in the production of human milk. The responsible physiology for milk production historically has been the mother’s, but as nature likes to keep things interesting, milk production is not 100% infallible. Infant formula, or supplemental food for human babies, is absolutely critical to our society. And while the history of baby food is long and sorted, “wet nurses” have been an occupation for longer than “Physician.” The World Health Organization is underfunded, and has a huge job. The health of the world is in WHO’s hands. The WHO recommends that for the first 3–6 months of an infant’s life, that food should nearly 100% come from the mother’s production. Thank goodness for organizations like this, because I was starting to feel inadequate during the feeding of my children until I realized that they put the responsibility only on women. All joking aside, it can be hurtful emotionally if there is difficulty with milk production, and our society already thrives on attacking women’s self-esteem. Infant formula is absolutely necessary, and breastfeeding is an empowered choice. I am hoping to discuss some of the world-wide patterns of changes in how humans feed their children. I was born in 1976, and was not a child that was ever fed with breast-milk. My mother was healthy, but had some health issues. Thankfully nearly 50 years later she is still around and doing OK. While never had the benefits of passive antibody transmission, past my mid-40s I will guarantee that my immune system is an absolute ninja-warrior. While I was not optimally given the human delivered fatty acids for early brain development, I think my brain turned out at least average. I am making © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5_6

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this statement due to the emotional attachment that human adults have to human children, and that while recommended for “optimal” infant nutrition, breast feeding is not 100% necessary for early human development. The United Nations children’s fund has an annual budget around 2.5 billion dollars. The United states has about 1 birth for every 40 births throughout the world. Roughly 2.6% of all new children born globally, are born in the USA. Globally, our country uses 10% of all baby formula produced. We are using 400% more infant formula per child than the rest of the world, and the WHO has several statements that remark on the global overuse of infant formula and reliance on Mother’s milk. We sell about five billion dollars-worth of baby formula annually in this country. Much of this goes through the very necessary WIC program established by the act of 1966. The Year infant formula was covered by these programs was 1974. The amount sold in the United states is shockingly high compared to the rest of the world. Whereas less than 50% of children born in the United states are exclusively breast fed, and in the poorest populations of the US, less than 40% get any breast milk at all. Now there is scientific evidence that food insecurity is directly linked to increase risk of death, abuse, and other negative health consequences. It is possible that 50–60% of American children are unlikely to be born to mother’s incapable of making milk, but more likely vocational, social, or other additive pressures on the person limit the ability to commit that human body to become a producer of human baby food. I’d hate to make a statement that mother should feel the responsibility to breast feed their children, there is already way too many unhealthy negative pressures placed on women. Breastfeeding infants is a defining aspect of being a mammal, and if and when possible should be supported. Breast milk substitution has been a necessary aspect of survival for as long as humans have been recording history, and clearly the food scientists still haven’t been beat or matched the original. There was and will likely always be the need for infant formula, and investment and research for improvement in the formulas will be a worthwhile endeavor. I never had the grades for Veterinary school, but I do recognize that humans belong to an order of vertebrates that nurse their young. “Mammals,’ in honor of the mammary glands, which most physicians refer to as “boobs.” What could the possible reason be for the increased pressure to forgo the health data, and the millions of years of evolution, to provide an expensive product ($1500/month out of pocket.) It would be terrifying to think that there was an oligarchy in power that was directly putting pressure on government funded programs to reduce an activity that was proven to increase the health of vulnerable children of low socioeconomic status, right? I mean, no decent society would ever let their government or large corporations to hurt their population. Human milk contains human Immune system. Not only does human milk contain everything necessary for the development of an extremely young human, it also directly aids in defending their body from contagious infections. Human milk contains human Immunoglobulin, which is a protein made up of amino acids the exact same amino acids as every other digestible protein. However, Immunoglobulins in

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breast milk are absorbed in a way allowing human babies to supplement the immune system. This is known to occur for at least the first 6  months of life, and likely beyond. Immunologists are aware of this phenomenal mother to baby transfer from studying children born without fully functional immune systems. It is not currently known how babies absorb and utilize these Immunoglobulins for their protection.

6.2 The Mouth Is a Mucosal Barrier, But More Like a Bouncer Most modern-day humans don’t eat much food that doesn’t taste bad nor have strong texture. In fact much of our food has been changed to improve taste/texture. Some foods go through a lot of processing to make them easier to chew and swallow. There is a pattern to the barrier defense, and this pattern of distribution of Immune programmers seems to be set up to keep humans from becoming allergic, or having an “Immune-Overreaction” to the stuff they put in their mouth. The mast cells in the mouth program for defense, and the promotion, of allergy. People that have allergies will occasionally report itching or burning of the mouth eating allergic foods; that’s mast cell release of histamine. They were there the whole time, ready to make the mouth itch. Mast cells are not the only defense mechanism in the mouth, there are other kinds of immune cells. I’ll not try to overly complicate the description, but there are many lymph nodes that collect immune signals from the mouth and throat. The locations of these gateway Immune Cells (in the gateway to the digestive system) are clearly set up in a manner that is deliberate. The area of the mouth underneath the tongue is special, with ready access to areas draining to lymph node; however no mast cells. Allergists and Ear Nose and Throat doctors for several decades in the USA, and even longer in Europe, have been using this organizational Immune programming for the treatment of allergies. Sublingual Immunotherapy is the treatment of a human’s allergies by placing the stuff that causes allergies under the tongue. This treatment is effective much of the time, and the sensation of itching if the mouth usually goes away after a day(mast cells) but the continued regular use continues to deprogram the immune system. Mast Cells are like muskets, once they go off, they need some time to reload. Regular daily sublingual saturation with the allergen trigger can keep local mast cells from activating and developing allergies in the mouth. There is no conclusive or even remote evidence that longer time in the mouth will return less immune activation from food. However, I’m trying to make an argument for increased chewing for many other reasons.

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6.3 Sugar, High Fructose Diets, Even Sugar-Free Sugar, Reduce the Sensitivity of the Vagus Nerve to Calories The autonomic nervous system gets its name because it does stuff automatically. The body gets hot, it automatically starts to sweat. The body gets too cool, it automatically starts to shiver. If the blood pressure drops, usually the heart rate increases to keep the blood flow normal. The actions of the autonomic nervous system, these automatic actions of the body are in response to the influences of the environment on the body. When the immune system gets involved, like with a really bad infection, the temperature of the body can become critical, sweating and shivering can occur simultaneously, blood pressure can drop so low that the heart rate cannot match. These very normal and healthy autonomic responses can become hurtful if they are amplified by other systems, particularly the immune system. The autonomic responses of the body can be “reset,” and a good example is high blood pressure. Most people would consider a health blood pressure to be 120/80, and physicians are very well taught that the body organs are built to handle the blood in that pressure range. Pressure goes too high, organs are damaged, too low, organs can die. Over time close to a decade with increased blood pressure, the body and its organs can get adjusted to a higher blood pressure, and at that point if it is dropped too quickly to normal (120/80) the effect can be hurtful. Every autonomic response of the body can be amplified or reduced, in the short term and long term, based on the signals from the environment. While using terms like “programming” are fairly obvious to people that grew up with computers in the home, that term was not in general use when stuff like blood pressure was characterized. Eating sugar directly rewards the brain starting in the mouth and continuing into the stomach. This effect occurs even without a change in blood sugar, meaning “sugar rush,” is really a “dopamine fix.” However, diets that are high in sugar or sweetener overload that signal, and chronically lead to maladjustment. Over time the signal mechanism becomes blunted, and the reward signal requires ever higher amounts of signal to achieve. The impacts of this time of high sugar signal programming is problematic and drives increased calorie consumption. The communication between stomach and brain/body becomes blunted and the amount of digestive energy dedicated becomes blunted as well. Not feeling full not only encourages calorie consumption, but impairs digestion, which leads to incomplete achievement of a resting state. Personally, I had a sugar habit that I am not proud of, and even before I was middle age it had clear effects on my weight and energy level. Not only did I have to quit sugar, but I had to quit diet soda drinks as well. The sweetness of the diet soda had the same programming effect on me as sugar itself, just without the guilt. I personally dropped about 25% of my body weight (315 pounds to 250 pounds) in about 6 months removing “sweets” from my diet. I can personally attest that over

6.5  A Tale of Two Vitamins (Vitamin B12 and Vitamin C)

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time, the total amount of food it took me to feel full decreased substantially adhering to the removal of sweeteners of all forms from my diet. The concept that needs to be highlighted here is the escalating nature of the process. This is one of several processes leading to obesity and other forms of chronic bad health. The shut off switch never needed to exist, because the “foods” that need to be shut off were not in existence during the development. Aspartame was approved for addition into human foods in 1981, prior to that point it was saccharin or nothing. The effects of chronic consumption of diet soda being associated with central obesity was published in 2015 (PMID: 25780952); this study was conducted over 9  years. These sweeteners do not seem to be immediately harmful, but the long-term adjustment seems to lead to unwanted outcomes. Making humans fat is not a criminal act, but this stuff did not exist for human consumption prior to 1981.

6.4 There Is in Existence an “Anti-Inflammatory Diet” I will frequently get the question, “what can I eat to strengthen my Immune system,” and immune boosting supplements are a big business. Can’t find a lot of data behind, but the problem is that it’s not “boosting,” anything, it is “removing extra work.” The more difficult to process, higher oxidized, processed, food, the more angry the microbiome associated with that digestion, the more work is necessary by the immune system—this is wasted effort (Cavicchia et al. 2009).

6.5 A Tale of Two Vitamins (Vitamin B12 and Vitamin C) A “vitamin” is a chemical in food that is “vital” or necessary for life. There are more than two of these that we know about, but these two: Vitamin B12 and C, are two that really tie the room together. Vitamin B12 is a fragile molecule, certain types of cooking and preparation of food can remove the B12 before the human even has a chance. The absorption of B12 starts in the mouth, saliva contains a “bodyguard” molecule “R-factor” that binds to B12 to protect it from stomach acid. The stomach also produces a completely different “bodyguard,” molecule called “intrinsic factor.” Lastly, this complex of vitamin, molecule, has its own VIP entrance through the gut wall—the B12 transporter. All of this happens within the first part (30–60 min) of digestion, and right after the stomach, this drama queen of a vitamin gets the red carpet VIP treatment. Vitamin C is sour on the whole early admittance deal, and is a little jealous of the B12 treatment, as it has to wait until the bitter end of the good part of digestion, right before food spends its last minutes as food and right before it turns into poop. The terminal ileum, contains the direct entry for vitamin C (Fig.  6.1). So in perfectly working digestive system, B12 is absorbed very early under specific and difficult circumstances (Fig. 6.2). However, if the human has a dry mouth, eats too fast, has too much (or too little) stomach acid and enzymes, the

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Fig. 6.1 Intestinal absorption of Vitamin C—The majority of the human body’s absorption of Vitamin C occurs in the terminal ileum, and bacterial overgrowth of this area can effectively lead to deficiency in vitamin C in the body, but not from the diet

B12 can fall apart and the human can be starved of it. Vitamin C is more robust to the changing digestive environment, and can wait until the end. Pretty much the only thing that can break this molecule is competition from other life forms, like bacteria and yeast that weren’t supposed to be invited to the party.

6.6  De Fish in C, Vitamin C Deficiency, Scurvy

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Fig. 6.2  Site of absorption of B12. The vitamin B12 has several parts of the human digestive system dedicated to protecting, and absorbing it. In the mouth, “R factor,” is in saliva, and in the stomach “Intrinsic Factor” is released to protect the vitamin until it can be officially absorbed into the body

6.6 De Fish in C, Vitamin C Deficiency, Scurvy In the days of the British Empire, there were many wooden ships that would sail all the way around the world. Not only were they slower moving ships that modern day, but they required a larger host of sailors to operate them. There was a plight on the professor of sailor, and it was not pirates. It was Scurvy. It is estimated that about two million sailors died from scurvy in the time between 1600 and the late 1700s. The British military was held together by the power of its navy, and it needed healthy seamen. The long voyages in the wooden ships meant that food had to be kept on board that would not rot, or whither in the unconditioned storage. So much of the food was dried grains, and/or salted meats. This is essentially a diet that is lacking in fresh fruits and vegetables, and le to the deficiency of vitamin C, and the condition Scurvy. Scurvy is a nasty condition of the gums, skin, and then eventually the rest of the body. The British Military had surgeons posted to their military ships, and it was one of those famous surgical sailors that ran a clinical trial on 12 or so sailors that developed scurvy. In 1747, a British naval surgeon ran a clinical trial on stricken sailors. Dividing the 12 sailors with scurvy into 6 groups of 2 each. Dr. Lind gave each group of 2 different foods in an attempt to treat the illness. Some of the men received vinegar,

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others sea water, but the group of 2 that was given oranges and limes recovered very quickly from the affliction of scurvy. Not much is known about the remaining 10 sailors, but we hope that Dr. Lind brought enough Oranges for everybody. Prior to the British adoption of the nutritional supplement for all seamen in 1795, it was common for HALF the member of a crew to die on a long voyage from Scurvy. While many people have heard this story, the connection I want to make here is that Scurvy is a fatal “man-made” disease. The environmental stress of taking humans away from their normal habitat (in this case, land) removed access to fresh food that was necessary. Salted meats and grains had been around for centuries, but removing humans away from any source of fresh fruit or vegetable was an unnatural environmental stress. If modern medicine were only that easy! None of the Sailors that got scurvy before they got on those ships, and all that was needed was some delicious citrus. This is a clear example that the sailors on those ships were not doing anything wrong, it was not their fault, they were put onto those several month voyages without the intention of robbing them of a vital nutrient. While the nature of vitamins were not really understood at the time of Dr. Lind’s involuntary clinical trial, the first recorded instance of a food curing a disease. Food in this case may appear to be medicine, but this disease was an artificial environmental change, removing humans from sources of fresh food. Removing this environmental change, in this case bringing the food to the human fixed the condition. There are modern day cases of scurvy, although we should probably come up with a more catchy or less insulting name. The freedom of choice can allow humans to avoid fresh fruits and vitamin pills for long enough to deprive the body of vitamin C. However, bacterial overgrowth can affect the absorption of Vitamin C (Fig. 6.1) In this case, a change in the gut environment can lead to the same disease.

6.7 The Second Managed Disease: Pernicious Anemia Notice the term “managed” and not “cured” autoimmune disease, as Pernicious Anemia was fatal 100% of the time until an intervention was developed. The first technical autoimmune disease that was managed was Thyroid disease, and was first treated with sheep thyroid hormone in the 1890s. The first use of Insulin to manage Diabetes (also autoimmune) was in 1926, and both therapies weren’t vegan or kosher, they were taken out of animals and then injected into humans. Thyroid Disease and Diabetes led to fatality from the failure of a hormone that the body produced, thankfully sheep and cow endocrine glands were close enough to human glands to make it work. Pernicious Anemia is an autoimmune disease of the stomach, and wasn’t treated by feeding or injection animal stomachs, it was a different form of animal—the liver Deficiency of vitamin B12 causes a multitude of health problem before leading to eventual death from failure to make new red blood cells. These early cases of B12 deficiency were termed “Pernicious Anemia,” because the course was gradual and observable, and therefore predictable.

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These patients had months of slowly advancing debilitating disease prior to the final act. As the humans that developed this condition had developed a characteristically anemic appearance, it also took enough time to result in death that it gave the Physician-chef’s of the day lots of time to treat it with diet. Even though food is most definitely not medicine. The first successful management of this disease was a room temperature raw beef liver consumption in the range of over a pound per day. Cooking the beef liver destroyed the necessary vitamins, so the treatment was then turned to a raw beef liver injection. Not to be outdone by the greatest surgeon of all time, Whipple, the other Physicians working on Pernicious Anemia found an astonishing discovery that separated out this condition from the hormone crazy physicians of the day. Patients that had died from Diabetes were known to have inflamed pancreas, and likewise patients with Thyroid Disease had grossly abnormal thyroids, but Pernicious Anemia while localized to an organ, small part of the stomach, it was not a large or visible change to the stomach (Fig 6.3). Science at that time showed that the beef injections were necessary, as eating the liver would not be enough to result in successful treatment of the disease. While large amounts of raw beef liver had to be consumed to overcome the difficulty in digestion, raw beef liver was just very difficult to eat. Cooking the beef liver destroyed the B12, and patients did not recover when fed cooked beef liver. Because of the level of protection that is necessary to get B12 from food(R-factor and Intrinsic Factor), a small disruption in absorption can cause a big problem like a fatal disease. The discovery of “Intrinsic Factor” came about with another disgusting experiment, refeeding sick patients partially digested raw beef liver. Humans with Pernicious Anemia that consumed already partially digested raw beef liver (then vomited) by another person, restored the ability to absorb the vitamin from their food. The digestive factor was called “Intrinsic” and that loss of Intrinsic Factor was the cause of the disease. It wasn’t until 30 years later that Pernicious Anemia was determined to be an autoimmune disease directed at a part of the stomach. So, the first three treatments were high volumes of raw liver ingestion, smaller and more disgusting ingestion of raw beef liver that some other human had started to digest already, or the beef liver injections. In the very first case of “food is medicine,” 100% of the humans chose to get the shot instead of changing their diet. The Immune system attacks a part of the stomach, and over 100 years after the slimy discovery, it is commonly known that the stomach’s “Parietal Cells” are the target of the Immune system. It is easily managed by regular B12 injections; however much like thyroid disease, diabetes, the absolute cause is still unknown and modern medicine can’t reverse or restore the organ dysfunction. Prior to the initial management of Pernicous Anemia, the average time of survival from diagnosis was 1–3 years (Bunn 2014. Nowadays, I will occasionally hear that a patient was given some strange food to “cure” an autoimmune disease by some Quack Internet doctor, I remember that less than 100 years ago some people were given regurgitated raw beef liver by Nobel Prize Winning Physicians.

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Fig. 6.3  Parietal cells site of host injury in Pernicious anemia—The small part of the stomach, identified under microscopes as the “Parietal cells,” are attacked by the human system in pernicious anemia. While it is only a small area, this small area prevents the B12 in the diet from being absorbed, and this results in the previously fatal condition “Pernicous Anemia”

6.8 There Have Always Been Toxins in Human Diet While the absorption of friendly vitamins from food is tightly regulated, the protection from overabsorption of potential toxins is also tight. I do not wish to impose a myth about food, there has been a change, and prior to the most recent couple of decades there has been plenty of harmful stuff in food. I am not aware, nor have I gone into and looked at what other countries around the world have been doing about their food supply, but in the United States there used to be a lot of people that

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were directly or indirectly killed by food. Either by contamination of the food product, or spoilage along the way from the source, something had to be done to monitor the food supply to protect the population. The creation of food standards was necessary, and fines and other penalties have been instituted to keep the food supply safe. My lifetime has not known a major world-wide disruption of the food supply, however starvation continues to be a notable problem across the globe. Food can kill people in a number of fun ways. Bacteria can multiply in food not only as a cause of spoilage, but bacteria can increase in number and volume in food that the drive a large amount of inflammation from the infectious organisms or from the activation of the immune system. Salmonella for example can cause a serious infection with only a few of the individual bacteria. Mold in food kills people differently, generally but the release of toxins—aflatoxin spoilage of grain is estimated to result in 40,000 cases of death each year. Not to mention worms, parasites, amoebas, and all other manner of beast that can spoil food prior to consumption. Antibiotics are a great way to prevent the growth of bacteria, and very obviously they have been added to the food supply at various parts of the chain.

6.9 Dietary Proteins Should Only Be Purchased from the “The Leftorium” Kindergarten was a lot of fun, filled all the crafts and other art projects that eventually led me to decide on a career in science. Most humans have been in such an environment, and have picked up the wrong kind of scissors. Left-handed scissors. Nearly complete indistinguishable from normal scissors, except they magically just did not work in the right hand. They fit into the right hand, however it mangled paper instead of a clean cut. This wizardry, this magical “one-handedness” is also important for numerous processes in the body. This lack of symmetry, this handedness, is actually extremely important to how many processes in the body work. The body’s Alphabet, or Amino Acids, all are like a pair of scissors, in that they have a “right” and a “left” form. The exact same chemical compound can look exactly the same, however when it comes to function, the wrong hand just doesn’t work right. Nearly 100% of the Amino acids that humans use the L-Amino form. Both the L and the D forms are found in nature, however nearly all the complex organisms (Plants, Animals) make 100% of the proteins using the L-form. That leaves some bacteria as a major source of life and/or nutrients that actively make or contain the D-amino acids. Scientists have been finding a very high rate of the D-Amino Acids in things like human cancer, and there is a active brand of science that is looking to the role that the D-Amino acids have in disorders of brain function like depression and schizophrenia. There is very little data about the actual bad problems that these D-aminos have in the human body, but it is very clear that the overall total amount that is being

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consumed and absorbed is increasing. I have contacted several labs companies over the years, and tried to arrange testing for the D-amino acids that could be found polluting my patients, however I have yet to find any lab company that can perform the study. Humans did not land in this century without an adapted ability to protect ourselves from these amino acids, there is an enzyme named “D-Amino Acid Oxidase,” of DAO that lines the human gut, to protect the rest of the human body from accidental absorption and incorporation. Benzoic Acid—a food preservative frequently used in processed foods—is an inhibitor of the enzyme that eliminates D-amino acids as a toxin. It has been only established in 2008 that the more D-amino acids in a food, the less the nutritional value (Khoronenkova and Tishkov 2008). Humans use Amino Acids in several different ways, and one very important function is the building of proteins. There is very solid evidence that D-amino acids cannot be used to become part of proteins. There is a use for the D-amino Acids when instead of becoming a structure, they become a signal. All neurotransmitters (Table.  6.1) are only one or two simple chemical reactions from becoming brain juice. Now, many of these are “essential amino acids” which means the only way the body can get them is from the diet. In turn, that means the proportions of the D/L in the gut, and the ability to filter these out, is also essential. Benzoate, the preservative mentioned above, is widely considered harmless. While it may not be directly poisonous to the body, there are several animal studies showing direct effect on production of Thyroid hormones, as well as behaviors that mimicked anxiety. What is reassuring is that in biology, any Serotonin or Melatonin Table 6.1  Amino acids and neurotransmitters

Amino acid L-Glutamate L-Glycine L-Choline L-Tyrosine L-Tryptophan L-Tryptophan L-Histidine D-Aspartate D-serine Amino acid L-Tyrosine

Neurotransmitter L-Glutamate, GABA L-Glycine, GABA Acetylcholine Dopamine/norepinephrine Serotonin Melatonin Histamine D-Aspartate D-Serine Hormone L-Thyroxine “thyroid hormone” L-Norepinephrine D-Tyrosine D-Thyroxine (much less potent as hormone) D-Norepinephrine “false” neurotransmitter L-Tryptophan Serotonin/melatonin D-Tryptophan Serotonin/melatonin No difference in final structure

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that might be produced from D-Amino will still give the same hormone/neurotransmitter at the end. This is not true for D-Tyrosine. Both hormones made from Tyrosine still maintain their one-handedness, and in effect act as blockers of the real hormone. D-norepinephrine is defined as a “false neurotransmitter,” which blocks the actions of L-norepinephrine. L-norepinephrine is the action point of drugs for depression, obesity, sleepiness, and attention deficit. Ma et al. (2021) found that gut microbiome was directly associated with the presence of D-tyrosine in patients with neuromuscular disease, and in that paper there is a recovery of that patient with the use of gut-microbiome shifting antibiotics. Physicians use drugs that are mixtures of both “right-handed,” and “left-handed,” and there is not a single drug that is used on neurotransmitters that has the same actions when used as both a right handed or a left handed form. However we use the actual drugs like Epinephrine, or Norepinephrine, it is well known that only the L-form is the biologically active form. So it is established in nutrition circles that there is an increasing amount of the D-aminos, when Human life needs only the L-aminos. The essential amino acids (only found in diet) contain the main amino acids that are affected by the widespread use of herbicides, which alters their concentration in Human diet as well as microbiome. The D-Amino forms are found in cancer, mental illness, and imbalance is found in many other conditions. There clearly is a norepinephrine deficiency, but it is not known how much of actual norepinephrine in humans is the in active or the false form. Mast cells rely on the signal of norepinephrine to allow stored fat to be burned (PMID: Finlin et  al. 2019), and targets of drugs that increase norepinephrine to reduce inflammation are mucosal(barrier) mast cells. (PMID: Burchett et al. 2022) This is a very strong example that the environmental sensing sensors of the body the mast cells have very different responses in different tissues. The mucosal(barrier) mast cells decrease the level of inflammation they produce when signaled with norepinephrine, while adipose (fat tissue) mast cells increase the level of fat burning action when receiving the norepinephrine signal. Thus, disruption of the functionality of norepinephrine in the body can have direct effect on the brain, but also the immune system and overall metabolism.

6.10 “Round Up” the Wrong-Handed Aminos The herbicide glyphosate, or “Round up,” blocks the plant, fungal, and bacterial ability to make the L-amino acids. This kills plants that are sensitive to the compound, as these are the molecules necessary for life. The plants that can tolerate glyphosate, end up actually concentrating this in their tissues. What effect that this has on the gut microbiome, or the ability of the human body to keep the D-amino acids out is not known. This compound affects L-Tyrosine, but actually increase the amount of L-tryptophan in plant tissues (Vivancos et al. 2011). This compound was brought the market in 1974. It was considered “safe” because the pathway that it

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blocks (makes: phenylalanine, Tyrosine, and tryptophan) does not exist in animals like humans and for crying out loud makes these amino acids essential to the human diet.

6.11 Pile Hate on Glyphosate (GLEE-fo-sayt) This molecule has been blamed for a host of human health issues in the past 30+ years. This compound was first sold in 1974, and quickly became the most common used herbicide (plant killer) world-wide. An herbicide it is like an antibiotic for plants, can affect undesirable plants but leave the desirable ones still living. This is a great way to invent a pesticide because it poisons an enzyme that humans do not have, so there can’t be any direct effect on humans. There are plants that are resistant to glyphosate, and they contain all the Phenylalanine, Tyrosine and Tryptophan necessary (Fig. 6.4). These plants also absorb glyphosate, and it is estimated that the average American consumes an unknown amount of glyphosate each year. There has been an NIH funded research study reviewing both farmers with occupational exposure, and consumers of products containing this herbicide (PMID:

Fig. 6.4  Glyphosphate. The mechanism of action of this herbicide turned food additive is to shut down amino acid production. Try writing words in English without “F,” “Y,” and “W.” F-phenylalanine, Y-Tyrosine, and W-tryptophan. While this kills plants that cannot process this chemical, it is present in food, and can effect the human gut microbiome. Neurotransmitters and hormones made from the mirror versions of these amino acids do not work like they are supposed to work

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30612564), and it was not possible to determine how much is ingested, only that there was. Humans are only part of the human ecosystem, and bacteria do not abide by the laws of asymmetry, they make the D’s and the L’s of everything. In fact, some forms of D-molecules can only come from bacteria (D-lactic acidosis.) The glyphosate blocks the “Life” versions, and shifts it to a “D” friendly environment. These D-amino acids—D-phenylalanine, D-Tyrosine, and D-Tryptophan are usually filtered out by gut protection enzymes. These toxins have always been present, however the glyphosate in food can inhibit bacterial formation of the L-versions, increasing the portion of D. The body cannot make proteins with the D-version; however, Tyrosine and Phenylalanine not only make proteins, but they make neurotransmitters such as Norepinephrine, Epinephrine, and Dopamine. Serotonin made from D or L is the same serotonin. However, D-norepinephrine acts as a “false” or blocking neurotransmitter, and gets cycled through with the L-norepinephrine. D-dopamine also acts on the L-dopamine receptor but changes the signal. Tyrosine(D and L) can also be used to make thyroid hormone. However L-Tyrosine makes Levothyroxine and D-Tyrosine makes Dextrothyroxine. This mirror version of thyroid hormone is 500 times less potent than the real version. Measuring the amount of D-amino acids in a human body is not commercially available. D-Lactate, or D- Lactic Acid is available commercially, as a marker for gut bacterial overgrowth, and can be a cause of metabolic acidosis. The effect of D-norepinephrine on attention, memory and learning is not known. The effect of D-dopamine on behavior and impulse regulation is not known. The actual burden of D-amino acids in the human body is not known. However, the number of behavioral therapeutic drugs for attention deficit, depression, bipolar, and psychosis related behaviors is markedly increased in the past 50 years. L-Norepinephrine is also one of the few molecules made by the body that can turn off mast cells. Mast cells absorb Tyrosine and chemically turn it into dopamine. They also can take tryptophan and turn it into serotonin, or even melatonin.

6.12 Simplified Summary Human Health and Human food have always been understood to be directly linked. The monitoring of the food supply has focused on protection from infection, bacteria and spoilage, and in the mostly successful effort to provide adequate calories and micronutrients for a growing population, the composition of the food supply has changed, with immediate, long term, and likely not yet understood impacts on human health. This environmental change, including the changes to the microbiome, has made the barrier of the gut an increased source of mast cell activation and stress on the human immune system and nervous system.

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Key Terms • Vagus Nerve : The largest connection of the Autonomic nervous system, connecting the human back and forth to much of the rest of the body, including the brain. • Anti-Inflammatory Diet: The listing of different dietary foods based on the average effects on human body inflammatory markers. • Pernicious Anemia: The disease name of Vitamin B12 Deficiency. This is a complex degenerative disorder that is both autoimmune and vitamin deficiency. Largely treatable with injections of the purified vitamin. Pernicious means a slow and progressively harmful action. • Scurvy: The disease name of Vitamin C deficiency. This is also a degenerative disorder from either dietary deficiency or from environmentally caused malabsorption of the vitamin. • Glyphosate: A herbicide that affects a chemical pathway that makes amino acids. These amino acids are all considered “essential” to the human diet, because humans do not make them. While plants treated with this are generally resistant, the chemical remains in the food and can effect the human microbiome.

References World Health Organization Statement on Infant Formula Bunn HF. Vitamin B12 and pernicious anemia—the dawn of molecular medicine. N Engl J Med. 2014;370(8):773–6. https://doi.org/10.1056/NEJMcibr1315544. Burchett JR, Dailey JM, Kee SA, Pryor DT, Kotha A, Kankaria RA, Straus DB, Ryan JJ. Targeting mast cells in allergic disease: current therapies and drug repurposing. Cell. 2022;11(19):3031. https://doi.org/10.3390/cells11193031. PMID: 36230993; PMCID: PMC9564111 Cavicchia PP, Steck SE, Hurley TG, Hussey JR, Ma Y, Ockene IS, Hébert JR.  A new dietary inflammatory index predicts interval changes in serum high-sensitivity C-reactive protein. J Nutr. 2009;139(12):2365–72. https://doi.org/10.3945/jn.109.114025. Epub 2009 Oct 28. PMID: 19864399; PMCID: PMC2777480 Fowler SP, Williams K, Hazuda HP.  Diet soda intake is associated with long-term increases in waist circumference in a biethnic cohort of older adults: the San Antonio longitudinal study of aging. J Am Geriatr Soc. 2015;63(4):708–15. https://doi.org/10.1111/jgs.13376. Epub 2015 Mar 17. PMID: 25780952; PMCID: PMC4498394 Finlin BS, Confides AL, Zhu B, Boulanger MC, Memetimin H, Taylor KW, Johnson ZR, Westgate PM, Dupont-Versteegden EE, Kern PA. Adipose tissue mast cells promote human adipose beiging in response to cold. Sci Rep. 2019;9(1):8658. https://doi.org/10.1038/ s41598-­019-­45136-­9. PMID: 31209239; PMCID: PMC6572779 Khoronenkova SV, Tishkov VI.  D-amino acid oxidase: physiological role and applications. Biochemistry (Mosc). 2008;73(13):1511–8. https://doi.org/10.1134/s0006297908130105. Ma L, Keng J, Cheng M, Pan H, Feng B, Hu Y, Feng T, Yang F. Gut microbiome and serum metabolome alterations associated with isolated dystonia. mSphere. 2021;6(4):e0028321. https://doi. org/10.1128/mSphere.00283-­21. Epub 2021 Aug 4. PMID: 34346706; PMCID: PMC8386414 Vivancos PD, Driscoll SP, Bulman CA, Ying L, Emami K, Treumann A, Mauve C, Noctor G, Foyer CH. Perturbations of amino acid metabolism associated with glyphosate-dependent inhi-

References

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bition of shikimic acid metabolism affect cellular redox homeostasis and alter the abundance of proteins involved in photosynthesis and photorespiration. Plant Physiol. 2011;157(1):256–68. https://doi.org/10.1104/pp.111.181024. Epub 2011 Jul 14. PMID: 21757634; PMCID: PMC3165874

Chapter 7

It’s About Time to Eat

7.1 Life = Finding Food Versus Not Becoming Food There are many “states of being” for the human body, but to keep things simple we’ll just describe the main opposing states of autonomic function: “fight or flight to not become food,” and the opposite state of “rest and digest all that yummy food.” To keep this entire exercise simple, we are going to assume that all of the predator/ prey, ecosystem, evolutionary pressures that shaped the human species over the last million years can be summed up as “energy efficiency.” Efficient use of energy requires separation between these rest/digest and fight/flight. Any life form has trouble feeding itself if it is also fighting off predators, or running from them. Life has to switch between these different states, and the higher complexity of the brain, the less it can be trusted to efficiently manage energy. Most humans consider ourselves the apex predator of Planet Earth, but we have lost the old fight/flight response system. There is still lots of power in the system of the body that keeps humans from becoming food. Think out it, humans can store energy to the point that we can go for 7 earth days or so without eating, however if any human becomes food just once that human is dead. There is great importance in both finding food and avoiding becoming food, however finding food to eat and digest is remarkably easy for many humans and there is not much time spent on this activity. That leaves the remainder of time spent running for safety from their place of employment. Humans don’t have tusks, horns, wings, fur, venom or any of the cool adaptations our earthly competition developed. Humans developed big beautiful brains(some of them), for memory, communication, problem solving, planning and learning. While the human brain is the pinnacle of evolutionary ingenuity, it’s also the cause of some of humanity’s biggest problems. Finding food has been the largest limiting survival factor. However, once humans didn’t have to constantly worry about where the next meal was coming from, those brains started coming up with © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5_7

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really creative stuff. Unfortunately, now-a-days there is so much to occupy human brains, humans often don’t have adequate time to eat. More importantly, they way humans were taught to eat was built on tradition and not on science. When any silly human tries to “eat and run,” they screw up both the eating and the running. This is actually quite an obvious description. Prior to most professional sporting competitions, right before go-time, many successful athletes enjoy a large turkey dinner, a pint of ice cream, soft lighting, and the entire musical catalog of Michael Bolton. Put any human body/brain combination through that gauntlet and it will taste victory. OK, exaggerated examples aside, nobody thinks that would be an effective pre-game ritual. Prior to most sporting competitions, the best athlete’s clear their mind of distractions, move, stretch, keep the body warm, and only then crank up MB’s greatest love songs. Preparation is also called, “getting in the zone,” but it is preparing the body to be most efficiently in a “fight or flight” zone. Any athlete will admit that pregame rituals are important for successful participation in sports or other related activity. Competition is not the only state, or “zone” that proper preparation can move the body into. While exciting to watch on television or in person, the physical intensity of these competitions is actually how hard life was for most humans for 99% of development. Before human civilization could get sushi delivered using an application on a hand held device, life was mostly just physical activity. Not only was food scarce, much of the day was spend in the hunt for food, or even in the preparation of food. There were less meals during the day, and it took longer to eat them. Keep in mind, no human alive right now has access to the food sources that developed our species. Food is easier to obtain, quicker to prepare, quicker to digest, higher calories but less nutrients, and occasionally includes poisonous additives. While diseases of the digestive tract and food choices got their own chapter, the human body is very much rejecting how it is being fed as much as what it is being fed. The human species has survived through ice ages, comets, earthquakes, wars, plagues, and even the Kardashians. More than hunger, there is resilience in human DNA. We will survive this, but it helps to know where the product doesn’t meet the design.

7.2 Food Always Stays Outside the Body Which Means It Is Part of Our Environment But it goes inside the body, right? Food goes into the mouth and comes out the bottom as poop, and never actually enters the body. However, food interacts with the borders of the body for the entire time it is being turned into poop. The parts of the body, the immune system and the autonomic nervous system are the interfaces between the body and the external environment. So the amount of time it takes to

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eat allows for efficiency of digestion, which minimizes the inflammation food can cause and maximizes the extraction of nutrients. Digestion is complicated, and in the drive to simplify it, our digestive systems have substantially weakened. One of the most shocking concepts I learned in Doctor school was that if a human body is constantly fed, it loses its ability to digest. WTF? (Why Then Food?) Feeding a human body around the clock leads to “villous atrophy” which is a loss of the tiny little digestive glands that line the gut. No, this is not the human body rejecting food, but that would make a pretty cool tie in to the title of the book. This is because the product does not meet the design. Digestion is hard work, and the body needs to recover from it. Be nice to that human body, don’t overfeed it. Personally, I lost weight by skipping breakfast, eating a small lunch, and then a healthy, low carbohydrate dinner. I did not make this up, it was recommended to me by my Chiropractor—who saved my life. Now a days, we call the low carbohydrate diet “keto,” and we call skipping breakfast “intermittent fasting,” and they are both wonderfully healthy ways to feed the human body, and likely closer to the patterns that humanity evolved that strongly favored “Fight/Flight” to “Rest/Digest.”

7.3 Fasting Is Probably How the Body Should Be Most of the Time Constant feeding leads to destruction of the gut. This was pretty shocking to learn, and can be avoiding by feeding the human in short amounts, several times per day, or leaving the gut to rest overnight. Gut rest is very important, but not intuitive. Resting from physical exertion, that is intuitive. Most people understand that if the human body is made to walk constantly, 24 h per day, the human legs eventually get really bad at walking. Incessant physical activity makes that human unable to walk at all. The body needs rest too. How convenient that both need to rest, seems like one should take a break with the other one acts. “No swimming for at least an hour after eating.” While there is no real link between the development of muscle cramps and food ingestion prior to swimming, there is certainly quite a bit of wisdom and the recommendation to avoid activity for at least 60 min following ingestion of food. While this is a recommendation to avoid cramping, it also helps prevent regurgitation of undigested food into the pool. When physicians measure the stomach timing, we will typically order a test called “Gastric Emptying Study.” This is thrilling, because the name also states what the test actually measures. This test is nutritious—we feed the human radioactively labeled (completely harmless) eggs and toast, and then measure how long it takes for the labeled food to leave the stomach. Normal times—the most of the food has moved out of the stomach after 90–120 min. This small, 350 calorie meal, takes 2 h to move through the healthy human stomach. The stomach can sense calories, and higher calories usually means more time in the stomach. Like most Americans,

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I haven’t had a meal under 500 calories ever. Not being very good at math, this time of digestive timing matches up to not puking in the pool, however it does not match up to 3 meals a day. By the time the stomach has emptied 90% of breakfast, humans are eating lunch. Fasting refers to not eating food. This is counter a billion years of nature’s influence on the importance of food to living things. However, for the body ‘not eating’ is also the best time to get stuff done. As much as every instinct in every living creature screams “eat food!” whenever it has food, the pressure was always due to the scarcity of food. Biology was not prepared for an abundance of food. While the abundance of food is unnatural, it doesn’t prevent humans from eating it all up. Continuous feeding refers to tubes going into the digestive tract, usually providing 60 to 90 calories per hour. This constant workload to the digestive tract is destructive. Outside of forced feeding with tubes, modern day human behavior is not much better to the digestive system. Too much of a good thing, or even too much of great thing, can be bad. Intermittent fasting, or “not eating most of the time,” is exactly how proper digestion fits into a 24 h day.

7.4 Explain Intermittent Fasting to a Sixteen-Year-Old “All work and no food makes human muscles unable to work”. “All food and no work makes human gut unable to digest.” “Separating the physical aspects of the human body between work mode and food mode makes both of them much more efficient.”

7.5 Explain Intermittent Fasting to a Six-Year-Old “The body will tell you when its time to eat. Unless its fed things that trick the brain into believing that it needs to eat more. Also, eat your vegetables.”

7.6 Food Shuts Down the Body, or Is Supposed to Shut Down the Body Movement between the far ends of the different energy states sometimes happens on its own, because of the environment. One can imagine going very quickly from rest/ digest to fight/flight if a hungry lion broke into their house at dinner time. Personally, I hate that when it happens. This surge of signals comes from the big beautiful human brain, and once it sees hungry lion, it cannot be ignored. Loss of appetite

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may not be the first thing that a human in that situation would feel, but I promise that mealtime is over. While at this point I’ve probably over-shared personal details of my life, I need to share the environmental sensation that shifts my energy state out from running away from lions, and that’s the smell of fresh baking cookies. Once that scent hits my brain, game over. That aroma is very difficult to fight or flight away from, it has a power over fear and self-preservation. While there are hundreds of danger signals in the environment, only food signals feeding time. The impulse is there, time even seems to slow down when humans start to smell food cooking. While running for our lives is important, humans are still wired to get food. Eating itself, produces an effect on the body that tries to push it into rest/digest mode. Now this is more than eating to cope with stress, the act of eating begins a cascade of events that affect the entire human body to stop doing the action, and start getting ready for digestion. It’s the silly human brain that doesn’t listen to the body that ignores these impulses to slow down and digest. All humans feel this impulse to slow down when they eat, but the question is “how long is necessary?” At least 90–120 min if modern science has anything to say about mealtime. The human brain does not actively control the autonomic nervous system, it responds to the environment. More than eating too often, and not resting the body after a meal, the human mealtime has lost much of the charm of the good old days.

7.7 Swallowing Can Wait, Masticate Chewing is extremely important, not only for the obvious need to smash the food into digestible bits, but the act of chewing is one of the numerous examples of redundancy of the human body. The actions of chewing itself sends signals to the rest of the body that its about time to start digestion. Sounds about right, chewing food is usually the action that occurs right before swallowing. This has been proven to occur even with food in the mouth. The action of “chewing” can be separated from the process of “eating” by performing science on humans that are chewing gum. The actions of chewing (not food) helps the production of saliva (for digestion) and also sends nerve action signals to the body to activate the digestive organs. The pro-digestion effect of chewing effect is independent from eating, but can also continue its effect AFTER a meal. While not a “hack,” chewing non-flavored gum prior to and after a meal can be helpful for digestion. Chewing gum will not “speed up” the process of gastric emptying, however it does seem to keep the body focused on the process of digestion. Chewing signals production of digestive enzymes, and keeps blood going to the organs of digestion. There is a reason that it is hard to walk and chew gum at the same time, the same reason it is impossible to eat and run from a lion. That reason my fellow humans, is evolution.

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Flavorless gum—chew for 15 min prior to meal, Flavorless gum—chew for 30 min after a meal, while sitting up. The reason I write flavorless, is basically to avoid the potential for sweetener to affect the gut/brain connection. While the complex and moody human brain can’t consciously control the body’s energy resources, chewing gum can keep some focus on digestion. Just be sure to bring enough for everybody. While there are 6 major salivary glands, there are hundreds of minor salivary glands in the mouth. There is a surprising amount of the body dedicated to making salvia, and for good reason. Salvia is important for digestion. Saliva helps non-­ liquid food become more liquid-like, breaks down some carbohydrates, and also help preserve vitamin B12. I’m not sure how long that food needs to be in contact with the saliva for the liquid do optimally contribute to digestion, but its longer than the time most people have food in their mouth. Chewing food, not only neurologically signal the body to be in a digestive state, but also keeps food in contact with saliva and ensures proper mixing and texture for swallowing and subsequent ingestion.

7.8 What Happens in Vagus, Gets Sent to the Whole Body While the city of Las Vegas, NV has built an entire economy on indulgence, the Vagus nerve exists likes to play by the rules. The Vagus nerve is the major connection between body and mind, and they stay in constant communication. While the conscious brain cannot control digestion, or other autonomic functions, the Vagus nerve does not plug into the conscious brain. The Vagus nerve(left and right) plug into the bottom of the brain, where humans still have some animal instinct. It is a pair of nerves that does many things—but the only muscles it goes to are the muscles needed for chewing and talking, but definitely NOT at the same time. The main autonomic nerve connection is directly tied to the muscles of chewing. See where this is going? The rest of the Vagus nerve goes to the all organs of the body, heart, lungs, stomach, and even the organs involved in human reproduction. Eating food is tied to the entire body, and there are nerve roots to prove it. But like most things that control human speech, it like to talk back. Like a lot. The Vagus nerve is a two way street of communication, connecting what the gut senses, cardiovascular stress/strain. Whenever a human faints, the medical term that applies is “vasovagal.” As in a gasp of air, holding breath, or sudden change in blood pressure causes the vagal nerve to take matter in its own hands and faints the human. No signal actually “stays in Vagus,” that nerve is a big time snitch. Where there are nerve endings, there are also usually mast cells. There is good understanding that mast cells can occupy ends of both lines of communication going back and forth from brain bottom to body. One of the key associations is the mind/pain connection, and mast cell action is involved in this effect. Visceral pain(gut pain, organ pain, etc.) is frequently associated with vague symptoms like “brain fog,” or other difficulty with short term memory or even word finding. There

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is good evidence emerging that signals coming from the body to the brain, trigger mast cells in the brain which are implicated in the brain dysfunction (Yang et al. 2022). This experiment showed that the Vagus nerve and the mast cells in the brain are both completely necessary for the reduced brain function caused by body pain. Other science has demonstrated that signaling from the gut to the brain can directly lead to symptoms of depression and anxiety (Cordner et al. 2021). Gut pain or hypersensitivity has been linked to anxious behavior, and cutting the Vagus nerve in an experiment will prevent this effect. For these negative effects, Mast cells in the gut are also necessary. This means that Mast Cells act as both “microphone and speaker” in the neuroinflammatory symptoms related to gut pain. Using ketotifen, a mast cell stabilizer, will decrease the signal going from the gut to the brain. The connection between gut and brain, is capped at both ends by an adjustable inflammatory compartment that is directly amplified by environmental stress. The vagal nerve influence on whole body health cannot be minimized, and there are discoveries published monthly throughout many models of disease. The bidirectional nature of the body-brain communication is not a new concept, in many cultures the ideas trace back hundreds if not thousands of years. The “autonomic nervous system,” is the mechanism for adjustment to larger environmental stresses, including “fight or flight.” The contributory effect of psychologic stress on chronic disease is common knowledge. It is only in the recent decade that the combined impacts of allergy, pollution, food sourced inflammation, autoimmune diseases and psychological stress all have been removed from an “isolationist” view in human disease. The interconnected nature of these inflammatory conditions is glued together by more than mast cells, but these cells make a lot of noise and the whole-­ body listens.

7.9 It’s Only in Your Head. I.E. “Imaginary Symptoms” Allow me to take a moment to shed some daylight on this absolute Gaslamp of a statement. Nothing in medicine, except perhaps a brain tumor or a sinus infection, can exist only inside of a human head. The amount of redundancies, back-ups, interwoven immune and neurologic connections between the mind and body make it impossible for any type of physical ailment to exist only in the mind. Furthermore, modern science has compelling evidence that isolated psychologic stress can cause body pain and other non-brain organ dysfunction. This type of statement hurts humans; it prevents healing and could actually cause harm. More importantly, it’s not a factual statement. While the human body and brain speak the same language, its not English. Therefore, difficulty exists in the process of communicating to someone outside the body. Sometimes its better to look for a different provider of healthcare.

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7.10 Take a Walk Down the Vagus Nerve One of my favorite questions to ruin a dinner party with is “When does the human body start to digest food?” Including myself, nearly 100% of people polled reply that food begins the process of digestion once in the stomach. Digestion begins in the brain. Sometimes the process of even thinking about food, can increase the production of saliva and trigger the production of digestive enzymes and stomach acid. Getting into the “digestion zone” takes focus, planning, and discipline. Not only preparing a safe place that is in a lion-free area, but also where other interruptions can be minimized. Salivation starts with the brain, and does not start with the Vagus nerve. Chewing the food is the first part of digestion that begins the walk down Vagus Boulevard. Everything after the brain is Vagus. The wires start by the skull, and travel in a sheath with very important arteries(carotid) to get from the head to the body. While the vagus nerve can slow down the heart rate, we count its actions on swallowing(esophagus) as digestion. The nerve that connects jaw muscles, also controls the part of swallowing that the brain does not control. There are nerves, sensory and others, in the stomach, and lower in the digestive tube that communicate back and forth. The digestive system can sense the type of food, as well as calorie load. There as many moving parts in the endocrine, neurologic, and Immunologic response to the food environment as there are different foods going into the body. The Vagus nerve signals the stomach to make stomach acid, and also start to make enzymes to break down food. Not only the stomach, but also the pancreas makes digestive enzymes. The Pancreas also makes digestive(insulin) and stress(glucagon) hormones, but the Vagus nerve only triggers the digestive hormone. It ends its involvement in digestion with only a few feet of colon left in the body before the exit. Vagus is a Parasympathetic nerve—this is only rest and digest. It is a two-way back and forth connection. The Sympathetic nervous system, this comes from different areas and most certainly does NOT help digestion. Vomiting, and other types of expulsive events from the digestive tract are the fight/flight responses. Mast cells, get involved on both sides of the action. They exist on both sides the brain and the digestive system to sense and react to the environment(food) and also amplify the signal that goes to the brain to affect behavior. The brain gut connection is wired by nerves, but glued together by mast cells. Unfortunately, the mast cells do not seem to be helpful with the process of resting and digesting, and many of the gut actions seem very counter productive to quiet and peaceful digestion. While the Vagus nerve is the major connection between brain and body organs, mast cells that go to barrier areas in response to stress make it harder to digest, and the humans more aware of discomfort in the area of the gut.

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7.11 Digestive and Immune Systems Are One and the Same for About 2 Ft If we need to be strictly to code on the metric system, that’s only about 40 cm. The human body has an immune organs called “Thoracic Duct” or the “Thoracic Lymph Chain.” This is a fluid collection system, that drains the legs, and abdomen of the extra tissue fluid. The Lymphatic drainage system of the body is an Immune organ, and the Lymph nodes are where the organization of the memory responses to the Immune system takes place. Think of tissue, every tissue of the body, being mostly made up of fluid. There is fluid moving in and out, and there is always some spillage. That spillage or “lymph” is collected through lymph nodes and moved to recirculate through the body. When some human’s legs swell up, we call that “Lymphedema.” That is just a bunch of extra fluid in that area of the body—that hasn’t been drained back into circulation by the Lymphatic System. That sounds like a very efficient way to surveil the whole body, by draining it through the immune system. Now, ingested sugar enters the body super-quickly, and proteins are digested also quite fast, but fats are not broken down quickly. All fat that is small and medium in molecule size (up to medium chain triglycerides—MCT) are absorbed directly in through the gut. Which leave out the large fat bodies. Larger molecule fats(most digestive fats), as well as fat-soluble vitamins, those are packaged perfectly into little globules by the intestines and sent for a journey through the Immune system before being dumped right back into the circulation. This journey through the thoracic duct is about 2 ft. long, but we’re not sure how long that takes. The force that pushes this fluid upwards from digestion into circulation is the motion of breathing. Heavy deep and fast breathing moves the fatty liquid faster. This is too intimate of a relationship to ignore, and the body does not ignore either digestion or Immunity. Mast cells line every inch of the gut, from mouth to bottom, and are reactive to environmental irritants, allergens, and also contribute to programing the draining lymph nodes. What does this double duty mean to the average human? Eating fat means inflammation. This does not mean dietary fat is “bad,” because it is not, however it does raise some very interesting connections. There is strong connection between the production of inflammatory messages following high fat meals (PMID: 25182144 and PMID: 25182144). This production of inflammation signal lasts for over an hour, and there is debate on whether or not humans actually feel this signal after meals. This is very interesting, but also concerning. There is no need to abstain from eating fats, but perhaps limiting fat ingestion to only a few hours or once a day (intermittent fasting) is actually really good for the human body because of how the human immune system helps digest fats. The Immune signal released during digestion of large molecule fats is called “IL-6.” Unfortunately, the connection between IL-6, autoimmunity, Immunodeficiency, and even allergy is too big of a concept to detail. Also, I read about this type of stuff almost daily and I’m not sure what it actually means to

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humans. However, I have gone from adding flax seed to adding MCT oil to my fruit smoothies.

7.12 Mixing Up “Fight or Flight” and/or “Rest and Digest” Humans of modern day are not doing a lot of physical fighting or flighting, there just aren’t that many sabretooth tigers or other predators looking to eat humans for dinner. Most of the Fight/Flight stressors come at modern day humans from their employer, or their government. Many ways, in the modern-day parlance, we call the fight for survival “a job.” After a long workday of evading pterodactyls and Human Resource Managers, most humans feel the need to unwind a little bit. Psychological stress is very similar to Physical Environmental stress, except it exists in a human’s brain, making it tougher to run away from. After coming from a stressful day of “job,” it takes a certain amount of time to shift the human body from fighting to resting. While this amount of time varies from human to human, my guess is on average about 30 s of transitional time per year of age. A newborn can immediately go from stressed(crying) to rest(fed) to stressed(crying) in mere seconds, but a 20-year-old male may take about 10 min after the day to relax and prepare the body to be nourished. I’m approaching the age of 50 I need to sit down(cry), and both physically and mentally prepare myself(cry) to consume food. Now this has not been measured with monitors or vital signs. This takes a full circle back to the very first part of digestion. The human mind is the human body’s biggest problem. Every athlete takes time to “get into the zone,” warm up, or get their body into the correct functional mode to perform (Fig. 7.1).

Fig. 7.1  Switching the “zones” of the body. Managing the human body’s energy efficiency is complicated work. Preparing the body for athletic competition not only requires a clear but focused brain, but warmed up muscles, and occasionally theme music. Resting the body does not happen on its own either, clearing the mind of stresses and threats, cooling the muscles, and friendly companionship. There are many signals, hormones, and nerve impulses involved, these are only a few of the many different state switching activities or messages

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One of the most confusing differentials in sports entertainment is the original catch phrase of Dwayne “The Rock” Johnson when he would ask his competitors if they could “Smell what The Rock is cooking.” He was not extending a hearty welcome to relax and enjoy a freshly prepared meal—which is the confusing part. The Rock was pandering to the crowds of hungry wrestling fans, about his metaphorical plan to “cook the competition.” So as The Rock’s wrestling combatants approached the ring undoubtably salivating in advance of a deliciously prepared high protein meal, their body was in the zone for rest and digest, and they could not fight The Rock. The rest is sports entertainment history. To ensure proper digestion, humans need to approach food like athletes in the Superbowl, the world series, or just a good old-fashioned smack down. Focus the body and mind. Slow the breathing. Smell the food (not the competition). Feel the comfort of the chair. Get a glass of water, smack the licks, but most importantly focus on the food and every bite like it was the most important thing on planet earth in that moment. The action, the ritual, of food consumption can be itself a way to “switch” the body from fight or flight into resting. However, meal preparation, has become almost a burden on peoples time, and the availability of a “quick bite” has near completely eliminated any “pregame ritual” the humans had prior to a large meal.

7.13 Everything About How Humans Eat Has Changed in the Past 50 Years The aroma of food can directly activate compartments of the brain that can shift the body from stressed to rest, and vice versa. I was not around the planet prior to 1976, but more meals were consumed in the home, and cooking was slower, and the ability to store food was not so Tupperware available. There was a reason Grandma’s house always had “that certain smell,” it’s because they were cooking all the time on the stove and without microwaves or sushi delivery. Large family dinners not only allowed humans to mentally refocus from work stress to refueling the body, but the wafting odors cleared the mind, and that long preparatory time gave the bodies plenty of time to warm up the digestive system. Most of the enzymes necessary for digestion in the stomach (like pepsin,) need the environment to be acidic (more acidic than tomato sauce or lemon juice) to be maximally effective. Creating this low pH environment does not happen instantaneously, and can in fact take up to 25–30 min. This acidic environment usually lasts until the food leaves the stomach, so it might be a good idea to not eat that often. Also, improperly conditioning the stomach by feeding before the correct pH has been reached, causes more than indigestion, but also malabsorption of micronutrients. Grandma knew what she was doing in that kitchen, and that was only 2 generations ago.

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7.14 Rushed Food Ingestion Leads to Improper Digestion Macronutrients such as carbohydrates will almost always be digested, and subsequent absorbed and likely stored as excess energy. If carbs aren’t absorbed into human bloodstream as sugars, the starches will be easily broken down or they’ll be fermented by microorganisms in the human. Complex proteins and fats, have a multi-step process for digestion. Consuming food without properly preparing for digestion can lead to a state of absorption of carbohydrate calories, and inadequate absorption of protein. This only effects in reinforcing human hunger sensations, and overeating, etc. Human stomachs have the ability to sense and determine calorie load. It is not just the volume of food consumed, but the total amount of calories that are responsible for telling the brain to stop filling the stomach. The stomach is a 3 dimensional organ, meaning that the geometric principal of surface area is necessary for sensation. The calories need to touch the surface of the stomach, the stomach and only sense what it touches. The larger the food particle, the smaller the surface area sensed by the stomach. The longer the food is chewed, the more it is pulverized into a liquid or near liquid, the higher the surface area to calorie ratio, and the less ingested but better digested. Also, better feelings of satisfaction from the meal itself. Chewing food such as pasta, or at least comparable forms of starches, greatly changes the body’s digestive hormonal response. The size of the structure of the food affects the speed of digestion, and it is all about efficiency (Vanhatalo et al. 2022).

7.15 Simplified Summary Digestion is not easy, and speeding up the whole process may not be the best thing for the human body. Recent studies looking at the reduction of inflammation from fasting, or eating simpler foods, may not be new discoveries, but understanding the best way to eat and digest in the most efficient way possible. This represents a strong opportunity to improve interpersonal relationships, and to explore the shift to parasympathetic, rest and digest state. The past 50 years have resulted in a large increase in the number of exciting or even necessary stuff to do in human life, however humans still have the same 24 h each as they did long ago. While the preparation of food was a necessary and time-­ consuming chore, turns out it was a healthy action. Longer preparation time for meals also forced better preparation for the human to digest a meal, and we’re figuring this out only recently. Taking an imaginary walk down the human body’s relaxation boulevard, also referred to as the “Vagus Nerve” highlights exactly how eating food is directly wired into the mechanisms of calming the body to “rest and digest.”

Bibliography

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Key Terms • Inflammation: This is a response to stress, and involves the immune system. Human food, and how humans are fed, is a source of inflammation that is likely new to this half century and is currently being investigated. • Medium Chain Triglyceride (MCT): This is a form of fat calorie that is smaller in molecule size compared to other fats like vegetable oil or butter. This can be absorbed as calories by the body, and does not pass through the chain of lymph nodes called the thoracic duct and does not cause the body to release inflammatory messages. • Digestion: The process of extracting calories and nutrients from those things that are placed in the mouth. • Thoracic Duct: A chain of lymph nodes connecting the Immune system from the lower half of the body to the digestive system, it carries larger fat particles from the intestines into back into the circulation. If this is harmed, humans can have poor absorption of fat calories and fat soluble vitamins. • Parasympathetic: The Rest/Digest system, the Vagus nerve is the major neurologic connection that supports resting and digestion.

Bibliography Cordner ZA, Li Q, Liu L, Tamashiro KL, Bhargava A, Moran TH, Pasricha PJ. Vagal gut-brain signaling mediates amygdaloid plasticity, affect, and pain in a functional dyspepsia model. JCI Insight. 2021;6(6):e144046. https://doi.org/10.1172/jci.insight.144046. PMID: 33591956; PMCID: PMC8026195 Reynier-Rebuffel AM, Mathiau P, Callebert J, Dimitriadou V, Farjaudon N, Kacem K, Launay JM, Seylaz J, Abineau P. Substance P, calcitonin gene-related peptide, and capsaicin release serotonin from cerebrovascular mast cells. Am J Phys. 1994;267(5 Pt 2):R1421–9. https://doi. org/10.1152/ajpregu.1994.267.5.R1421. Yang J, Dong HQ, Liu YH, Ji MH, Zhang X, Dai HY, Sun ZC, Liu L, Zhou J, Sha HH, Qian YN, Li QG, Yao H, Li NN. Laparotomy-induced peripheral inflammation activates NR2B receptors on the brain mast cells and results in neuroinflammation in a vagus nerve-dependent manner. Front Cell Neurosci. 2022;16:771156. https://doi.org/10.3389/fncel.2022.771156. PMID: 35221919; PMCID: PMC8866729 Vanhatalo S, Dall’Asta M, Cossu M, Chiavaroli L, Francinelli V, Pede GD, Dodi R, Närväinen J, Antonini M, Goldoni M, Holopainen-Mantila U, Cas AD, Bonadonna R, Brighenti F, Poutanen K, Scazzina F. Pasta structure affects mastication, bolus properties, and postprandial glucose and insulin metabolism in healthy adults. J Nutr. 2022;152(4):994–1005. https://doi. org/10.1093/jn/nxab361. Epub 2023 Feb 18

Chapter 8

Indoor/Outdoor Air Quality

8.1 It’s Human Nature Human Nature is an oxymoron, kind of like a “Jumbo Shrimp.” Because we can’t really determine exactly what is “naturally human,” and what has been constructed in the past 70 years. Is it truly in Human Nature to directly hurt other humans? It likely hasn’t changed much, despite the advances in technology of the past half century, or even the past few millennia. The oath that Modern Day Physicians take is grounded from the establishment of the profession in Ancient Greece. The “Hippocratic Oath,” dates to 2500 years ago, and while there has been some minor changes, it still pretty much starts off with “Don’t Hurt Humans.” I wish everybody would swear by Apollo to forgo hurting other humans, think the world would be a better place. Not trying out Philosophy here, but something made it very important along time ago to make it clear that Physicians aren’t allowed to hurt people. This could be because everybody else 2500 years ago hurt other people routinely. The Physician skill set has changed since the good old days of Hippocrates. Speaking only of myself, my ability to practice medicine is nearly 100% reliant on current technology, so thank goodness I haven’t been sent back in time to those days. Human Nature hasn’t changed in the slightest. The scientific method is generally practiced by scientists. Scientific discoveries are used by all kinds of humans, even those humans who have not sworn an oath to “not harm.” There are countless examples of scientific or medicine advances used for heath and harm. Not long after the adoption of a vaccine to prevent death from smallpox, there was documented use of the contagious nature of the virus to eliminate large groups of people sponsored by a democratically elected government. The healing profession takes ownership that advanced knowledge of human health can be used to harm as well as heal. These refer to the actions of the Physician. It does not mean that there is an oath to prevent any human on human harm, or even from human self-harm. In the civilized world, the protection of a people is charged to those in leadership of the people, I.E. government. The lengthy and drawn out

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example is trying to get to the point that the regulatory changes of the past 50 years have allowed human on human harm to dramatically increase through inaction.

8.2 By the Humans, for the Humans Not hurting people on purpose is a tough job, and thankfully the United States government and the Health Insurance Industry has greatly simplified the process. Obstructive regulations and predatory authorization practices prevent action and result in harm by inaction, which is perfectly acceptable. They do not stand in the way delivery of healthcare, they simply don’t pay for stuff. I have never seen an employee of a health insurer steal medication out of the hands of the vulnerable, such action would never be allowed in a civilized society. Likewise, the tobacco companies do not directly harm anyone, however they profit from the ability to make it possible for somebody to hurt themselves. This passive approach, this absentminded governance, has allowed the healthy air to vanish from the world entirely.

8.3 The United States (Healthcare System) Is Bad at Math On a per person calculation every US taxpayer pays $2000 annually for the healthcare costs related to tobacco ($300 billion, 150 million taxpayers.) Thankfully, the tax revenue from the sale of tobacco products comes up to about $10.6 billion dollars ($68 per taxpayer) to offset some of the burden. The annual revenue of the United states Tobacco Industry is around $100 billion. The country-wide productivity loss directly due to tobacco smoking is greater that the entire revenue of tobacco industry. Which means eliminating all tobacco products would result in a 2000% annual return on investment. I never had the aptitude for macroeconomics, so I’m sure that I am missing some sort of National altruistic benefit that having a highly harmful and addictive drug legal for sale. At least there is mostly a ban on publicly smoking indoors in the United States. That is not even just tobacco products, smoking anything inside is prohibited. This includes burning garbage, spare tires, and even dog hair—smoking any of that is not allowed indoors in the United States. This is clearly a ridiculous exaggeration of an analogy; no correctly mindful human would ever purposefully set ablaze for the purpose of inhaling such awful things, without an addictive drug convincing the brain to do it. Tobacco Smoking is an easy target, any health conscious fifth grader could hit this softball with a strong argument. While the past 50+ years have seen an overall reduction in tobacco use, the warning labels don’t seem to have the intended effect. The elimination of the “Smoking Section,” and “denormalization” of smoking have been positive trends for the good health of all. Globally there has been a 400%

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increase in the number of cigarettes produced each year, while the population of the world has only grown from three billion to eight billion(266% increase). So mathematically speaking, cigarettes aren’t killing humans faster than we can replace them. An aggressive effort to limit the public indoor exposure to second hand smoke is obvious, it was not outlawed in individuals’ homes. Even if the indoor smoking exposed children, it is still completely legal to fill up a private home with harmful air. So the government stepped up, and prevented humans from harming other humans in public places, but not themselves or their vulnerable family members.

8.4 The Air Which Does Not Kill Us, Makes It Harder Us Breath Harder When people ask me the best possible exercise to strengthen their lungs, I usually tell them to start smoking cigarettes. I mean, inhaling hot toxic dirty air is just like lifting weights for the lungs, or cruising on an exercise bike for the cardiovascular system, right? Not true, all forms of smoking directly hurt the body. Its not just nicotine, purposely inhaling something that was recently on fire is just plain silly. Living with someone that burns stuff inside the house is also pretty silly. The body does not thrive on this type of stress, it leads to permanent injury. Inhalation of smoke is bad for health, and smoking was not invented recently. However, the acknowledgement by the scientific community that smoking directly hurts smokers became unanimously accepted within the past 50  years. Now, no government in the world has completely outlawed the practice of smoking,

8.5 Medication Induced Airway Change I would never want to single out anything specifically not something produced by a billion dollar drug company, as being potentially harmful to the human body. However, pretty much everyone that has had nasal congestion knows how amazingly effective topical nasal decongestants are to relief symptoms. These medications, phenylephrine and oxymetolazine(quiz later), cause near immediate contraction of the tissue blocking air movement in the nose. Instant relief. Never fail. However, this is an example of medications working way too well. There is actually a medical diagnostic term “Rhinitis Medicamentosa” translation: nasal inflammation only caused by overuse of a medication. Turns out, continuous use of this amazingly effective medication ends up causing a change in the body, that is completely the opposite of the intended effect of the medication. After the shrinking of the tissue wears off, there is a rebound. The nose closes up again. Continued use over a long period of time causes the person to be dependent on the

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medication, and even more use results in permanent closure of the nose to the point that surgery is needed to remove the excess tissue. Thank goodness people have not been applying medications like this to other body parts to attempt to trigger long term hypertrophic growth.

8.6 What Exactly Is “Smoke” Where there is smoke, there’s fire. Simple. Not all fire produces visible smoke. Gas stoves, candles, don’t produce very much visible smoke. The reason that there is no visible smoke from these sources of heat is efficiency. The material that burns almost completely turns from material to hot air and light. Every little bit of smoke is just leftover garbage from a chemical reaction that can’t get its molecules together.

8.7 Smoke Is Not the Only Thing That Hurts to Inhale The global effort for reduction of air pollution is a remarkable project, dedicating time, effort, money to reduce the burden of pollution on our population, and for our children. This effort, is spearheaded by nearly every other country in the world other than the USA. I mean, our grandpa’s “greatest generation” cleared the world of fascism, but we Americans have been kind of coasting on the moral authority for some time. Our environmental protection agency is the world’s finest. From 1981 to 2015, the control on burning fossil fuels, and generation of particulates reduced detectable Particulates in half! Don’t ask me what its supposed to be, but we’re doing really good. How did we, as human race, join together and hold hands across the globe and celebrate this success? We started spending a lot more time indoors, because we loved to inhale garbage we chased it inside the house (Fig. 8.1). It is getting warmer

Fig. 8.1  This is a comparative scale of major allergens, irritants, and infectious particles. Grass pollen usually needs wind to disperse it, and coarse particulates tend to settle. Around the size of animal dander, the particles can be suspended in air for hours or days. While this is a scale of sizes, it is not drawn to scale

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outside, so why not spend all that time indoors using the air conditioner at maximum blast? The World Health organization estimates that in 2019, 3.2 million people died because of air pollution—inside their homes. That’s really not many people, out of seven billion, right? Turns out that the air in homes is responsible for 1  in every 20 deaths every year. If you combine all the forms of inhaling garbage (including smoking) that ends up being 1 in every four deaths each year. So what about the remaining 99.95% of people that weren’t killed by the airborne garbage in their home—their lungs didn’t get stronger because of it, there was damage. Deaths get attention, and rightly so, however there is a very long list of problems that harm human bodies without killing them. This list includes, but is certainly not limited to, weaken the body, overburden the immune system, and generally make people feel like they are dying, but not dead yet. The effects of inhalational pollutant damage, which has changed in the past 50  years, is INFLAMMATION.

8.8 Indoor Air Quality: Who’s Fault Is it Anyway Indoor air pollution has been an important focus of public health for several decades, its been studied at length as a contributing factor to human disease, school performance, and even dental health. For the most part—smoking cigarettes isn’t allowed inside, wood or other fuel burning stoves are uncommon, and there continues to be exciting studies on the impact of improving air quality in schools and in the poorer communities. There has been even enough to think that maybe this is a potential way that our civilization has improved the environment, especially compared to any other time since the dawn of the industrial revolution. In the first half of the 1900s there were some events of massive air quality crisis—which lead to severe and immediate impacts on deaths and hospitalizations. However, as the dirty air became visibly cleaner, we became a plastic civilization. Not that homes aren’t made out of wood and concrete anymore, but building materials for the sake of saving money and energy costs(insulation) have become “synthetic.” I use the word synthetic to describe a “man-made,” or otherwise artificial process to create something. An oak tree can take 50 or more years to turn water, carbon dioxide, and sunlight into a couple of wooden oak planks. However, this pace is too slow for the modern world, we need building materials STAT. The safety limits on this air trash is 35 μg/m3 (short) and 12 long. They set the estimate of 50 for “unhealthy,” and 250 for “really, really, really freaking dangerous.” Direct health effects A study done in Baltimore in 2009 (McCormack 2009), looked at indoor air particulates, lung disease, and obesity in kids. Looking at particulates, the average indoor particulate concentration was 40, and twice the outdoor concentration. So the Average air quality for long term exposure limits is 12 μg/m3, and short term is 35, these kids lived at 40 (unhealthy for a short period of time.)

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The worse the air became, the more obese and trouble breathing the children had. I mean a cubic meter is a full 1000 L. Well, average person breaths about 10 m3 per day. So quick math translates to these kids inhaling on average a pack of cigarettes per year. I don’t actually prescribe smoking cigarettes, I don’t have to, these addictive and poisonous products are legal for any idiot to purchase over the counter. No health insurance required. I know that I really give cigarettes a hard time, and I really shouldn’t. The tobacco companies give a lot back to the community. By community, I mean the lawmakers that allow these things to continue to kill people (www. opensecrets.org/federal-­lobbying/industries). But in real numbers, this type of pollution is small enough to get into the deepest part of the lungs. Looking at these numbers again in “real terms,” If the average particulate air concentration is 40  μg/m3, that is one half milligram per day, one third of a pound of garbage per year. How does the body get rid of all that garbage? Coughing will clear some of it, but after a while, the lungs stop coughing. Ultimately it falls upon the immune system to digest this stuff. Our bodies are quite capable of processing and removing environmental waste, but we have to pay the price of inflammation for it. While the death toll attributed to dirty air is shocking, those of us who survive are still breathing the deadly air and are feeling the cost of the constant inflammatory responses in every warm part of ours bodies.

8.9 But How Does Breathing Tiny Pieces of Garbage Hurt Our Bodies? In many cases, its not actually the fault of the garbage. Its how we handle the garbage. Every time I’m told to take out the garbage, my response is to complain, kick, scream and cry, and in many other ways cause a highly dramatic scene due to the imposed injustice. Despite my responses, I still get told to take out the trash all the time. The surface layers of our body have response mechanisms, and these response mechanisms respond immediately, and in many cases make a pretty big fuss about taking out the trash. Coughing is very important for clearing crap out of the lungs. However, the queen of expulsion is Mucous, oh my goodness I love mucous. I love thick mucous, I love thin mucous, I love clear mucous, I love yellow mucous, its like mucous was made specifically for our membranes. Mucous is a harmony of proteins, a fusion of ammonia and sugar and sulfur. If your mouth isn’t watering right now its because saliva is getting very jealous of all the praise I’m heaping on mucous. Mucous is the

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battlefield upon which our body is defended from this hostile toxic environment we live in. Word to your mucous. The surface layer of the body is the mucous factory, and that is where the mast cell magic happens. Pretty much every surface of out body that is not skin, from the insides of our nose to the bottom of our lungs, also the digest system and genitourinary system. Mast cells live and work around these factories, and as the area becomes injured, more mast cells show up. Mast cells do different thing different places, in the lungs the stuff they produce flexes airway muscles and narrows the diameter of the airway, which makes the force of coughing better for……taking out the trash. The other stuff produced also changes the character of the mucous, and calls in help. The quick responses of making more and thicker mucous, AND making the cough more forceful are immediate, and all bodies are born with the ability to clear garbage out of the lungs. However, when protective system is chronically over-stimulated, the response of the body to grow bigger things to respond to the stimulus. This hypertrophic response cannot be unmade, and will result in a chronic productive cough for years.

8.10 The Size Matters, But Not in the Way Most People Think The natural concern is that the larger the inhaled particle, the more potential damage it will cause the lungs. This may make sense from a collision perspective, but the body’s longer-term responses are inflammatory. The human nose is good for a few things, and filtering out particles is the largest and most successful job of the human nose. The larger the particle, the easier it is to filter, cough, and clear. The smaller the particle, the deeper into the lungs in can be inhaled. The approximate area of the lungs (stretched out to measure surface area) is the size of an American football field, which is about 80% the size of a Canadian football field, and 50% the size of the rest of the world’s futbol fields. This potential area of exposure is enormous, and is necessary to move gasses quickly in and out of the body. However, the large area also means the larger potential area to trigger inflammation. Human inflammatory markers (stuff produced from inflammation) are elevated most heavily in regards to being exposure to these ultrafine particle (Fig. 8.2).

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Fig. 8.2  Particulate pollution/inflammation The Environmental Protection Agency follows two major categories of particulate pollution that are known to affect humans. The PM2.5 are smaller, and are capable of penetrating deeper into the lung and triggering inflammation. While in the United States has reduced these outdoors, indoors—where humans spent 95% of their time, are not monitored

8.11 When the Air Is Clean, Less People Die When factories shut down, the immediate effect noticed is that there is substantially less “all cause mortality.” No, this does not mean that workers were dying on the job, it means that the side effect of production is directly bad for human health. There are several known examples which show the decrease in heart attacks, stroke, asthma exacerbations, and all sorts of healthy problems. This is the point. Air pollution is a cause of a lot of pain, both directly and as a contributing source of inflammation. It is difficult to know the full extent of the health effects because of its inescapability. We cannot make a comparison between a “controlled” group or “wild type,” because air quality is wildly out of control.

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8.12 High Efficiency Means Recycled Air Recycling is a good thing most of the time. Despite my attempt to convince people that there is no such thing as “fresh air,” anymore, there is a concept of “used air.” I experienced this personally. I had an issue with air quality, where I felt sleepy but not tired, headaches, lethargy—it used to hit me every work day around 3 pm. My clinic was about 2400 ft2, and had a relatively large waiting room. Turns out, there was an afterschool rush of families coming to bring one member for an allergy injection. For about an hour, there were way too many people in my clinic, all using the same air. That air became well used, and the concentration of Carbon Dioxide(exhaled) went over 2000 ppm. Carbon Dioxide is a human waste product, and it was accumulating to the point that myself and my staff were feeling sick. I was able to purchase an inexpensive CO2 detector online for only a few dollars. The additional venting and air conditioning costs were not as cheap as the detector, but we haven’t had the problem recently. Turns out, I’m not the only human that feels bad from breathing in human waste gas. Some countries have limits, these generally re between 1000 to 5000. I started feeling awful at around 1400 to 1500, and my staff was as well. Many people start to feel bad at around 1000—but can get dizzy and lose coordination at 5000—which happens to be the recognized exposure limit in public building in the USA. There is no home monitoring or recommendations. This is not Carbon Monoxide which kills people, this has legislation and mandated detecting. Carbon Dioxide is still pretty gross. There is mandatory high efficiency air conditioning, which is designed to reduce energy consumption by limiting indoor/outdoor air exchange. This was necessary legislation of the past 50 so years, however there was no mandate about removal of waste gasses. As the increased efficacy and availability of climate cooling systems have become widespread, the design and construction of buildings have also focused on this efficiency. While the outdoor air has had detectable reduction in inflammation triggering pollution, Public Indoor air has less stringent standards, and Private Indoor air is allowed to be toxic.

8.13 All Inhaled Forms of Garbage Trigger Mast Cells From the small particulates, to the charged oxygen species, and even smoke, the mucosal barriers (nose, lungs) that interacts with this environmental stress is laden with, and driven by mast cells. These are the same cells which are activated though the conventional allergy mechanism, but also program the Immune System and drive chronic inflammation and autoimmunity. Even the small chemicals that are like smell molecules can trigger the mast cells, who can actually act as accessory nasal sensory cells.

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There are more parts to the human immune system than mast cells, however starting to look at the changes to the daily climate leading to increase in parasites that directly activate, alterations of the ecosystem of borders, changes in everything about food that interacts with the immune system, and now the very air being breathed all share a common fundamental pathway of inflammation and disease programming to the human body.

8.14 This Generation Has Never Breathed Air without Plastic While we are celebrating some partial victories on indoor smoking, and particulate pollution, smoke very weird stuff started happening. Plastics, a marvel of modern technology, haven’t been around very long. But because of what plastics are, they are actually going to stay around forever. Being a Generation X slacker, I grew up watching movies and wearing baggy clothes. I still watch movies, but my clothes are getting a bit snug. I am a student of Nature, but I am a fan of movies. But the movie about the original aimless Generation X slacker, Benjamin Braddock in 1967s The Graduate. The character played by Dustin Hoffman is finishing college, but relatively aimless in life. There are many famous scenes in this movie, but the young male character gets some great advice on a future industry: “Plastics.” Apparently in 1967, there was going to be a big future in the plastic industry. Just 55  years later, that little slacker pervert has successfully spread this industry to every square centimeter of the planet. The 60s must have been a crazy decade, because I went to dozens of college graduation parties in the 90s trying to emulate that film. I never met any adulterous baby mommas, however I got a ton of good advice like “One word, Frank: Internet. There’s a big future in this internet thing, will you think about it?” What can I say, I didn’t think this world wide web thing had staying power. Back in the 1990s I had no idea what open trade and communication from Internet technology would be like in 30 years, but needless to say it has had an effect on the global economy. I doubt in the 1960s that the Plastics industry knew where their products would be in 60 years. Certainly no one knew that it would be dissolved in every drop of water and liter of air on the planet. I’m not sure about the first time I read about “microplastics,” but it was well after Medical School (2000), and probably well into the current career path. I nearly always take a healthy skeptical view of any new finding or medical procedure, and these are now accepted as truth. The findings on microplastics are just starting to be peer reviewed, but honestly microplastic are just another form of garbage. But the key lies in understanding that the plastics were designed to be indestructible. It ended up being true, however while decomposition or digestion is extremely slow, apparently these things can get broken up into tiny little particles that can be suspended in the air, and still not “go away.”

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While I hate to bring up smoking, its more “natural” for the body to process and get rid of compared to undigestible plastics. While smoke is “hot garbage” from incomplete combustion, it is garbage made in the same fundamental way as our bodies work, I.E. a “biologic process.” The power of immune system’s enzymes, oxidation, and clearance has a chance against burnt trash. But the process that makes plastics plastic, makes them invincible to biologic decay. Scientific papers are showing that up to 10% of the particulate pollution is now made up of microplastics, which are alien substances to the body. There are scientists that are developing ways of detecting microplastics in the human body, they have found that it accumulates in animals. We can speculate on the impact on human health, but we certainly do not know the full impact. The mighty mast cell compartment gets engaged, Particulates activate mast cells, and makes airborne interactions more “allergic.” There are many observations in humans and in experimental models which show that the mast cells in the lung will trigger the acute cough and wheeze. Repetitive short-term activation leads to long term responses, and with mast cells those programed long term responses are allergic inflammation.

8.15 Plant Reproduction Is Getting to Be a Problem There are schools of thought that believe some plants have feelings, and can even communicate. I’m no botanist, but I know what pollen is, and it’s the outward expulsion of plant DNA for sexual reproduction. We have a big oak tree in our back yard, and I disown any thoughts on what it is feeling every springtime when our back-­ porch gets covered in its attempt to reproduce. I mean, we get covered to the point that it looks like a yellow powder was spray painted all over the porch. It’s not just that our oak tree is some kind of deciduous adult all-star, pollen loads are getting bigger every year. This is a noticeable trend, that has been verified year after year. Schmidt (2016), not only is the amount of pollen increasing, the length of the pollen seasons are also increasing. Weed pollen, particularly ragweed pollen is different in cities, compared to outside. Cities tend to hang on to Carbon Dioxide, and tend to hang on to heat.

8.16 Pollen Is Just Nature Doing Its Freaky Thing Pollen is a part of the reproductive mechanism of plants, there is no need to make this more awkward that it already is, so stop giggling. These giving trees produce enough pollen so that enough is carried in the air sometimes to other trees hundreds of miles away. There is no gathering place to find a mate, so it has to carpet the local area. Pollen is all over the place, but so are flowers. With hundreds of different species, different trees like fruit tree and pine trees don’t co-mingle. They are a little

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closed minded when it comes to interspecies reproduction, but cross pollination can occur. Much like the flowering part of trees can recognize the appropriate pollen, our bodies recognize the different outer coatings and enzymes of pollen and can develop a defensive response to each specific pollen. The processes that make someone allergic include being exposed to allergens. So more pollen, and longer pollen seasons mean more allergy symptoms, longer allergy seasons, and more allergy sufferers.

8.17 There Are Gateway Allergens Pollen is a relatively compact and complex allergen. We can’t really call it a “pollutant,” because plants were here first. There are over 190 different pollens that are allergens known to affect allergens, and many of the specific parts are digestive enzymes. Pollen is different than other allergens, it that if it is broken down into its different components, it can’t program allergies (Pointner et al. 2020). While the whole extract is needed to program allergies, only a few of the nearly 200 pollens are the whole package—that they can irritate the nose, command a response and promote long term allergic responses. In other words, snorting most pollens will make someone sneeze, but it won’t cause them to have permanent allergies. Only Birch, Ragweed, and some grasses can cause the whole cycle, and even then it’s a weak cycle. There is a combination of local viruses, irritants, bacteria that live on the pollen, that can build the allergic response to pollen. However, the strongest partner to trigger allergies is a form of pollution called ozone.

8.18 Get Out of the “Friend Zone” with Ozone Plants are harmless, right? I mean they make a reproductive mess during the mating season, but pollen certainly doesn’t cause an invasive infection ever. Pollen can be changed by the Chemicals it shares the air with. When I was a kid, we learned that we were losing our ozone layer, but the ozone that interacts with pollen is ground-­ level ozone, that’s bad ozone. All ozone is very reactive, but ground level ozone is especially reactive. It combines with the outer layers of pollen (Beck et al. 2013), and changes the composition just enough to change how the Immune system interprets its signal. Pollen isn’t that bad on its own, but its gets altered it a bad way due to pollution. Despite success with reduction in Sulphur, nitrogen oxide pollutants, ozone(oxygen oxide) is staying the same, and in some cases increasing. Ozone is difficult to make, it nature—ozone is made from lightning, that gigantic million volt shock that thunders the ground. We have a little more lighting now a days, than a few decades ago, but estimates are tough. Monitoring worldwide lightning strike takes a large network. There is one company, Vaisala, that counts lightning strikes. Skeptism of a

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company that makes environmental safety equipment reporting a more dangerous environment is natural, but there reported findings make sense. In the USA alone, there was a 14% increase in the number of lightning strikes from 2020 to 2021. Nearly 200 million lightning strikes. What makes sense is that weather patterns are becoming more severe as the planet warms. Higher latitudes are experiencing more summer storms, longer pollen seasons too. Pollen + Ozone = airway inflammation. Even if our planet gets it act together in the next few years, the trend of longer, heavier, are more sensitizing pollen is going to get worse before it gets better. https://www.vaisala.com/en/digital-­and-­data-­services/lightning

8.19 There Is a Fungus Among Us There is a fundamental difference between each of the following: VOC pollution, particulate pollution, pollen, and dust mite allergens. While all trigger mast cells and drive chronic inflammation, but seem to be limited to their own range. This limitation does not apply to the human Immune interactions with inhaled fungal spores. Fungal spores can act as irritant, pollutant, allergen, infectious agent, and direct mast cell activator. Thankfully the 50 year time scale I’m focusing on hasn’t seen then the aggressive evolution encountered in bacteria, but the world is becoming a friendlier place for fungi. Individual spore counts have not been tracked like pollen has over the years, but EPA review of multiple country data sets are strongly suggesting that increased agricultural land, hotter, more humid days, and even extremes of weather all contribute to the increasing spore counts being reported across the planet. More heavy rains, more floods and water damage, leads to more indoor mold. Mold spores are part of the reproductive cycle of the mold, however spore are destined to digest what they land on immediately when wet, and to not have stored energy like seeds. Mold spores have active digestive enzymes that specifically activate the surface detectors of mast cells.

8.20 Simple Summary Outdoor climate change has taken the spotlight for the past decade. This has clearly resulted in increased pollen seasons, and increase in allergy symptoms from pollen. Air pollution mixed with pollen inflame the body more than either individually. However, in partial response to outdoor climate change, people are spending more time inside, and the air inside homes is less healthy than suspected and has none of the protective governmental oversight that has cleaned some of the outdoor air. Every single breath counts—This marked shift indoors, with increased inhaled triggers of inflammation, has affected every human body.

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Key Terms • Pollution: Garbage from human activity. There is airborne garbage, waterborne garbage, hot garbage and frozen garbage. Human garbage causes human inflammation. • Particulates: Airborne particles that are too small to fall to the ground so they stay airborne, and these are also light enough to be inhaled deep into lungs. • Ozone: This is a form of oxygen molecules that is “high energy,” and can be harmful to the body. Similar to the ozone in the ozone-layer, ozone that human’s breath is much lower in altitude. This is a form of human pollution that is harmful to humans, however when ozone is present at around 20,000  m above sea level, it filters out lethal ultraviolet radiation from the sun. When mixed with pollen, it makes pollen more allergic. • Mold/Fungus/Yeast: This is a form of life that does not move or make its own food. Yeast and Mold are both synonymous with Fungus. The spores are a form of reproduction of life that can be inhaled and lead to allergy or asthma.

References Beck I, Jochner S, Gilles S, McIntyre M, Buters JT, Schmidt-Weber C, Behrendt H, Ring J, Menzel A, Traidl-Hoffmann C. High environmental ozone levels lead to enhanced allergenicity of birch pollen. PLoS One. 2013;8(11):e80147. https://doi.org/10.1371/journal.pone.0080147. PMID: 24278250; PMCID: PMC3835901 McCormack MC, Breysse PN, Matsui EC, Hansel NN, Williams D, Curtin-Brosnan J, Eggleston P, Diette GB, Center for Childhood Asthma in the Urban Environment. In-home particle concentrations and childhood asthma morbidity. Environ Health Perspect. 2009;117(2):294–8. https:// doi.org/10.1289/ehp.11770. Epub 2008 Oct 24. PMID: 19270802; PMCID: PMC2649234 Pointner L, Bethanis A, Thaler M, Traidl-Hoffmann C, Gilles S, Ferreira F, Aglas L.  Initiating pollen sensitization—complex source, complex mechanisms. Clin Transl Allergy. 2020;10:36. https://doi.org/10.1186/s13601-­020-­00341-­y. PMID: 32884636; PMCID: PMC7461309 Schmidt CW. Pollen overload: seasonal allergies in a changing climate. Environ Health Perspect. 2016;124(4):A70–5. https://doi.org/10.1289/ehp.124-­A70. PMID: 27035881; PMCID: PMC4829390

Chapter 9

Human Social Interactions

9.1 Despite All Human Rage, We Are Still Just Rats in a Cage A long time ago (1972), when humans experimented on mice to make correlations to human health, a horrific experiment was undertaken to determine the social impact on a family of mice give limited resources over time. Super freaking boring, until it got interesting. It seemed that when there was enough food for the entirety of the population, they seemed to treat each other pretty well. However, as the population increased near to or in excess of the amount of food resources, it became a fight. Mice that were friends generations ago, killed each other trying to get at the food. No differences in genetics, just more bodies in close quarters with each other. This experiment was used to make societal statements about “carrying capacity,” and how the world needed to control its population. Like those mice subjected to a horrific life during an experiment, almost all other animals behave differently based on how many of them are in a group. Some animals are so dependent on social interaction that it is not legal to own only one of them. Behavior almost always becomes more aggressive towards other members of the species when things get….. “crowded,” almost like a biological proximity trigger. Different species have different “happy levels” of populations, but they all seem to have a critical mass of density when things start to turn sour and they start acting aggressively towards one another. Triggered aggression against one’s own species doesn’t necessarily make sense in the grand scheme of “survival of the species.” In simple terms, it would make more sense that a species would survive if it had evolved the inability to hurt its own members. But this seems to a very common trait amongst animals that seems to increase as they become more “social animals.” The formation of territory, or “pack structure,” amongst social animals is also commonly seen and increases in complexity the more social the animal’s species. Even today, in the virtual world humans © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5_9

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have aligned ourselves into various exclusive groups according to common attributes. On the opposite side, most animals with brains don’t like to be alone. I’m not talking those snakes that only meet randomly to reproduce once per season, most mammals are naturally pack animals and need others around them. Solitary Confinement is cruel—harmful to the brain. Isolation is very harmful. On one end, not having any contact with another human being is very harmful to the mind, on the other too much contact with others causes aggressive destructive behavior. There is only a limited amount of time and brain capacity to accurately determine if another human is a threat or a friend, this amount of time per day decreases the more daily social interactions. There does not appear to be a uniform “social comfort zone,” that is widely applicable to human kind. Personally, I get saturated or even overwhelmed with social interactions much quicker that many of my close friends. Prior to being aware that my brain was different than other brains, my saturation point typically turned into negative reactions. The learning effect on my brain reinforced the saturation point by associating the negative emotions I was bringing to the interaction, leading me to increasingly limit social interactions.

9.2 Bring Your Friends, It’s Fun to Lose and to Pretend In a gross over-simplification of human brain function: the social environment that is currently understood as “normal,” is an uncontrolled experiment. This happened entirely in my conscious lifetime, and I highly doubt that any human that started this experiment had intentions of creating something harmful. Despite being an uncontrolled experiment, there is an enormous amount of data being collected on every single human brain that gets into a computer-based form of socialization. However, none of the information being gathered in this social experiment is concerned with the mental health of the brain connected to it. Why should any company bear any responsibility on the long-term health consequences of its product? Social media while highly entertaining massively increases the sheer number of proximity alarms, but negates all the pheromonal oxytocin feel good hormones from social interaction. It can cause all of the depression and harm of social isolation yet also increase the aggressive desire to attack ones own species.

9.3 Here We Are Now, Entertain Us Once upon a time, I was peer pressured to take an oath to “do no harm.” I took this oath prior to the invention, and subsequent explosion of social media. Being oath-­ bound to not hurt people, I could not have been involved in the invention of social media because it was created without any oversight on hurting humans. It also would have been extremely boring and a colossal failure. The primary difference

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behind the creation of the non-existent “no-harm” social media would be in the algorithms which drive utilization. I do not know any lawyer good enough for me to say that any social media platform was molded with the intention to “cause harm.” If fact, many of the figureheads behind this “civilization-buster” took the initiative to regulate themselves once it became known that it also became a mechanism of human to human harm. Disclosure: my thesis is rooted in discussing the comprehensive change of human environment within a few generations. There should be no implications of “good or bad,” or “right or wrong.” The ability to instantly meet and share scientific, cultural and other information with humans across our planet is a landmark achievement— like splitting the atom or discovering antibiotics. “No-harm” social media would still need to gather data about each individual user, however instead of algorithms to induce user expense (time, emotion, and then money) “No-harm” would have needed algorithms to determine what each individual human brain most needed in that moment to better exist in its current environment. Then to each needy brain, deliver positive reassurance, in an efficient and inexpensive manner. Some specific examples of this hypothetical Hippocratic hyper-media would have been to limit visible pictures of people to those only less attractive than the user. This to limit relationship anxiety and to make sure that no human would feel any subconscious threat regarding personal attractiveness and other distractions from intrinsic self-worth. News and searches would highlight examples of responsible utilization of financial resources, as to discourage negative-­ emotional driven spending of money leading to financial insecurity. Most importantly, humans that utilized this social media would have their self-esteem reaffirmed without feeling the need to evoke negative emotional responses in people that have different opinions. This obviously exaggerated Imaginary internet would not be very popular, profitable, nor do I think such a thing would be possible. I think I got bored just writing about this imaginary impossibility. The Social Media that helps brains “relax, repair, and reset” would never work because it’s boring. Fight or Flight gets attention. Nothing about the “absence of harm” chemically maintains attention. It is hard work getting somebody’s attention to the stuff that keeps them healthy, and much easier to identify threats. Threats not only maintain attention, they trigger rapidly sharing the message to notify other humans. This chain reaction of the most brain-jarring media grabbing attention and then which is quickly shared is in infective amplification, much like a virus going through an immunocompromised host. My hope is that 1 day, a vaccine that prevents viral social media will be invented, however I’m not entirely sure how to get the word out.

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9.4 Over-Bored and Self Assured I personally love television and movies, all of these forms of entertainment that are somewhat of a “Story (di)Version” of the human condition. While Science Fiction has always been my preferred diversion, I also enjoy comedy, but would never admit to enjoying drama or suspense. However, if somebody was tracking my television watching patterns, there is a clear trend of “binge watching,” which I am clearly affected by. It does not seem that I am able to binge watch Comedy Movies, and frequently I am able to fall asleep during some of the modern comedies (Tongue in cheek joke about how they aren’t as good as they used to be.) One thing I did not have enough of when I was a younger individual was access to quality diversions such as television. In this past decade, there is unprecedented access to television, movies, documentaries, and much of it is very entertaining. There is even a new term, “Binge Watching,” which refers to prolonged sessions of same-show watching multiple hours in a row. I have binged, and I am not ashamed. There is the obvious lack of interpersonal engagement, physical exercise, and a few other negative aspects of watching 6+ h of television in a row. Tension, fear, anticipation, excitement are the emotional states that keep human attention for hours at time. Sexual tension is an attention grabber as well, but that lasts at most 10 min on good days. Becoming distracted by high tension human stories with “nail biting” cliff hangers really push the “fight and flight,” of the autonomic nervous system. I’ve watched Television so good that my pulse rate was 20–30 beats higher than resting during much of the show. I loved every minute of it. Many times, I have trouble sleeping after binge watching high tension shows, several times this also included hours of lost sleep. This “binge watching” thing did not exist just a few decades ago, and there has not been any thought to how this could impact human health. While there is no “Peaky Blinders” health syndrome, the action/drama/tension market share of movies in a recent between 1995–2023 Comedy was less than 20%. (the-­numbers.com, genre) Now it is generally known that by 1960 most American households had one television, and that 1980s was considered the decade of “Music Television.” When Cable led to streaming, and bam, there went my weekends. The entertainment industry has been criticized nearly as much as the medical industry, and at last they have been able to reduce the amount of people smoking tobacco in their products. Now science is starting to catch up to the effect, or at least the association of mental health conditions at binge-watching of television (Starosta et al. 2021). Prior to the COVID19 Pandemic, the amount of binge watching significantly increased from 2015 to 2020 (Rubenking and Bracken 2021). Thankfully, the swiss have looked at the ability to fall and stay asleep after binge-watching television (Baselgia et al. 2023) and there were not major problems between the groups that watched suspenseful television or normal television right before bedtime, all participants were in there early 20s. No longitudinal studies have been completed, again because this behavior is a very modern invention. Physical Health, which is

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also important (Shirakawa et  al. 2016) is also affected by watching television in consecutive hours.

9.5 Where Do Emotions Come From? Human emotions come from weakness and they must be controlled at all costs. Seriously, the depth and diversity of the human emotional experience are one of the most special parts of being human that I have read about and hope to experience 1 day. Another very special part of being human that I have read about, is the process leading to human reproduction. While human the human emotional and reproductive experience are foreign and mysterious to most physicians like myself, they are very important to the survival of the human species. In fact, stripping away every other social construct, humans having emotional attachment and the ability to reproduce with other humans might be the only things necessary for species survival. The part of the brain that is responsible for emotions is called the diencephalon and it is packed with mast cells. The genitalia, which is responsible for human reproduction, is also packed with mast cells. This is not a straight forward observation, as many mast cell type medications are not considered to have an effect on emotions, libido or reproduction. The conceptual spectrum of human sexuality is well beyond the scope herein, however the sexuality of rodents is something that scientists have much more knowledge on. The mast cells in rat brains change the way the rat brain works—if a hormone is given during growth that increases rat mast cells in the rat brain, it will make a “female” rat have brain firing patterns like a “male” rat. It is important that topics such as human emotions and sexuality are discussed in a mature, and non-judgmental fashion. I’d like to apologize for only being able to be non-judgmental. Human sexual physiology is not a topic of open discussion; however, it is does not disappear just because humans stop talking about it. The human body has accumulations of the environmental response mechanism, connecting both the Immune system and the autonomic nervous system, in the centers of emotion and reproduction. Emotion and reproduction are big parts of human sexuality—and the role mast cells play in these interactions is not completely understood in rats. So maybe humans should better understand our own species sexuality prior to being all judgmental about it.

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9.6 Laughter Is the Best Medicine (Please Don’t Tell the Drug Companies) There are humans who “do not like to laugh,” and those are generally sad and/or angry humans. One possible reason any human in these negative emotional states try to avoid laughing is urge to stay empowered by their emotion. These negative emotions have a purpose, other than being a “party pooper,” these are fight/flight switches and usually there are stresses or threats pushing these emotions. The implied reason to suppress laughter: laughter relaxes, and helps humans feel better. Unless of course, that laughter is directionally aimed at a particular human or group of humans, without their permission. This type of laughter is actually threatening. While it might be enjoyable for Cardiologists to make fun of Allergists, it is very hurtful. I don’t wish to get philosophical here, but the health benefits of human laughter date to a very long time ago. Humor was invented prior to writing, but the first known documented joke is from Ancient Sumerian texts and reads: “A dog walks into a tavern and said, ‘I can’t see a thing, I’ll open this one.’” It’s pretty cool to note that the oldest documented joke is an “inside joke,” because it doesn’t make any sense whatsoever to modern day humans—but it scientifically qualifies as humor. Humor has been around longer than Immunology, and much like Immunology the responses to humor are not perfect nor are they entirely predictable. Two very similar humans may find very differing levels of humor in the same joke. While I wrote above that there are humans that purposefully repress laughter to empower their negative emotions, this does not mean that anyone that doesn’t laugh at a specific joke is depressed. Laughter is the best medicine, but like all medicine it works differently in different human bodies.

9.7 The DNA of a Human Human children inherit physical traits from each of their parents, and this is NOT a new development. Neither is this understanding of passing of traits to offspring recently understood. The understanding that human children look like human parents has been around longer than humans have been writing stuff down. Interestingly, the following discoveries were all made in the last 70 years: 1. The structure of DNA, the building block of all known life forms, in three dimensions. 2. The storage form of DNA information in a “four-letter” format (A-T-C-G) and 3. The translation of this DNA storage language into the 20 letter Amino Acid alphabet. These three major advancements have unlocked the mysteries of the human genome, and solved every physical, mental, and social illness our species has ever had to deal

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with. At least we hoped that the human genome project would do such things. Human scientists “solved” the language of life, years after splitting the atom, after building rockets that can leave Earth’s orbit, establishing a system of instantaneous communication with others around the world. Knowing where the information is, how to read it, and what the interpretation of these four letters mean. My point here is relatively simple—just because humans have developed a technology, it doesn’t mean that humans are going to use that technology to heal people. It is interesting to note that the “human genome code” is written in a language simpler than English. It terms of real information, such as that information stored in a computer memory, estimates usually run between 1 to 3 “gigabytes” of information can be stored on the amount of DNA that humans have. Computer and console games made specifically for human entertainment have carried more information than a gigabyte for close to 20 years, and now some are upwards of 100 gigabytes. Humans should be easy to figure out, right? I started using human genetic testing in clinic in 2014, and I sent less than a handful per year. Around 5 years later (2019), the cost and the accuracy had evolved to the point of it actually making sense to routinely order genetic testing in an outpatient clinic such as mine. Diagnosing a sick or unwell human is a dangerous endeavor, as many current treatments contain the capability for harm as well as healing. Having access to each human’s DNA blueprint is like “cheat codes” for healing them, because in many cases the knowledge about what will heal and what could harm is written in their code. Unexpectedly, DNA testing also opened up many patients to an entire new source of guilt and self-blame. Specifically: Human reproductive pairs tend to view genetic testing results of their child as the assignment of blame, I.E. “He got it from his Dad.” Human brains are so conditioned to blame ourselves that the exclusive four-­ letter code of life, which has been around for a BILLION years, “discovered” less than a few lifetimes ago, routine testing being available only a few years ago, could possibly be something that any single human could shoulder responsibility. Explaining this statement on “genetic-blame,” has been the closest I have ever come to scientifically invalidating someone’s feelings.

9.8 The DNA of a Human-to-Human Healing: Apology Passing on DNA to offspring is never something that needs an apology. However, there is a lot of other shenanigans humans need to start apologizing. The scientific code of an apology is not a four-letter word, and remains difficult for most. Humans know the language of apology, however that does not mean that they use it for healing other humans. The scientific code of apology is the language of human-to-­ human healing, and represents something for which any human CAN take responsibility. For simplicity sake, I have replaced the A-G-C-T from DNA with R-A-G-E. Clinical Example:

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Human #1 does something that hurts Human #2. Human #1 can start to repair this hurt with RAGE: Responsibility. Acknowledgement. Grace. Empowerment Responsibility—Human #1 must take ownership for the action that caused harm to Human #2. The healing will not go well if Human #1 blames Human #2 for the harm. Acknowledgement—Human #1 must validate the harm caused to Human #2. Healing can only happen if the harm is validated, and otherwise appreciated by the person taking responsibility. Grace—Human #1 must allow Human #2 whatever time or action is necessary for Human #2 to begin healing. This cannot be forced or demanded by Human #1. Empowerment—Human #1 must agree with Human #2s decision on repairing the relationship, which means giving away the power that may have allowed the harm to occur. This apology acronym: R.A.G.E., can be a basis for healing for BOTH humans in the disagreement. Humans need other humans, and frequently humans hurt those humans closest to them the most. Guilt is real, and is harmful to all involved. Healing can’t begin until the human believes that they deserve to feel better. Trying to manipulate Human #2 into removing Human #1s guilt only drives further harm to the #1-#2 relationship. This is a commitment to the importance of the human-human relationship, Bad Example: “Human #1 is sorry that Human #2 was hurt, however it was Human #2 that caused the situation that led to Human #1s hurtful action. If Human #2 was more robust to such actions, or more careful, there would be no harm. Human #2 doesn’t really need to heal because the harm is not real. Human #2 needs to get over the action right away, they owe it to Human #1.” Good Example: “Human #1 takes responsibility for the actions of Human #1, these actions resulted in harm to Human #2. Human #1 recognizes that this harm was real, and expresses sorrow that Human #2 has been hurt. Human #1 will make an effort to understand what led to Human #1s action, and makes an offer to deliver what is asked by Human #2 to assist in recovery from the harm. Human #1 gives the power to reconcile the relationship to Human #2 without contingency.” This is as close as I have come to a “scientific expression” of apology. Also, by stripping this healing action down to just the basic RAGE, it becomes obvious that the social environment in which modern day humans exist is 100% Bad Examples of scientific code of apology. Humans learn by observing other humans. Humans hurt other humans, and the instructional behavioral examples remove the guilt by shifting the blame to those humans who have been hurt. This just makes humans better at causing hurt. Personally, I spent 25  years so far learning to heal people with the Science of Immunology. However, its been 46 years as a human, and I’m still having trouble actually practicing the Science of Apology. This is an important skill for any human to develop, as within this expression is power to heal other humans—particularly the humans most important to them.

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9.9 After Saying “I’m Sorry,” Don’t Forget “Please” and “Thank You” I have seen humans blame themselves for their body’s response to an unhealthy and alien environment, and it is quite common. After accepting the fact that all humans hurt other humans, intentionally or unintentionally, apology can start the healing. Gratitude is showing another human that they or their actions are appreciated. Also, expressing gratitude reduces interpersonal tension, stress, and all forms of fight or flight. Humans are a social species and are interdependent on each other. Expressions of gratitude strengthen human to human connections, and remember humans are the biggest threat to other humans.

9.10 Get Mellow with Melatonin, Get Anxious with Histamine Mast cells are the major producers of histamine in the world of humans, and this is where they get much of the recognition. Histamine as a cause of allergic seasonal symptoms is older than color television, and antihistamines have long been used for such symptoms. Also, anti-histamines have been useful for putting people to sleep. I mean helping humans fall asleep. The two largest sellers in the Over-the-counter sleep medicine are diphenhydramine and doxylamine, both are “old-school,” or first generation antihistamines. Much of this effect was thought to be due to these medicines have side effects by acting outside of histamine receptors, however in the past decade histamine is found to be very important for waking up the brain. Histamine is an alertness molecule, and high levels can make people anxious. Interestingly, another highly popular over the counter sleep hormone is melatonin. Melatonin and Histamine may not seem like they have much in common, however they are both major neurotransmitters that can both be made by mast cells. In fact, other than the pineal gland in the brain, mast cells are the only part of the body that can produce melatonin for export to other parts of the body. While the sleep-­ wake-­cycle is important, this relationship between histamine and melatonin is in regards to socialization. The exact spacing, placement, timing of the interplay between these two neurotransmitter and human behavior is only currently being explored—but mast cells can bring them both. Histamine and melatonin are both made same cell compartment, however it is more like that they “can’” be made by the same type, but not at the same time, or not in the same location. There has been some small studies that show antihistamines to not reduce or impair the release of histamine at night time. My focus has been that the mast cell compartment is a focus point of the human body’s adjustment to harmful environmental stimuli. This focus point that responds to stresses by going to body parts that need boosting, can boost all the body responses.

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9.11 Social Sensitization, Social Hypersensitivity Think of emotions as kind of like the “volume” switch during the recording of memories. The louder the volume when its recorded, the deeper the imprint. Thus, the best memories have the best place in our metaphorical heart, while the most traumatic experiences have the worst place. So bad, that the brain can suppress or “black out” certain memories in attempt to prevent living with the deep adjustments. Experiences can happen to people so mind-blowingly bad, that if they processed it all, they might not ever be able not feel that negative. The hippie generation called this war. My generation (Gen X) were called slackers because we didn’t get drafted into a war traumatize us, so we invented Reality TV. Some combat soldiers have trouble processing the potentially horrific events that occur, and deal with substantial long-term psychological consequences. Experience shock can come from other ends too. Really, really good experiences, like winning the lottery, or winning a gold medal, also shock human memory-­ making system. Many Olympic athletes battle depression following competition, presumably they are unable to feel anything any close to the emotional excitement like winning a gold medal in a sport that counts. Any human experience that is way ‘outside the range’ of normal can adjust the brain in a way can affect future experiences. Thinking Exercise • Take 5 min to close the eyes, and try to remember the 5 most traumatic experiences in life—were people involved? • Now, take 5 min also with the eyes closed, and try to remember the 5 most “wonderful” experiences in life—were people involved? Now, most humans do not like to remember past trauma, and if the reader completed the exercise they’ll understand, because the brain relives past trauma. This is protective, and a normal response. However, for those humans that have suffered past trauma it can be very difficult to “feel normal.” Stress results from being sensitized. Like signals from infectious sources signal the appropriate Immune or Inflammatory response, anxiety is a signal that heightens the response. This is usually for bad, but I was anxious the day I married April and when my girls were born, and those were the best days I’ve lived. Being afraid also kind of works like a chemical. The tension, the heightened anxiety, all lead to bigger emotions. So those SOBs on the News provoke anxiety in people to addict them, just like tobacco, sugar, and Columbian bam-bam. Works the same way with human interaction, good or bad. Social media conglomerates are run by some pretty darn smart dudes, and believe it or not many of them have high aptitude for mathematic and analytics. They titrate these algorithms to increase usage. Usage is maximized by generating memorable experiences. Like or Fight, the effect is the same. Both of which are designed to drive anxiety. Nothing happy and/or healthy promotes anxiety induced compulsive defensive behavior.

9.13  A Little Tribe Has Always Been, and Always Will, Until the End

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9.12 I Feel Stupid, and Contagious Whether we like it or not, every single human being has a multi-million year evolutionary programmed desire to be accepted to part of a “pack.” Immunologically speaking, other people represent the largest threat to healthy Immunity. Communicable infectious diseases such as staph, strep, go from person to person, and the more people someone has contact with—the higher the risk of infection. So there is no “right” number of infections that someone needs, but our systems exist in a setting of overstressed, and are having a hypertrophic response. There are numerous signals that involve the allergic mechanisms of the body, and the changing environment directly is changing how the body reacts. Socialization with other humans is just as important to the mind and body as many environmental influences. Its necessary, but we don’t really have a good objective way of measuring adequacy of socialization. What is the right number of friends to have? No doctor can tell you that answer. However, everyone is aware of the connection between close friends. There is a behavior change that only comes from comfort, recognition, and most people are in almost constant searching for this type of connection. My face, my posture, my collective level of tension noticeable improves when I am in the presence of old pack members. If we think about a inter-human connection as a necessary component for a healthy mind, like a vitamin or exercise, it changes how we perceive our friendships. During the development of our brains, how many different humans were each other coming into contact with? A few hundred? Maybe a thousand? We know that solitude it toxic, solitary confinement has direct effects on brain function. Emotions are more than chemicals, but histamine is a neurotransmitter that is directly related to alertness to an acute stress response. Mast cells accumulate in the brain in response to stress, and very much heighten the ability for the brain to sense its environment. While this was likely such a powerful force out of necessity, modern day is a time of abundance for human-to-human interaction and most of it is negative.

9.13 A Little Tribe Has Always Been, and Always Will, Until the End An argument ends when someone changes their mind, or someone changes their emotional state. On the pack-acceptance level, there needs to be a connection. We have a need to see the same level of involvement in other people so feel comforted by the pack. What has happened is overload, the human brain is under constant invasive challenge to emotionally connect and response, that there has been a mutation of the original programming. Speaking with Doctors, healthcare Providers, is somewhat frustrating. Very few people, if they had the choice, would chose to do this sort of activity instead of

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working, playing, or spending time with Family. This is a vulnerable situation for any human, to enter the lair of a Physician, wait in various rooms, poked, prodded by the staff, and interrogated multiple times about “why are they here?” By the time we actually get face to face, there is a differing level of warmth and comfort amongst the various people that I am able to see. In the colder and less comfortable encounters, I can tell that the communication is off and that I either do not understand the concerns or unable to accurately express my opinion or knowledge.

9.14 Human Culture and Traditions Are a Way of Defining the Pack of Humans There is safety in numbers, large numbers of people. However generally when two very large groups of humans get together, it depends on the colors of cloths they wear. Humans take their sports teams very seriously, and even more so when large groups of them gather together all wearing the colors of their established team. But most serious is when one human, or smaller group of humans, wearing colors of the opposing team gets in close proximity to the first group. For humans, being accepted and held close to a pack meant survival, reproduction, security. It very much was a developmental pressure the created current humans, and critical as the instinct to breath, eat, or sleep. There is a realness to this—and for most humans the “set pack” is as unique as their height/weight/hair color. The desire to form new connections means more units of survival, this rewards reinforcement is high intensity to new interactions (tribal man could only meet 200 people in their entire life (4 new people per year). High energy for the rare event (meeting possible new pack) high rewards, low energy reward for maintaining the high frequency (maintenance of relationships). Today somebody can get the chemical rush of meeting hundreds of new people per DAY—its completely overwhelming. Thinking Exercise • How many people can be met in 1 day? • How many friendships can be formed in 1 week? • How many relationships can be maintained for a lifetime? Most humans are capable of meeting more people in a single day than are able to maintain a lifetime relationship. This is a brand-new phenomenon, and it is not good or bad, it is barely understood. Social Isolation, or “Losing the Pack,” triggers inflammation. The lack of pack support triggers anxiety, while closeness relieves stress. Human brains evolved under the pressure to recognize maybe 500 faces/personalities in the life to find a reproductive partner, and by the age of family formation—those humans had already met all the potential partners possible. 99% of evolutionary drive humans existed in one single area their whole lives—the desire to get away from people led to more

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people. As ancestors migrated, they left an area with a small group of people the greatly expanded the number of reproducing humans with their genes, so modern day genes favor dispersal and distance. Native cultures kept their distance from one another, and took centuries for traditions to intermingle. Human conditioned learning drives us socially forward while our survival instinct pulls us back, tearing our brains apart from our souls. It is a simple concept, like a fish out of water. Fish do not have an evolved mechanism to find water—their existence depends on it, they die within minutes without water. The survival instinct presents as struggle to flop back into the water—they just do it without the gigantic human brain to back it up. The modern human social condition is like fish jumping out of water due to fear/anxiety, then jumping back just to take a breath of water.

9.15 Simplified Summary Doctors have to take an oath before they treat patient and call themselves “Physicians.” While it may seem like a silly idea, no other industry starts out with a promise not to harm other humans. I think that many of the current forms of media that have exploded in the past 50 years should also be examined for the possibility of harming humans. Entertainment and socialization have always been a part of human civilization, however at no other point was access to nearly infinite forms of sensitizing stress available to adjust any human mind. This is a drastic change, that was not anticipated to cause anything but a lack of boredom. This type of mental programming and stress is obvious, but sometimes only if the brain is asked to specifically think about it. Key Terms • Triggered Aggression: Taking action that is hurtful in response to some form of stimuli. • Social Media: Something that is new to human existence, and makes a lot of money for the people that control it. Also leads to high levels of stress and anxiety that are affecting human brains in a way that has never before been studied. • Laughter: An expression of joy, relief, and happiness in response to something funny. I am unable to define what “funny” is according to my wife. • Apology: Once a human has accepted that humans hurt other humans, the healing can begin with an apology. This is not an easy thing to do, and very few humans know how to do this correctly. Also, this is something I frequently need to do after trying to make other humans laugh. • Packs of Humans: This is not just groups sports fans rooting for their chosen team, this is a true psychosocial need that extends through and beyond just a family.

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Bibliography Baselgia S, Combertaldi SL, Fahr A, Wirz DS, Ort A, Rasch B.  Pre-sleep arousal induced by suspenseful series and cliffhangers have only minor effects on sleep: a sleep laboratory study. Sleep Med. 2023;102:186–98. https://doi.org/10.1016/j.sleep.2023.01.005. Epub 2023 Jan 11 Costa A, Rani B, Bastiaanssen TFS, Bonfiglio F, Gunnigle E, Provensi G, Rossitto M, Boehme M, Strain C, Martínez CS, Blandina P, Cryan JF, Layé S, Corradetti R, Passani MB.  Diet prevents social stress-induced maladaptive neurobehavioural and gut microbiota changes in a h­istamine-­dependent manner. Int J Mol Sci. 2022;23(2):862. https://doi.org/10.3390/ ijms23020862. PMID: 35055048; PMCID: PMC8775792 Lenz KM, Pickett LA, Wright CL, Davis KT, Joshi A, McCarthy MM. Mast cells in the developing brain determine adult sexual behavior. J Neurosci. 2018;38(37):8044–59. https://doi. org/10.1523/JNEUROSCI.1176-­18.2018. Epub 2018 Aug 7. PMID: 30093566; PMCID: PMC6136154 Pham L, Baiocchi L, Kennedy L, Sato K, Meadows V, Meng F, Huang CK, Kundu D, Zhou T, Chen L, Alpini G, Francis H. The interplay between mast cells, pineal gland, and circadian rhythm: links between histamine, melatonin, and inflammatory mediators. J Pineal Res. 2021;70(2):e12699. https://doi.org/10.1111/jpi.12699. Epub 2020 Nov 29. PMID: 33020940; PMCID: PMC9275476 Rubenking B, Bracken CC.  Binge watching and serial viewing: comparing new media viewing habits in 2015 and 2020. Addict Behav Rep. 2021;14:100356. https://doi.org/10.1016/j. abrep.2021.100356. PMID: 34124334; PMCID: PMC8173264 Shirakawa T, Iso H, Yamagishi K, Yatsuya H, Tanabe N, Ikehara S, Ukawa S, Tamakoshi A. Watching television and risk of mortality from pulmonary embolism among Japanese men and women: the JACC study (Japan collaborative cohort). Circulation. 2016;134(4):355–7. https://doi.org/10.1161/CIRCULATIONAHA.116.023671. Starosta J, Izydorczyk B, Wontorczyk A. Anxiety-depressive syndrome and binge-watching among young adults. Front Psychol. 2021;12:689944. https://doi.org/10.3389/fpsyg.2021.689944. PMID: 34335407; PMCID: PMC8322237

Chapter 10

The Human Brain/Body Input/Output

10.1 The Father of Stress As my wife loves to remind me, “stress was invented by a MAN.” The famed Doctor Hans Selye is credited with being the first scientist to describe health changes to an organism from environmental demand. His observations started by connecting various similarities between sick patients with different illnesses. The symptoms of foul mood, fatigue, and loss of appetite. This initial observation in humans was the theme that carried into his scientific career which at the time was discovery of the hormones. He made observations that through the experiments all of the laboratory animals showed the same negative effects on the animal’s organs—regardless of the hormone he injected them with. Then he tried various other types of environmental stresses such as heat, cold, and got the exact same response. Dr. Selye observations, particularly on the adrenal glands (endocrine) and the thymus (Immune), was the first discovery on the road to stress related changes. Our current understanding is that the Immune and endocrine systems are not only the “work horses” of the chronic stress response, but also the victims. While stress and mood have likely been tied together since the dawn of human history, it is only within the past decade or two that the understanding of how the immune adaptive mechanisms can be changing the brain itself in response to stress. Further reading, The stress of life Hans Selye written in 1956. This was also an interesting time “circa dies” or latin for “about a day,” became returned “circadian.” These rhythms of life are necessary for efficiency, survival, but also at the time in human scientific achievement when it was actually plausible that members of the human population were starting to really deviate from a standard 24-h day. Now, of course humanity had people awake all night such as “night watchmen,” and other third-shifters, but the widespread population to work or stay stressed longer than 12 h per day is only 4–5 decades old. It is not a random occurrence that the human body’s daily budget and energy is entirely structured on a quantity of time that is exactly the duration of an Earth day. Humans evolved on planet earth, and the length of a day has not changed since © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5_10

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humans became humans. If humans went to a planet that had a 40 h “day” these circadian cycles would fall apart. Unfortunately, human scientists are not able to determine the exact specifics on how human brains respond to the stress of circadian disruption. I’m told that this is because of the difficulty in obtaining fresh human brains for testing, or perhaps of the lack of volunteers. However, in humanity’s greatest cousins the laboratory mice, this adjustment mechanism has been found to be mast cells in the brain and fat tissue of the body (Nishino et al. 2022). Brain and fat—that is what this chapter is all about. This is new information at the time I’m writing this chapter, published with peer review within that last 5 years. To get to this point, we collectively had to learn that the mast cells did more for the body than just fight off parasites and dog hair. If fact, they are one of the most versatile parts of the human body and brain. Finding immune cells moving into the brain in response to stress is a big discovery. This has not yet made its way into clinical practice, but the increasing knowledge link between mental health, mental function, and environmental inflammation is very exciting to witness. The combination of emotions admixed with experiences drives future behavior. As we want to make more good memories, and learn from the mistakes that led to bad or painful memories. Go ask a recovering addict how they remember being stoned? Generally speaking, the association of past-trauma with depression and/or addiction is extremely high (no pun here, too dark to joke.) The term “self-­ medicating,” is highly accurate—as in a chemical is used to produce a feeling, or at least block another feeling. Drinking wine was technically the first “Alternative Medicine.” Its fact, dealing with past trauma helps people deal with present day depression, and also is important with getting people into recovery from addiction. The many “steps” of the 12-step program focus on reduction of self-blame. (1) It’s not up to self, (2) Self needs help, remove expectation of self, (3) Self will atone for my actions, to stop the negative reinforcement. Feeling bad about oneself makes all experiences negative, only reinforcing the need for Alternative Medicine. Openly discussing leads to acceptance and removal of guilt.

10.2 Seasonal Affect Disorder (SAD) This is something difficult to explain, as the term “Affect” usually is used to describe the purpose of an action on something. I still have trouble using Effect v Affect, but in the Medical term Affect speak to the immediate display of the emotional state. So instead of reading this as “Seasons changes affect the person,” is should be “Human emotional states are affected by seasonal change.” This usually means that some humans get more sad than others in the winter, and others get a little to happy in summertime. This makes a ton of sense in the terms of animals and resource conservation. It’s that darn pesky emotional human brain that gets it all messed up. The effect of seasonal change on mood is nothing new, but the term “Seasonal Affect

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Disorder” was first used in 1984. While this was initially attributed to the production value of the “Superbowl Shuffle” performed by the Chicago Bears, it has since been specifically attributed to the variability of light encounter by the human body. The ultraviolet light exposure is the highest correlation with mood and well-being improvement (PMID: 2033028). While the 24-h day is a constant, the amount of visible light, warmth, and available food tends to change with the seasons. The changing daylight duration requires some human adjustment, to allow to more activity when the duration of light is longer, and less utilization of energy and less activity when the days are shorter. Simply put, if there are 16 h of daylight at maximum (Summer), 8 h of daylight at minimum (Winter), any non-alien species on that planet probably evolved the ability to alter its food intake and metabolism so that its maximum is twice its minimum. While the specific on energy, metabolism, and mood are not completely figured out—for example there is no blood test to determine the difference between “fatigue” and “depression.” They do tend to be parts of each other, but I don’t think I can say inseparable. There are many high activity, high metabolism human beings out there that are still dealing with depression. Neurotransmitter imbalances between Norepinephrine/dopamine/Serotonin are where much of the pharmaceutical interventions are focused. Melatonin is one molecule that has many uses, and is made by every single cell in the body, also all non-bacteria forms of life make melatonin. This is a form of the amino-acid tryptophan, and the agreed upon role for this molecule is an “anti-­ oxidant.” This is a tough concept, because Oxygen is good, and being against using oxygen is probably bad. Well, not all oxygen behaves itself, it can become radicalized and angry. Melatonin—in the inside form, mellows out only these angry oxygens. Immune cells need lots of melatonin, especially the parts that produces lots of angry oxygen to kill invading bacteria. Scavenging and disappearing angry oxygen radicals from every living cell in existence is only melatonin’s side hustle. Melatonin is a product of mast cells— however while EVERY cell makes melatonin, mast cells make it for exportation outside of themselves, however the specifics of this are not clearly worked out. Mast Cells—in the mouse model—are the immune cell that is responsible for protection and response of skin to ultraviolet light (PMID: 25776520).

10.3 Human Brains Have Functions That Exist in Addition to Emotions Emotions are important, and I do not mean to minimize them in any way. However, the human brain can do amazing and inexplicable things such as imagining something that has never been done before—creativity. Also, there is the ability to remember experiences and to learn from those experiences. While I would argue with anyone that my dog Copper has both a creative and emotional brain, he also

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has a tremendous capacity for memory and learning—especially when it comes to foraging through the house for food. Creativity is difficult to quantify and measure, and we are also not clear what level brain development or Earth species is capable of such thoughts. However, our beloved mice are able to form memories and learn new things. This has given us a window into how the human brain learns, and processes memories, and especially when this comes to stresses learning and memory (Fig. 10.1). Brains are complicated, but the important part here, is that adjusting the brain to and from stress involves the mast cell compartment. It should be stressed that this is interesting research but the true implication to the human brain is not known, and this is not the cause or mechanism for the effects of antihistamines on the formation of memories. Mast cells are the remodeling factor of the body to stress, this may have been mentioned a few times already. Mast cells go into the brain for learning, and for fear, family, or as Dr. Selyne would state “any type of change.”

TEST Normal Mouse

Learning

TEST Can't Learn

Mast Cell (—) Serotonin

TEST Mast Cell (—) Serotonin serotonin reuptake inihibitor

Can Learn

Fig. 10.1  Description. Stress Learning, with our volunteer mice. Mast cells move into the brain of mice when they get stressed by scientists. If the mice have the serotonin removed from their mast cells selectively, they don’t learn. However, if chemically added extra serotonin is increased with “selective serotonin reuptake inhibitors” then those mice are able to learn. How this looks in the human brain, and how histamine is involved is not understood yet

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10.4 The Importance of Body Heat When listing life’s necessities, we will frequently go to the list of “food, clothing, and shelter.” This is interesting, because at first glance, two of those items—clothes and shelter, the specific purpose is to keep human bodies warm. Even more specifically, of the food we eat, about 50% of the calories are used to maintain our body temperature. So technically 2.5 out of 3 of life’s necessities are about keeping warm. Our body temperature of 37  °C, however if we were outside in temperatures of 37 °C, the exact temperature of our body, it would feel hot. It would feel hot enough that we would not only be uncomfortable, and our body would begin efforts to cool it down. If we got into water that was 37 °, we would call it a “hot tub.” Prolonged exposure (>6  h) to environment exactly the temperature of our body is actually potentially harmful. It seems pretty far-fetched to think that our forehead can be 37 °C, be exposed to exactly 37 ° weather, and not only feel the difference, but it would feel noticeably hot. Its actually a pretty narrow window of temperature. Only a few degrees up or down, and a bunch of stuff stops working. If the human core temperature gets about 3 °C too hot, and enzymes stop working, and its tough to get oxygen to the brain. About 3 ° to cool, the heart conduction system gets slowed, and the brain starts to slow down. I like to think of the brain as a giant super-computer that is housed in a very strict environmentally controlled outfit. With dozens of controls that flash warning signs when there is the slightest change in the environment. The human body increases its temperature in response to several different types of infections, we call it a fever. Much of human behavior, migration, housing, is tightly regulated to body temperature. Humans have lived inside artificial structures for longer than we’ve had history, and have been able to warm our selves with fire since the invention of fire. However, the ability to cool a room, or refrigerate food, is only very recently. This allowed humans to move and live farther from food, and farther from Ohio. It also made us very lazy when it comes to cooling off our bodies. We share 98% of our genes with chimps, 90% with house casts, and 82% with dogs. We use mice in the majority of genetic experiments and that species shares only 67% of its genes with us. If we wanted to study the impact of sweating, which is the primary method a human body cools itself, we can only look at our very closely related species. There are only a few other primates that are able to cool themselves by sweating, and its not developed in other mammals and certainly not in the ones we use for most experimental models. Comparatively intelligence, communication, and other higher level brain functions are similarly evolved in our primate cousins. However, I didn’t typically consider the act of sweating to be as important as thinking, talking, or snuggling. There is not a lot of unnecessary functions of body organs, and as we learn more about the molecular level of interaction we find shocking amounts of polymorphic importance to body processes. Take allergies for example, in modern humans this seems to be a complete waste of energy and Immune system resources. There is no

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modern use for allergies, however 7it was once a very necessary body function. Human sweating is not just an annoyance, it is not just to cool the body, it is fundamentally necessary for the autonomic nervous system and the Immune system. A major arch I am putting forth is that changes in the environment that our species has caused are different than those that drove our evolution. This is not good for our species. The species fits its environment—not everything that lives in the ocean has gills. Dolphins, whales, have lungs just like people, but they can’t live on land. If a large whale ends up on the beach, the change in its local environment cause its demise relatively quickly. A whale needs to be floating in water to survive, on land it will over-heat quickly, or even become crushed under its own weight. Whales have B-cells, T-cells, and pretty much the same Immune system as humans, however they lack the core strength to hold up their own weight to gravity, or the ability to sweat to cool themselves down.

10.5 Life: Temperature Variance Outdoors Life evolved by efficiency, there is no wasted space in the body, and there certainly is no wasted energy process. All of the body’s energy processes need oxygen—it was in the atmosphere, its great to inhale. But the day-to-day aspects of using our body have multiple uses, I mean, why not use physical activity to pump the immune system? It was a given that movement of all limbs, and exposure to swings in temperature was hard-wired into our efficiency—and so it is. Motion is implied in human life, well a heck of a lot more motion than most of us get these days. Exposure to temperature changes is implied, and in modern life can be near completely avoided. Sweating is known to cool humans down, however only in the past few decades has it become possible if not highly common for people to go a full day without sweating.

10.6 In Experimental Models of Obesity, Mast Cells Are the Switch Life is about finding food, and not becoming food for other kinds of life. However, all of the time and effort put into evolution—food was scarce. Long term survival meant a potent avenue for storing food energy for later, in case the food became scarce again. All animals can overstore food and become “fat,” or overly laden with stored energy. Even snakes, lizards, and other reptiles can develop stored fat. However only mammals—those animals that make their own body heat—can become obese. In the scientific approach to studying obesity—many mice have been harmed.

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Mice differ from humans in several ways, but cellularly and below they are quite similar. Mice have fur, which helps them retain heat—humans do not. Humans can sweat to cool down—mice do not. Mice are very small compared to humans, and because they are so small they lose heat energy very quickly. They huddle in groups to conserve body heat, and spend a large portion of their total calorie intake on their brown fat—this is a type of fat cell that burns fat to make heat, like a stove. Turning off the brown fat in mice drops the body temperature, and it happens quickly. These little creatures are extremely efficient at warming their own body. In fact, if mice are placed in a warmer room, and fed the same calories, they noticeably gain weight. However if those mice were genetically engineered to have mast cells without the ability to make serotonin—the mice do not gain weight (Fig. 10.2) This is an interesting finding, and my first question was “how do I get my mast cells to stop making serotonin.” Mast cells go to places in the body that are stressed. The mice experiments in learning and obesity show how only one or two products of the mast cells can completely change the response, let alone the survival of the organism. Mast cells are in large quantities in modern humanity’s adipose tissue—shut down fat burning(serotonin.) This has the effect of reducing body heat production, not cooling, but reduction in metabolism. As of 2022, scientists are working on a way to shut off adipose mast cells—to lose weight (Fig. 10.3).

Control Mice

Thermal Stress

Gain Weight

Thermal Stress Mast cells ØSerotonin Mice

Stay Thin

Fig. 10.2  Mast cells and weight gain. Scientists do so really weird stuff to mice. The can make mice gain weight by putting them in a warmer room, and feeding them the same. Less calorie burn to stay warm, more calories stored. If the scientists remove only the mast cells ability to make serotonin (tryptophan hydroxylase), the mice don’t gain weight in the experiment

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10.7 Fatigue, Plasma Volume, Sauna When I discuss humans, I usually do not discuss Olympic level athletes—they are not technically human. Well, not technically “normal” humans. There is a level of physical and mental ability that outranks the vast majority of the other members of our species. I was shocked to learn that some of these finely tuned exercise machines were having trouble exercising in excessive heat. The Tokyo Olympics was the hottest Olympics on record, and many of the races were outdoors. These elite athletes, just like every human, had trouble competing when they became over heated. In fact—any human body that gets over-heated—feels fatigued.

Fig. 10.3  Nerve/stress/mast cell. White adipose tissue stores fat, and Brown adipose tissue burns fat for heat. Mast cells are they switch: Mast cell histamine activates brown adipose to burn and white adipose to send its stored energy out for burning. Mast Cell serotonin inactivates brown adipose, and causes white adipose to store fat. Neurohormonal compounds, like substance P, direct the mast cells to release serotonin. Histamine is not always the bad amine

10.8  Hibernation to Conserve Energy: Shivering to Warm the Body

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Prior to the Olympic games, there were many proposed recommendations to “acclimate” the human body to the heat. Different methods were proposed, including methods of heating including sauna and exercising in the heart of the sauna. Heating the body over 10 min, at least at 5 ° higher than human body temperature (42 °C) then there are measurable changes in the body. These measurable changes include changing in the liquid volume of the sweat, as well as the minerals in the sweat, as well as the internal temperature of the body. Those changes are measurable when the body is out of the sauna—the fatigue and discomfort from the heat in the sauna improves quickly as well. The technology and custom behind sauna has been around quite a bit longer than the past 50 years, however indoor climate control has only been widespread for the past 50 years or so. Human civilization wiped out the primal microbiome several decades before we realized those little pieces of stool were actually very important for optimal human health. It is very possible, but not provable, that there are many humans dealing with long term health consequences from atrophy of the ability to make proper sweat.

10.8 Hibernation to Conserve Energy: Shivering to Warm the Body Animals are very highly in tune with their environment, seasonally and otherwise. Many animals will migrate to stay in warmer weather, others will change their metabolism during the wintertime when food is scarce. These animals do not make the conscious decision to migrate or change their metabolism, their body just follows its programming. I do not know what happens if migratory birds or grizzly bears if they were kept in an environment that did not have seasonal change, but we are aware of the metabolic changes that affect humans during these times. In patients with Seasonal Affect Disorder, there are metabolic changes that overlap with the mood changes. While this is likely explained by the effects noted in brain chemistry, temperature differential between the human body and the environment can cause an immediate effect on human metabolism. Now this gets a little complicated, but the “heat balance” depends on whether that human is in water or air. Water can damage the human body at temperatures closer to human body temp (37.0 C, 98.6 F), and I write this as a warning that temperature of the environment is a major danger to human health. Think about what temperature feels hot outside? What about warm? What temperature does a hit tub feel hot? When the air temperature is 26 °C, most humans will feel warm, if not hot. However, putting a human body at 98.6 F into water that is 80 F, when the outdoor air is 80 F day will feel cool. So, “cold-shocking” the body submerging into a cold water bath (12 C, 55 F) will quickly quadruple the calories burned by the body (basal metabolic rate.) This feels like muscles shivering from the cold, but that’s metabolic response to warm the body—shivering. The link

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between poor thermoregulation and fatigue/Immunity issues is not new, however using climate(heat) acclimation on elite athletes is a new thing. While I mentioned above that this was a non-provable idea, taking a cold bath or getting into a sauna is not outside the spectrum of reason for most adults these days, and benefits can be felt quickly and without a pill. Lymphomania—lymph drainage, where all the higher level immune cells meet, is dependent on movement, the lymph node map shows concentration in the groin and the arm pit, which is the if the muscle movements are not linked, then the lymph does not go through as efficiently. If fact, if the body isn’t moving, the lymph barely flows at all. Muscle tone is also important, as the amount of passive tissue(adipose) increases the likelihood of swelling also increases. This is a very conserved relationship, and all warm-blooded animals are built with multi-purpose to every layer of tissue. This is another reason that if the body has recently ingested a high fat meal that it should not be moving, and should be resting so as to not flood the digestive system with unwanted fluids from the movement of the limbs. This is an automatic function of the body, and has millions of years of built in redundancy in form and function (Fig. 10.4).

10.9 Now I See the Light: Too Much Light Actually Sleep is fundamentally necessary for a heathy body, it is a staple of the parasympathetic nervous system(rest/digest.) Sleep disorders have become increasingly common, moreover the quantity and quality of sleep have become shockingly poor compared to 50–70 years ago. The lighting has changed, and this impacts our brain. The social environment that we exist in is also greatly changed, before we were really aware of the impact on our health.

10.9  Now I See the Light: Too Much Light Actually Fig. 10.4  Lymph node positions and physical activity. Thoracic Duct is not included in drawing. The position of the clusters of lymph nodes are placed very suspiciously in the areas of the body that are squeezed and expanded regularly, if the human body was in motion. Neck, arms, knees, groins, the function of the Immune fluid drainage systems was placed perfectly for walking and climbing. If there was every a reason to move the body, think of the immune system

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Lymph nodes Muscles sqeezing fluid through the lymph tissue

Small amounts of light disrupt sleep—When I was a kid, I turned off the TV before bed because at some point there stopped being anything good to watch on TV.  Not anymore, and the light from these modern devices directly affects the chemicals necessary to get efficient and restful sleep. Interesting studies show that even light from the outside, in places like large cities, that small amount of light that gets into the room can disrupt that human body’s clearance of inflammation.

10.10 With the Lights Out, Its Less Dangerous It used to get dark, and that was it. Good indoor lighting is a relative recent invention, come to think of it, so is electricity. Different animals have different abilities to see things in the dark, smell things in the dark. Humans are built to be awake in

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the daytime, and we are creatures of light. The color and intensity of light can affect human moods, but more importantly hormones, and most importantly it can affect immunity. This is different that sleeping, but it is related to sleeping. The relationship between light and sleeping is oppositional. It is hard for most humans to sleep when they are in a lit space, and likewise difficult for us to do anything else in a dark space. There are even recent studies that show small amounts of light during the night affect the production of melatonin—the sleep hormone. Eyelids are great, but they do not completely block out all forms of light. Personally, I got some of my best sleep brightly lit lecture rooms. Even worse, when they turned off the lights, my consciousness did not stand a chance. Studies today show that humans that live in cities as well as other places that have high levels of outdoor light, have higher levels of inflammation and certainly do not have proper restorative sleep. My grandmother used to tell me stories of the human invention of fire, and for the first few years of my life I thought she was an actual eye witness to the event. In truth, there has been some amazing improvement in lighting technology—since the time of the candles. These initial lighting was based on inefficient technology, in which the light came from a piece of metal that got really hot. This produced lots of heat, and fair amounts of light—but much of the light was in the red wavelength, or “warm light.” The energy of light waves increases as the rainbow progresses, red-­ orange-­yellow-something-something-blue-violet. Low efficiency light makes warm light, high efficiency light is cold and filled with hate. The idea behind florescent light is nearly as old as the lightbulb itself, however it did not take over in schools, workplaces and homes, until the cost of energy became a major consideration for bulb selection. The 1970s, with the oil crisis and disco music, is widely considered the time that energy production became a substantial expense for much of the population. This is when light bulbs were left on all night long, because they lasted longer and didn’t get hot enough to burn flesh. The efficiency of cold light, less red and more blue also led to being able to be awake substantially longer. I do not think that our current knowledge on the interaction of the wavelength of light, and the sleep wake cycle was available when this environmental change to humanity began. This was not a purposeful environmental change, and we are only two to three generations of human since artificial light became cheaply available 24 h a day. The term “light pollution” is now a medical term, and there is a now a rapidly advancing field of medicine looking into how the intensity of light, wavelength of light, all affect the metabolism of the body (Guan et al. 2022). This topic has many books and article detailing the subject, but relevant here are that the complete disruption of light/night is a relatively only modern thing for humans to deal with. The types of lights people are now exposed to more than 16 h a day are brighter and bluer than they were previously—this stress increases CRH, and decreases melatonin. Blue light brings on the mast cells—and scientists have started to use this to speed up the healing of wounds (in mice anyway) (Magni et al. 2022).

10.11  Methods of Measuring Autonomic Function(Ok to Try These At Home)

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10.11 Methods of Measuring Autonomic Function(Ok to Try These At Home) 1. Pupillary Constriction—Pupil constriction (small pupils) is driven by Parasympathetic Nerves, and Pupil dilation(large pupils) is sympathetic. In a dark room with a mirror, usually a bathroom, use s small source of light. Keep the head about 1–2 ft. from the mirror, and evaluate the pupil size with indirect light. It should be large compared to the iris(color). Then shine the light onto the pupil(not directly) and look at the pupil shrink. The pupil should shrink quickly and stay small as long as the light is light source is directed towards it. If the pupil does not shrink, if it shrinks only briefly, or begins to dilate(open) after a few seconds—there is an imbalance that is either high sympathetic or low parasympathetic. 2. Thermal Acclimation (short term)—Three bowls of water. Bowl A—chilled with ice, 4 °C Bowl B—room temperature, 25 °C Bowl C—at least 20–30 ° warmer, Ideally 40–45 °C. Place one hand in Bowl A, the other in Bowl C. Wait 5 min. The hand that is in the cold water should feel cool, but not cold, and should have lost some of the color. The hand that is in the warm water should feel warm, but not hot, should be bright red. After the 5 min acclimation, remove both hands and place them in Bowl B—room temperature. Bowl A hand should feel hot, Bowl C hand should feel cool. This is a measurement of sympathetic tone only. The more constricted and white the Bowl A hand is, the better the sympathetic response to cold stress. The more red and Bowl C, the better the ability to lose sympathetic tone. In the second part, if Hand A does not feel warm in bowl B, there is low sympathetic tone. If Hand C does not feel cold in Bowl B, then there is elevated sympathetic tone. 3. Vagal Tone (Breathing)—a pulse oximeter and a timer is necessary. Find a quiet place without distraction and focus on even breathing. Place the pulse oximeter on the second or third finger on your dominant hand. Continue to focus on your breathing until there is very little variability in the heart rate. That is the baseline heart rate. Take a deep breath and completely fill your lungs in no more than 3–4 s. Hold the breath for at least 7 s. Watch the heart rate, it should raise between 5–10 beats per minute while inhaling. After the 7 s, blow out the air over 8–10 s and wait as long as you can before taking a deep breath in. The baseline heart rate should drop by 15 beats per minute for a few seconds before coming back to normal. This is a measurement of the Vagus Nerves ability to Parasympathetically(slow down) regulate heart rate.

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4. Thermal Acclimation (intermediate term)—A non-touch skin thermometer is necessary. Prior to sleep, measure body temperature at the forehead and the palms and back of the hands. There should be a difference of at least 4–6 °F. Go to sleep, and measure it upon waking. There should be little to no difference between the temperature of the forehead and the hands. This measures the ability to lose heat at night, and is an indirect measurement of sleep efficiency. It takes into account the proper balance between sympathetic and parasympathetic. 5. Heart Rate variability—This will require a monitoring device, I.E. watch, ring, smart phone device that can measure and graph heart rate over time. During the night, there should be a “baseline” heart rate that is lower than daytime resting heart rate. There should be 2–3 periods of 30–90  min where there is a steady elevation of the heart rate. This is an indirect measurement of sleep quality, and shifting between REM and stage IV sleep. The higher quality sleep, the more sharp and steady the different stages will be. Key Terms • Hans Selye: The “Father of Stress.” A Physician that went through training almost a century ago that noted chronically ill humans had similar complaints, even if they had different conditions. Also, noted that experimental animals that were “stressed” had predictable endocrine(hormone) and Immune changes to the body. • Seasonal Affect Disorder: A human mood condition that seems to have “highs” in the summertime with longer and warmer days, and “lows” in the wintertime with shorter and colder days. There are inflammatory and metabolic parts of this condition, and if this is suspected, please discuss with health care provider. • Melatonin: This is a “circadian” or regulator of the 24-h cycle which helps the body switch its “mode” from awake to restful sleep. It’s a hormone, and its available over the counter in Gummy form. This is a great idea. • Temperature Regulation: For warm blooded creatures(mammals) this generally is driven by the burning of calories for food, or wearing warmer clothes, or migration. Turning on indoor climate control might be causing atrophy of this ability, and the long term effects on humans is not known. • Obesity: Uniquely a mammal ability, and this is a state of imbalance between the burning of calories for food. The condition is widespread, and not only related to highly dense calorie food, but changes to the basal metabolic rate from other conditions or adaptions. • Learning: For the sake of this book only: This is when a form of life experiences an event, and then adapts its behavior to prevent or to promote the event happening again. Also, something that I do not have when it comes to locking the back door before leaving the house. • Heart Rate Variability: This is evidence of “energy state shifting” during sleep. Finding good heart rate variability generally means restful sleep.

Bibliography

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Bibliography Confides AL, Zhu B, Boulanger MC, Memetimin H, Taylor KW, Johnson ZR, Westgate PM, Dupont-Versteegden EE, Kern PA. Adipose tissue mast cells promote human adipose beiging in response to cold. Sci Rep. 2019;9(1):8658. https://doi.org/10.1038/s41598-­019-­45136-­9. PMID: 31209239; PMCID: PMC6572779 Guan Q, Wang Z, Cao J, Dong Y, Chen Y. The role of light pollution in mammalian metabolic homeostasis and its potential interventions: a critical review. Environ Pollut. 2022;312:120045. https://doi.org/10.1016/j.envpol.2022.120045. Epub 2022 Aug 28 Magni G, Tatini F, Siena G, Pavone FS, Alfieri D, Cicchi R, Rossi M, Murciano N, Paroli G, Vannucci C, Sistri G, Pini R, Bacci S, Rossi F.  Blue-LED-light photobiomodulation of inflammatory responses and new tissue formation in mouse-skin wounds. Life (Basel). 2022;12(10):1564. https://doi.org/10.3390/life12101564. PMID: 36295000; PMCID: PMC9604901 Nishino S, Sakai N, Nishino N, Ono T. Brain mast cells in sleep and behavioral regulation. Curr Top Behav Neurosci. 2022;59:427–46. https://doi.org/10.1007/7854_2022_359. Siquier-Coll J, Bartolomé I, Pérez-Quintero M, Grijota FJ, Muñoz D, Maynar-Mariño M. Effect of heat exposure and physical exercise until exhaustion in normothermic and hyperthermic conditions on serum, sweat and urinary concentrations of magnesium and phosphorus. J Therm Biol. 2019;84:176–84. https://doi.org/10.1016/j.jtherbio.2019.07.010. Epub 2019 Jul 2

Chapter 11

The Adjustment Mechanism of the Body: Mast Cell

When choosing the title of this book, “Allergic to Life” had a much snappier sound than “Human Mast Cells are rejecting the Modern Human Environment.” The name comes from my patients with Mast Cell Activation Syndrome, as it seemed to be the symptoms that they were dealing with. While I have mentioned Mast Cells hundreds of times by this point, the descriptions have been about the environment and the human body. Humans have not evolved in any substantial genetic or physiologic way to adapt to these changes. Now, to formally introduce the part of the human body that is responsible for the way people feel because of all of those maladaptive environmental stressors. The Mast Cell is mainly considered an Immune Cell, and many of the jobs described are in protecting the body from, or controlling the response to, an infection (Fig. 11.1).

11.1 Mast Cells and the Immune System While I have written about the human mast cell compartment being the connection between the Immune and the Nervous system, after review of all of the modern day, out of place, Environmental stressors, let’s review where the mast cell sits in the whole Immune System. While the Immune System is not completely figured out, and it takes years of study, the simplest four functions are: 1. Recognize the Infection—Fight 2. Recognize the host—Do Nothing 3. Remove the Immune System once the Infection threat is resolved 4. Heal and Repair human body The Immune response works best when it is done in that order. Numbers 1 and 4, fighting and repairing, these areas that nutritional status is very important. If a © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5_11

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Fig. 11.1  Mast Cell in the Center of Immune Activity. Rotating around our friend, that mast cell, is the division of the major role attributed to the Immune system, including recognition and clearance. While the mast cell can be important in any one of these corners, the immune system and even the human body(likely) can exist perfectly healthy without any mast cells at all

human has a vitamin deficiency, or is malnourished it is failure to fight off infection or heal wounds and other injury that become most affected. Numbers 2 and 3, Recognition of host and clearance of inflammation, this is the area that chronic stress and multiple overstimulation can interfere. If there is too many “active” signals it both increases the eventual likelihood that the host human body will be attacked by its own Immune system, and the removal or deactivation of the inflammation is necessary for the next phase—healing. Mast cells reside in the areas of the body that sense and recognize infections and other stresses, and while the contribute to the defense, more importantly they call for the right type of help to fight off the stress to the body. They are programmed when they get to the tissue, and all of the environmental stresses from dust mite proteases, microbiome disruption, altered dietary substances and habits, pollution in all forms, human to human interactions, and then all of the other stuff about modern day sedentary but HIGH STRESS lifestyles—all greatly get these cells activated to get angry.

11.3  Mast Cells Both Detect and Respond to Environmental Stress

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11.2 Mast Cells and the Autonomic (Fight/Flight or Rest/ Digest) Nervous System It has been known for several decades that other than the barriers of the body, mast cells love to hang out where the autonomic nervous system hooks into body organs to do its job. They have been documented in experimental models to be the key adjustment factor leading to stress related changes in the organs, nerves, and brain. Neurotransmitters Products made by mast cells: histamine, dopamine, serotonin, melatonin, VIP, and many other. Every cell in the human body makes melatonin, but mast cells make them to send other places in the body. Anti-histamines are one of the most commonly used sleep medications in the United States, however histamine was only found to be a brain signaling molecule less than 15 years ago, around 2010. Melatonin has been a sleep inducing over the counter supplement for decades. Dopamine and serotonin have actions both inside the brain, in the autonomic nervous system, and in human organs and tissues. These neurotransmitters are not that complicated, usually just a few steps away from dietary amino acids which are common in all living things on Earth.

11.3 Mast Cells Both Detect and Respond to Environmental Stress Mast cells are found in every human tissue to some degree(skin, lung, muscle, gut), and interestingly they become different types of mast cells depending on the tissue that they are living in. Skin mast cells are different than lung mast cells, which are different than adipose tissue mast cells. There are even mast cells in the brain. Despite being everywhere in the body, every last one originated from the bone marrow as part of the precursors to the Immune and circulatory system. It is an obvious statement to say that air pollution damages to the lungs. However, inhaling lung pollution also causes heart disease and brain disease as well. Eating polluted food impairs digestion and causes a large distraction to the immune system. The environmental injury to the gut can spill over to the rest of the body much like the lung. The amplification point of all of this environmental injury is the mast cell compartment of the body, and the process sets the tone for the long-term defensive network of body which is exposed to these environmental triggers. I’ll be all around in the dark. I’ll be everywhere. Wherever you can look—wherever there’s a fight so hungry people can eat, I’ll be there.—Tom Joad “The Grapes of Wrath”

This quote has stuck with me since I was forced to report on it during my formal education. There is substantially more to the character and the quote, and I can’t really say I paid enough attention in 11th grade to discuss the social context of the great depression. However, this type of discussion of the humans spirit of revolution matches the compartment of the mast cells. Whenever there is an oppressive force

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on the body, the “Tom Joad” of the body is there in the spirit of response. This is the manifestation of the mast cell compartment. If there was no oppression of people, there would be no revolution of people. Much like any successful response, isolation means failure, and a systemic response gets results. The connection between the systemic illness of the body and the oppressive environment is the mast cell compartment of the body. The aspect of “sowing the Grapes of Wrath,” being the result to the human race for the careless changes me have made to the planet that evolved us does have a form of poetic harmony, and I’ll have to see if I can use this chapter as a make up to get a passing grade from High School English.

11.4 The Mast Cell Compartment of the Body: Can Also Keep Its Cool The signature of the mast cells doing their job is in the “immediate changes,” such as redness, swelling, congestion, coughing. We call this “Immediate Hypersensitivity.” The neuro-secretory coordinated movements of vomiting, diarrhea and sneezing are mast cell driven or amplified as well. The entire compartmental design of the cell is to keep these action molecules “ready to go” for immediate release, but dormant until triggered. This is a quick process, like a nerve twitch, but leads to inflammatory changes like the immune system. The “go molecules” are located in little pockets, and when the signal is hit, the cell releases all of the components into the surrounding environment. The “different types” of mast cells are designated by the contents of these pockets. This makes very logical sense, the skin reacts differently than the gut, so the explosive release of go-molecules works best if the go molecules fit the place that they go.

11.5 The “Signal Molecules” Are Determined by the Need of the Tissue No matter what part of the body mast cells end up, all of them start out in the bone marrow. It is still partially a mystery the specific signals which direct mast cells to their final destination. The signals that determine destination, also determine destiny of production. If a part of the body needs help, or distress, that part of the body calls for help. Skin calls for help differently than lungs, and they get different help in return. That’s why different parts of the body respond differently to infection, autoimmunity, or stress.

11.7  Mast Cells Program the Body for Allergies, Allergies Activate Mast Cells

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11.6 The Stress Molecule: CRH, Activates Mast Cells CRH- stands for Corticotropin Releasing Hormone. It actually is a hormone, that releases a hormone, that releases cortisol. Cortisol is elevated in times of stress, and is thought to cause things like stress-eating, and water retention during stress. In regards to energy management, stress signals shut down Immune Responses. Most people are aware that they get sick more frequently during and right after a period of high stress. CRH—is made by the brain. IT is made by the brain for all sorts of different kinds of stress. Scientist have not yet run out discovering how stressful or hurtful of humans creates CRH in the body. While much of the Immune system gets shut down during high stress, CRH directly gets Mast Cells fired up and ready to get busy. This is operationally different than much of the other parts of the immune system. Mental stress is a well-documented trigger for Urticaria(hives), which is the textbook form of mast cell activation in the skin.

11.7 Mast Cells Program the Body for Allergies, Allergies Activate Mast Cells There is a very clear pattern of inflammation. These Mast cells do not like to turn off, and they are dozens of pathways to generate inflammatory activity and only a few to turn off. One key function of mast cells is to take raw signals from environmental exposures like dust mites and mold spores, and then start the program for immune memory to make an “allergy.” This is a compartment redundancy that can cause a perpetual increase, without any “natural limit” to the expansion of the compartment. Through the past 50 years the incidence, and the severity of autoimmune and allergic reactions have grown in tandem with the changes to the environment. This was not purposeful, and I do not think that it could have even been predicted. Some of the early predictions about antibiotic resistance were creepy-accurate, and there has always been an aspect of human nature that is resistance to change. Allergists have been closely connected to the mast cell compartment of the body for longer than medicine has been aware of what mast cells actually did in the body. I am the beneficiary of greater than 100  years of specific medical discipline that started about completely by accident(ironically, many of the other discoveries were serendipitous). The first treatment of allergies was the environmental control. This goes back hundreds of years. Removal of the environmental triggers stops the symptoms, and this can also stop the development of disease. Around 100  years ago, Physicians that would later be called “Allergists,” starting injecting their patients with extracts of grass pollen. These injections fixed the symptoms, but more importantly they prevented them from getting worse. Modern day knowledge is that allergy shots(desensitization) can not only treat allergy symptoms, but PREVENT the consequential disease processes that build up from continued exposure triggered

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activation. Allergy injections to treat environmental symptoms can stop the progression and the development of asthma and eczema. This was figured out before I was a Physician, but also before science connected mast cell involvement to the development and progression of other diseases. Allergy shots are the repetition of injections (bypass skin barrier) of extracts of environment allergens. The method of delivery is very important, because continued exposure through the barriers leads to progressive disease. The sublingual route of desensitization is also effective, but less understood and data driven for only a few environmental exposures. However, either method stops the progression of environmentally caused diseases by controlling the mast cell compartment. This is extremely important, but also solidifies the mast cell compartment’s involvement in multiple conditions. These are very safe methods of management of environmentally driven conditions, in addition to the avoidance measures, but the current utilization does not match the utility. Moreover, the programming of environmental allergies is very well mapped out, and the steps of this process can be tracked as they happen.

11.8 Tryptase Might As Well Be a Dust Mite Parasite Digestive Enzyme Mast cells are not the most important cell in the immune system, in fact mammals seems to do just fine without them, my focus here is on mast cells as they are focally important at the interfaces of the body and the external environment. The external environment including air, food, and anywhere else a parasite can get too. Tryptase can be tested by any major commercial medical lab in the world. The enzyme itself, also activates mast cells. This enzyme, released by mast cells as part of an immune or irritant response can directly affect all of the surrounding cells and structures to signal like a parasite is affecting that part of the body. When tryptase is released from mast cells from an irritant, chemical, odor, or anything, it can feel just like an allergic reaction. People that deal with Mast cells activating all the time, or that have high levels of tryptase sometimes feel like they are allergic to their life.

11.9 Large Quick Release Can Cause a Chain Reaction Shockwave Through the Body: Anaphylaxis The mast cell compartment of the body is a very unique defense mechanism that is highly antiquated and almost certainly unnecessary for modern day survival. The mast cell mechanisms of immediate release of toxic components into the surrounding tissue is designed specifically for early defense against parasitic mechanisms of resource competition. The entirety function of immediate release, or even a

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“scorched earth” type defense is to cause a heavy amount of damage very quickly either to drive away a worm or parasite or at least cause enough damage that the post-mechanism fights off the infection by scratching, coughing, vomiting or having diarrhea to push out the invading mechanism. Mast cells line in her heavily involved in the interface of her body and the external environment. There are found on her membranes, skin, lungs and gut. Undoubtably there were very important for the survival of early mammals as nearly all surviving species have some level of mast cell compartment. Are mast cells necessary? Almost certainly not. Experimental models that absence of one major cell component of the immune system results in severe immune problems, severe invasive crippling infections if the unfortunate person survives long enough to be born. However when we think about mast cells, there is no function that they have a baseline that is absolutely necessary for our current survival. We have a tough time with experimental models of animals that are genetically bred to not have mast cells, because they are basically just the same under normal circumstances. Keeping track, allergies aren’t necessary, and neither are mast cells. Fortunately for many people in modern society the mast cell compartment of the body is dormant, or was dormant when most of the medical school textbooks were written. Very commonly patients will complain of itching out of proportion to condition, diarrhea, nausea vomiting, and many times this can be traced back to the mast cell compartment functioning on a level that is not consistent with its design, a hypertrophic reaction or a normal reaction to an abnormal situation. Mast cells cause almost all symptoms that we currently attribute to the modern sense of “allergy.” They release of histamine and in fact responsible for production of all histamine in the body. But histamine is not the only compound they produce. They were one of the first distinct cell types discovered in modern medicine because of their characteristic “granules,” sometime up to 1000 or more small “packets” that are filled with toxic small molecules and enzymes. Each tissue of the body such as lungs, stomach, lower gut, skin, all have mast cells but their granule composition is different from tissue to tissue. Scientists do not have these completely worked out, but more importantly we will never know what was supposed to be normal.

11.10 Too Many Mast Cells: Mastocytosis There are several diseases of the mast cell compartment, systemic mastocytosis is a proliferative condition. This means that on some level, the number of these cells of the body has expanded or grown beyond what the body normal will he requires. This increasing burden of mast cells can cause many symptoms that are exactly the same as severe allergic reactions including hives, anaphylaxis however the symptoms are related to the total burden of mast cells, sometimes several 100 times more than a typical human body is expecting. This is generally a slow advancing

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condition, and the mainstay of therapy usually revolves around controlling the symptoms caused by the growing number of mast cells.

11.11 Too Active Mast Cells: Mast Cell Activation Syndrome(MCAS) Compare this to mast cell activation syndrome, MCAS, which the total numerical burden of the mast cells is static, but they are much more “active” than someone without the condition. What is the difference between an allergy (which activates mast cells) and MCAS—specifically the IgE. IgE is a programmed response using much of the evolved and intricate immune system. Mast cell activation without IgE is certainly more unpredictable. While the number of mast cells that someone with MCAS is not increasing, we find the signature of mast cell activity much higher in people suffering from mast cell activation syndrome. The fact that mast cells activate mast cells and of all the human made environmental changes also seem to tickle the mast cell compartment in the same way.

11.12 Remember, Humans Don’t Like Humans Nearly 100% of smoking related human health problems can be prevented by removing smoking from the human. Likewise, nearly 100% of traffic related injuries can be prevented if humans did not drive. Both of these actions are highly regulated by the human governing regulatory system, however one is only still important for modern economies(driving.) I have strong opinions about the tobacco smoking industry, but the entire world allows it. The human world allows fellow humans hurt by the smoking to continue smoking until they die from it. Physicians sometimes try to get humans to stop smoking, but are remarkably unsuccessful motivating humans to take actions to help themselves. Humans have a natural resistance to other humans telling them what to put in their bodies, especially when it comes to vaccinations and health in general. These are the highly accessible and common knowledge examples referred to in the context of what humans allow humans to do to humans (themselves, family members, and the public.) Its tough enough to slow down an industry like the tobacco industry, which kills people in plain site. If humans make little action to prevent the killing of other humans, then what chance would there be for humans to take action to help humans? Environmental inflammation, poisonous food, pollution, stress-maximized social connections, all of these cause harm, and are going to be “regulated” to some extent. However, there is a collective understanding that the public will be protected from human action, but individuals are pretty much on their own to figure things out. This may have been acceptable

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50–70  years ago, when most governments sponsored things like institutionalized racism. Personally, I’ve spent a quarter of a century trying to learn much of this information from amazing instructors and also as a profession. That amount of time also saw the continued systemic changes to the human home planet. Human nature has not changed with the human environment, neither have genetics, laws, or other avenues for which human society protects humans. Critically pointing out the negative health impacts of this environmental change is kind of a “cheap-shot,” especially without planning any collective solution. There will be no collective solution, there is no motivation to prevent minor industry from selling addictive poison which results in enormous cost and health consequences, it is left up to each individual human to decide for themselves. No one is going to fix this mess for us. Therefore, my intention to enact change lies exactly where my impact could be most meaningful, the individual human. This started and ends now with the understanding that at this moment in time, it is impossible to feel like a “perfectly healthy” human.

11.13 Why Does Anyone Need to Know About Mast Cells? Like a human that inflicts change on the environment, the mast cell inflicts change on the human. The exact process is not identical between humans, but all humans are in some way affected by their environment. While humans cannot immediately correct the environment nor affect behavioral change in other humans, we are in the process of gaining control over the mast cell compartment of the body. We cannot reduce the increased burden of pollen season, but humans can master their own body’s response. No individual human could be held responsible to fix the air pollution, but each human should be aware, able to measure, and then improve the air quality in their own home. The health consequences of the Earth’s environmental inflammation are massive, and there are more on the way.

11.14 Summary The world that Human Life grew up on is gone. What humanity has instead is angry, more dangerous, and certainly less healthy planet for humans. Many of the health conditions in today’s world are misunderstood, and that ends up laying the blame for illness on the person dealing with it. This is isolating, hurtful, and very unhealthy. While the mast cell compartment makes up much of the professional world of allergy, there is much more to their story. Any human will hopefully understand just more of how amazing they are, and how their body is protecting them.

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Key Terms • Tom Joad: Fictional Character from a book about the Great Depression in the United States in the 1930s. • Stress Response: Pushback. When there is stress, there are body changes. In many cases of environmental interaction with the human body, mast cells are pushed there in response to stress. Much of the time, the mast cells then amplify a normal response to become a hypersensitive response. • Inflammation : In human medicine we refer to Inflammation as redness (rubor), swelling (tumour), heat (calor), pain (dolor) and loss of function (functio laesa). Mast Cells are experts at these things. • Anaphylaxis: A chain reaction of mast cell activation causing a systemic, or “whole body,” reaction to something. This is usually in response to an Allergen, but in the zany mixed up world of Mast Cells, the trigger can be almost anything.

Chapter 12

Desensitize from the World

12.1 Time to Find a New Planet? Sure, why not? Seems like moving on from here is the next logical step for the human species, and I honestly can’t wait. For arguments sake, even if it were possible this generation to move to a different plant, humans still wouldn’t belong there. Planet Earth is 100% honest to goodness directly and irreversibly tied into human DNA. From the water, to the dirt, daily light cycle, seasonal changes, plant and animal life, our home planet is as much a part of us as our family. While future generations more than likely will be traveling to distant areas of outer space, humans are genetically designed for planet Earth and any other environment will certainly bring use new health problems to complain about. There is no going back, and children of today are growing and adapting to a world that is comprehensively stressful. Any response mechanism humans possess, modern day environments are pushing beyond the safe point in the response. Humans can’t necessarily “upgrade” their DNA, at least as of 2023 anyways. While for the current time we are stuck with our grandparent’s DNA, and the planet they wrecked is decidedly different than the one that matches human DNA. Other than finding a brand-new planet to ruin, or reversing the human-triggered evolution of microorganisms, our species needs to take a stand with what we have.

12.2 Whose Fault Is It? The first step to healing is to understand the cause of hurting. Too many humans are hurting, blaming themselves, but also think they’re alone. Pretty much all actions that resulted in the major changes I am aware of started out with good intentions. However, the long-term action of creating an antibiotic to save lives causing the © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5_12

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effect of creating next generation “super-bugs” is some crazy literary-irony type problem that no one could have possibly foreseen—except the guy that got credit for inventing it. In this century, human bodies are responding appropriately, but it’s the environment that’s hurtful. We can’t leave the planet, and can’t start over. However, we can heal human-by-­ human. Physicians throughout the centuries have separated human from environment, with excellent results. Taking a dust-mite allergic patient to an environment that does not have dust mites- is good for that patient. Some fancy governments of the world have made many of the food-pollutants illegal, making it easier for their humans to stop be hurt instead of hungry. Most of the world’s government have even gotten together and made agreements to reduce the amounts of pollution, or eliminate them altogether. In a crazy twist, some countries have taken it upon themselves to care for their citizens that fall ill and eliminating the individual financial burden of becoming sick. These actions will hopefully prevent the changes to our planet from getting worse—but I don’t think we’ve even identified the full extent of the health impact that is already on top of us. However, even the modern-day governments that don’t do any of those helpful things for their citizens still aren’t purposefully trying to make anyone sick (I hope.) From the progressive changes in the indoor and outdoor air, the alterations and “additions” to the human food supply, the disintegrated original human microbiome replaced by more aggressive microorganisms, the overwhelming frequency of human-to-human stressors, and finally, the obliteration of the fundamental physical rhythm of life on Earth, I’m hoping nobody that had read this far would still have any ability to blame themselves. If anything, we should blame the human mast cell, but I promise that they’ve just been trying to do their job this whole time.

12.3 Drugs Are Not the Answer (Ok, Some of Them Might Be Part of the Answer) Symptoms are the processes that are felt by a human as their body is responding to s stress. Of course, not every symptom a human feels involves the mast cell compartment, but there is a drug for every symptom. Much of modern medicine, I.E. drug prescribing, is based on symptom control. Some times that also means “inflammation control,” which slows down or stops the damage to body. For much of my practice lifetime, the unwanted side effects from prescription drugs generally increased corresponding with the ability to control inflammation. This is getting better quickly, as the specific signals of human inflammation have been translated into very specific interventions, which stop the inflammation with substantially less side effects than the older drugs. These newer drugs tend to come with very large price tags, innovation is not cheap. The best, newest, and most specific drug being dispensed today may completely block symptoms, control the inflammation, and then eliminate the damage to the

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body—but the cause is still there. The original Allergists—centuries before Immunology was a concept—healed people by removing the environmental stress which caused the disease. While this is called “avoidance,” and we were taught not to run away from our problems, in this case it is the best idea. So, in many cases, say bad indoor air quality, the only option might be avoidance altogether if the air circulation cannot be fixed. So while newer drugs are really cool, and way better than the older drugs, they probably should not be the first choice. Identification of the stressor is necessary, if avoidance will be possible. When it comes to stuff like poison, I think the only reasonable option is avoidance. Now, when a human body has developed a “sensitivity,” or even a “hyper-sensitivity,” that is always a developed chronic response to a stressor. When there is developed sensitivity, there is then the ability to undo that sensitivity, we call that de-sensitization. While avoidance is preferable, it is not always possible.

12.4 The Mast Cell Compartment of the Human Body Is “Expendable,” and “Trainable” Allergic Rhinitis, in other words “a runny nose caused by environmental allergies,” is a great place to start. This is an easily recognizable condition that most humans should at least be aware of, if not have dealt with at some point. There are hundreds of medications that can help reduce the symptoms, and these continue to be best sellers in drug stores. However, none of those medicines can stop the runny nose from becoming something else—asthma. Allergic rhinitis, or environmental allergies is the single largest risk factor for the development of the lung disease asthma. Successfully avoiding the triggers, or allergy desensitization are the only possible way to prevent the development of allergic asthma from allergic rhinitis. Allergy desensitization, or allergy shots, has been proven in validated scientific studies to not only stop the progression of allergic asthma in children, but able to reverse and help them out grow it. While there are 30 million people in the United States with Allergic Asthma (24 million adults, 6 million children) less than 10% of those individuals are actually treated with allergy desensitization. Now obviously not every single human that has a runny nose develops asthma, but nearly everyone that develops asthma starts with a runny nose. Humanity is coming up on 70  years after identifying that there are biologic responses to “stress,” however Allergists have been desensitizing for nearly twice that long. The first human “trials” of allergy desensitization were done around 1911; and they started in the kitchen. Dr. Leonard Noon was operating under the belief that humans were getting sick from the “toxins” released from plants—I.E.  Hay fever. He took Timothy Grass (Hay) and boiled it in water to make an extract. After injecting people allergic to grass with his homemade grass extract in increasing doses, the humans improved.

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The year was 1911, and this was just after Epinephrine was first isolated (1901— Takamine), but long before steroids like prednisone and antihistamines were invented. Dust Mites were not event considered to be a major factor until the 1920’s. So, while modern pharmaceuticals may seem daunting or even suspicious, Allergy Desensitization has been proven safe and effective for over a century. I am not trying to make this a love story about Allergen Immunotherapy. But, the practice of allergy has an applicable simplicity which understates complexity of the Immune system, but delivers reproducible results. While the first recipe for allergy injections was made in a kitchen, currently there is an entire industry devoted to the safety, purity, and consistency in the development of allergy extracts for human use. There are not only injection forms of allergy desensitization, there are now commercially available tablets for several different allergens.

12.5 Developing a Healthy Relationship with Food When it comes to humans and food, we could spend all book trying to discuss all the good and bad things that can happen with this relationship. “Food Allergy,” as a term has different meanings to different people. What this approach is hoping to do is give anyone an idea of “what to do next.” The easiest way to determine the problem with the interaction between the human and food, is to listen to the human. The listed of sensitivity or reactions to food below is not comprehensive, but should be familiar to most people. The reactions listed can help determine the next step, to avoid, see an MD, or try an elimination diet at home. 1. Neurologic Hypersensitivity: This type of hypersensitivity is very easy to recognize, and I refer to the example of migraine triggers. There are humans alive that will develop a debilitating, severe, life-crushing headache when they smell a specific food—like popcorn, or cooking onions. What entices the palate for some, triggers negative neurologic symptoms in others. At age 21, I had a terrible experience with nutmeg. At age 46, quarter of a century later, I still cannot handle the smell or taste of that “spice.” This is just another way that the brain and body are connected, to help avoid the repeating the trauma associated with that nerve single(taste/smell.) Smell/taste = immediate symptoms. Avoidance only. 2. Immediate Type hypersensitivity: Also called “Type I hypersensitivity, “or “IgE mediated hypersensitivity.” This is a combination of Memory Immunity and Mast Cell Activation. Mast Cell on their own can do some damage, but when they are triggered by a specific protein in the environment which the Immune System remembers with IgE—it can kill somebody. This is called anaphylaxis, and due to the serious nature of this type of reaction, we (most Allergists) consider anyone with IgE to food, to have a potentially life-threatening allergy to that food.

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This should only be handled by a professional, not “the closest thing to a professional available online,” but a provider that has dedicated thousands of hours to diagnosis and treatment of Food Allergy. Thankfully, most of the IgE reactions do not send the human to the hospital. This is the mechanism of food allergy that has tripled in the last 25 years alone. This is also the same type of inflammation that causes allergy to tree pollen or ragweed. 3. Carbohydrate intolerance (Lactose, saccharidase deficiency, SIBO):This is a discomfort, or gas/bloating/diarrhea that results from the incomplete digestion and absorption of carbohydrate calories and/or the competition with the microbiome(bad) for the carbohydrates. This can be immediate symptoms with severe lactose allergy as an example. Occasionally this can be more subtle, chronic type symptoms. There are dedicated challenge testing (don’t try at home), and there are over the counter digestive enzymes like LactASE, which can be attempted at home to relief some of the pressure. Many people will “feel better” with a low carbohydrate diet, which will automatically treat carbohydrate intolerance because it is elimination of the carbohydrate. However, there are several other potential mechanisms that a low carb diet can help people feel better. SIBO, or Small Intestinal Bacterial Overgrowth, is when bacteria with more aggressive metabolism and inflammatory triggers exist in more of the human gut than feels OK. I estimate that in my Allergy practice that 50% of the adult consultations for food allergy end up being diagnosed with SIBO. It is much less common in children in my practice, but it may have different symptoms. I strongly recommend Board Certified Gastroenterology for an evaluation. Also, low carbohydrate diet seems to help. 4. Food protein triggered inflammation (Celiac Disease v Gluten Intolerance): Celiac Disease is an autoimmune condition that is triggered by the environment, but instead of a virus, bacteria, fungus, or ex-partner, this autoimmune condition is triggered by food. The complete understanding of the condition is not known by myself, but I have encountered this clinically on hundreds of occasions. The autoimmune disease can be tested by blood testing, or by having a doctor perform a procedure that samples some of the gut lining to look at the direct levels of inflammation. This is a disease. This is carried by the memory Immune system, and in the most potent class of Immune cells—the CD4+ cells. CD4+ cells that remember gluten hang around the human body for decades, and start to produce inflammation within hours of digestion of gluten even after a long period of gluten avoidance. I strongly recommend seeing a multi-disciplinary team including a Gastroenterologist, and possibly Allergy, Dietician, Nutrition. Milk protein, Rice Protein, and several other type of protein yet to be discovered by human scientists can trigger inflammation. These are no so easy to diagnose, in fact, they are easier to avoid than diagnose. Again, should food protein triggered inflammation be suspected this should be evaluated by a trained professional. 5. Eating Poison: Sometimes, there is poison in the food humans eat. This cannot be desensitized, and this must be avoided. Some humans are more sensitive than

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others, and some countries are more permissive with what types of poisons are allowed in the food that is sold to their population. One way to avoid poison in food is to leave the United States of America. Stop eating Poison.

12.6 Elimination Diet, Antigenic/Allergenic and Adding Back Foods When in doubt of the environment of food impacting health, a time-honored diagnostic method is called an “elimination diet.” Other terms are “elemental diet,” or “Sampling the cuisine of Great Britain.” This harkens back to the very first Allergist, and the very first Allergy Treatment: avoidance. If the testing methods are not helpful, or if there is just plain curiosity, and gut or other inflammatory symptoms persist, this has worked for a large portion of the patients I have recommended it. I did not make this up, this was taught to me by the Legendary Dr. Michael Kaliner, former head of everything that was important in Academic Allergy. My mother always used to tell me, “When in doubt, run away as fast as you can.” That advice has severed me very well in life. However, it is impossible to “run away from food.” Fasting is trendy and can be effective. But it means that some humans have to stop eating food. I am not recommending it here, and there are plenty of resources that can be evaluated if fasting is a desire. Elimination, in this case, means drastically reducing the variety of foods consumed. One protein source. One Carbohydrate source. That’s it: no spices, flavors, additives, or beverages other than water allowed in the body. Like climbing a mountain to avoid dust mites, or covering the pillows with tightly woven silk, this limits the potential environmental triggers exposed in the gut to as small as humanely possible. Disclaimer  The angriest a patient has ever been with me was from recommending this process, and it not working out for them. This diet is miserable. We humans get much enjoyment from our food, to cut out the diversity and keep everything identical for breakfast lunch and dinner really wears on the body. However, if belly pain, joint pain, headaches, etc. start to disappear, then we know the environment of food is the trigger of those symptoms, and that’s something we can work with.

12.7 Two Weeks Only Start with: 1. Protein: Meat: Lamb -ground or shank. Cooked similarly each day Or Chicken Breast—baked, not fried, no spices. Salt if anything. Vegetarian Option—Orange sweat potato, yam. Baked only.

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2. Starch: Rice—white rice, hopefully close to organic. Bottled or purified water to cook only. Salt only. I do not recommend white potato, or other starchy potatoes, which are nightshade family. Nightshades, while delicious, can be both addictive and/or poisonous. This elimination diet is like climbing to the top of a mountain to breath fresh air—to see if the body feels better. At the mountain top, there is no pollution of any kind. This will not tell us what type of pollution causes breathing issues, only confirm the cause. Therefore, while there are likely dozens of different non-sweat potatoes that don’t contain Nightshade alkaloids, this elimination diet is designed to. After 2 weeks of this combination for breakfast, lunch, and dinner there should be 2 major findings: 1. Did any type of symptom Improve? (If no, its OK to be mad—this was not easy.) If Yes, then continue reading. 2. How many days did it take for that symptom to improve? This is the number of days to wait, before adding in a different food “family.” That is all the information needed. After an unsuccessful elimination diet, its OK to immediately return to previous diet. Diet expansion based on Food Family is below. Anyone can reset digestive food system by going to the 1 protein, 1 starch, 2 weeks.

12.8 After Elimination: Measured Food Inclusion This part is only for humans that feel noticeable better following the elimination diet. After 2  weeks of isolating the food protein in the gut, its common to have dreams about things like hamburgers and tacos. This is normal, after the elimination diet. Protein(Meat): The Chicken/Lamb is generally the easiest to expand. Most of the animals that humans consume are similar in food protein, and pork or beef can be added back to replace the protein. The tricky part of protein is the spices, as these can have alkaloids or allergens and can cause any number of unpleasant reactions in humans. Fish(tuna, salmon) can be considered the same family. Shellfish is divided into crustaceans (shrimp, crab, lobster) and mollusks (clams, oysters.) Shellfish is going to have the highest likelihood of triggering an immune event, and should be considered the last to add back to the diet. Dairy: I think that this should only rarely be added back to the adult human diet. Organic butter as a source of fat calories is generally OK to add back early, but thinks like mold cheese or cheddar cheese are highly complex and difficult to determine if the cause symptoms. Eggs: Chicken eggs are different than chicken meat. To add hen’s egg to the diet, start with shell boiled egg, this will let the body see much of the egg protein in undercooked form and symptoms will be easier to notice if they return.

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Other Stuff(Grains, Legumes, Fruits, Vegetables): Rice is a grain, and is my recommended starch for the elimination diet. However, other grains like wheat, barley, oats, in the least processed form can be considered a family of gluten-­ containing, and gluten-free grains. These should be added back carefully, and after several fruits and vegetables. Legumes(Peas, beans, etc.) these also have harder to digest proteins than many of the meats or fish. They also have starches, and fiber. Nutritionally these are outstanding, some of the best foods on any version of planet earth. However, this is about dietary triggers of symptoms, and these are higher than fruits or vegetables in terms of likelihood to cause symptoms. Vegetables: Starting with cruciferous (cauliflower, broccoli, kale, bok choy, brussel sprouts.) And once this food family is added back to the diet following elimination then they can usually be added back very quickly. Other vegetables like gourds/squash, can be done quickly. Lily family such as onion and garlic should have more caution. Nightshades, like potato, tomato, eggplant should be added back several days apart from one another as these tend to be frequent triggers in humans.

12.9 Don’t Forget the Algae Chlorella is an algae that is available from many outlets as a supplement, and occasionally as a food source. This needs light to survive, and the human digestive system is not conducive to sunlight. Mealtime should put us into “Rest and Digest” mode. Here’s how: 1. Adequate time must be established for each meal, if you are like me and don’t have a “lunch hour,” then high fiber and high volume type foods such as apples and legumes, even peanut butter can satisfy the hunger. 2. When there is time for a full meal—make it a mealtime. Stop and smell the food, deeply inhale and close the yes. Think about each bite, think about the smell, the taste and texture of the food. This micro-meditation, coupled with chewing the food, will send the signals through the vagus nerve to get ready for digestion. 3. Small bites are not necessary, but avoid large or huge bites of food. Sips of liquid such as water, should be taken with every bite. But chewing should be continued until the food can be passed between each side of the mouth as a liquid without significant effort. This may take up to 30 s for some types of food, but it is necessary to get the process started. 4. Stress does not help humans digest. These exercises may seem silly, but if a human is counting the number of times they chew and thinking about each bite, that human mind is not thinking about Karen from Human resources. This is an OK time to listen to calming music, I recommend Michael Bolton. 5. Friends, and occasionally some family members are relaxing to enjoy a meal with. Hopefully, polite conversation will help to slow down the food consump-

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tion process. Friends, and other companions (don’t have to be human here) help us feel safe and can lower the threat detection and other stress mechanisms.

12.10 Physical Contact with Pack Humans need permission to make physical contact with another human, every single time. Even members of a human’s pack may not be open to physical contact at some points in time. However, making time for physical touch can be very helpful for destressing both humans. This is can be sexual relations between consenting humans as allowed by the various law of the state. However, a hug works too. A hug that lasts less than 1 s is awkward and should be avoided. A Hug that lasts between 2 and 15 s is OK, but generally not satisfying. However, two or more familiar humans making near circumferential contact with each other(hugging) for over 20 s is scientifically proven to activate the parasympathetic nervous system. It is more than the squeeze around the chest, which can also affect vagal tone independently. While this sounds like a kindergarten folk song, it has been validated with EKG, and vital sign monitoring. This is another reason to put down the tablet, and make some good old-fashioned human contact.

12.11 How Exactly Does Somebody Learn to Relax on Their Own? Human society has way too many things to do during the day to leave any time to relax and calm down. Most humans look at food time and bed time as pit-stops in-­ between the rest of their fast-paced lifestyle. There are many “apps” on humanity’s personal hand held electronic devices that produce anxiety driven behavior. However, there are also health-conscious applications developed that can teach humans how to relax both mind and body. This is not even medication, this is simply becoming aware of the mental tension, muscle tension, and mindfully having those areas relax. There are downloadable apps for meditation, breathing, and listening. There are too many to go through, and I do not have a favorite. The key here is that after mindfully relaxing the mind—the body should feel better. If there is no difference, or drop in tension, then pick another app—and eventually one will work.

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12.12 Try This At Home, and Try This on the Phone There is a self-perpetuating and reinforcing, polarizing that is programming our brains by using our brains. The search and destroy algorithms created by social media platforms are designed to drive use, simply put they diagnose individual human fear and then use that to manipulate human activity to generate revenue. It’s completely legal to sell addictive health destroying tobacco products to adults, so of course it’s completely legal to amplify all the social fear and anxiety for profit—I mean it’s better than Emphysema or lung cancer, right? I can’t say for certain that social media is responsible for mental health disorders, but many scientists have made such claims with studies. However, like the many changes to our society in the past 50 years, it is very difficult to find a control group of humans to compare. I don’t think that it is possible to trick these companies, however people can use the fear amplifiers to input their own “safe words.” If the searching and information collection tries to drive more activity, the appearance of “safe words,” in the information feeding trough should be enough to distract and reorient the interface experience. For examples, to regularly input “safe words,” and “safe phrases,” that are in the proper language, but aren’t necessarily things that are personally important the user.

Distracting the Search Strings “I think Penguins would be better at making friends if they were purple.” “Rain clouds are the happiest form of pink water.” “Pine cones smell even better than green raisins.” (Noun – subject) followed by (adjective – positive) then (color) and (another noun.) II personally find this helpful, as my phone and email already know way too much about me, not only that I am a Physician, but the specialty, and the types of medication I prescribe. It grabs the attention—until an article about penguin social hierarchy crosses my line of site—that is usually enough to re-direct my focus and stop the triggered fear-based scrolling and reading activity.

Alternative Exercise Pretend to a cartoon character, search for what he/she/they would be searching for, but without using proper names. Examples for the search bar: “I think my step-mother is concerned that I am currently living with a group of 7 dwarven laborers, and they are only calling each other by a single mood or behavior, no actual names.”

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“How do I stop turning things into solid ice?” or “Why doesn’t being cold bother me?” “I have a donkey colleague of mine that is usually very sad, and I try to walk around without any pants on while eating honey to cheer him up, but it just doesn’t work.” Once the search engine or social media starts showing the correct cartoon character (do not use the actual name), its time to move on.

12.13 Social DePrograming: “A Clockwork Human” My Grandmother used to call television shows “programming.” I don’t think that it was intentional, but in a very real way human brains become programmed by what we witness socially. The object here is not a replacement of medication. Neither is there any ability to diagnose or treat any human illness. Taking control of the environment’s impact has nothing to do. 1. Choose a specific Period of time between 4–6 weeks—stick to it. 2. For 7 days prior, take an inventory of personal thoughts of aggression, anger, and general negative emotions towards any other human. Reminders using calendar or even diet applications can help keep track or on top of these feelings. Emotional negativity stresses the mind and the body. This may seem silly, but most people I know can use a little silly in their social environment. However, imagine if the recommendations were opposite: Force yourself to watch violent actions on television everyday for a period of time. Measuring the desire to “punch” somebody prior to, then after the period of time. Our humble narrator believes that television programming might lead to the ultraviolence. Violent humans should be actively meeting with a professional to help them manage their actions of violence. Television probably does not make people violent, however humans are drawn to the tension and this can be additive to the stress levels. As the father of two daughters, I can attest that there is currently no shortage of programing available containing unicorns and/or puppies available for viewing.

12.14 We Must Adapt to the Parasites that Have Adapted to Our Lifestyles We’re talking about dust mites here, not our elected officials. While I have made sweeping statements like “dust mites are everywhere, “there is a way to actually determine if they are in the home. There are two methods I am currently aware of, the guanine detection and the antigen detection.

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Dust mites have a physiology very similar to spiders, in that their waste form of nitrogen is in the form of the molecule guanine. Humans have Ammonia, Urea, and creatinine, as the major molecules that we can rid ourselves of waste nitrogen. The kits, which used a form of sulfuric acid, are becoming increasingly difficult to find. However, a company named InBio, sells standardized kits to the public which can detect specific dust mite allergens from a home dust sample. The method is very similar to a home urine pregnancy test, or a in-office or home test for COVID-19. The presence of house dust mites in any home will cause symptoms to any human in that home, to at least some degree. However, the key point of this indoor allergen is that it is an inducer of mast cell activity, and an inducer of specific sensitization. Simply put: Dust mites make humans allergic to dust mites. It is part of how they feed themselves. House dust mite sensitivity is present in a large percentage of modern-day humans, and the conditions that are caused by dust mite allergy: allergy, asthma, and eczema, are a large healthcare cost and quality of life burden. While dust mite exposure is unavoidable, the development and progression of disease from house dust mite sensitization is certainly avoidable. House dust mite Immunotherapy is safe an effective, but significantly underutilized. The underutilization of prevention is not unique to Asthma and allergies, there are a ton of other avoidable health problems that are very common today due to underutilization of prevention. I don’t recommend dust mite immunotherapy for every single person I treat, its not the right thing for everyone. This is a clinical decision that the patient and I make together, once we have reviewed the data to make an informed healthcare decision. Immunotherapy is an excellent option for treatment, however it should only be considered after direct discussion with an experienced healthcare provider that can assess the unique aspects and risks that can occur with desensitization. However—it will only be an option for a human if that human is aware of the importance and the availability.

12.15 Time to Reheat the Meat Humans need to sweat, not only exercise, but sweat. The ability to control the internal temperature of the human body is more important that the need to feel comfortable all the time. In addition, sweating may also be the way to remove some of the harmful things that get stored in the body. Let alone impact to the skin microbiome with the improvement of sweat quality. The body feels tired when it is heated, especially when it is overheated. So purposefully heating up the body when it is already tired may not sound like a great idea—so we have to approach it scientifically. There are several known environmental temperature sensory triggers for the human body, and most of the time we do not get near the threshold. Most of the time, human body’s are in a completely temperature controlled environment and there is no temperature cue to cool down the body, or to heat it up. Overtime this

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leads to decreased thermal tolerance—and when this is treated fatigue seems to get better for many people. There are some important risks with heating the body—but there are some fantastic products that can be purchased for the home, or many gyms with memberships will have sauna as an amenity. No human should ever expose themselves to potentially dangerous heat levels without some available to turn it off or get them out of the sauna. I have recommended this for patients, and while effective for many—it doesn’t fix every symptom—but does help the body improve autonomic nerve function. Several of my patients were not able to even tolerate the lowest temperature for even w few minutes, becoming “light headed” seemed to be the largest reproducible complaint. The key to desensitization is the journey to the destination, not about where the starting point. There just needs to be a start, and then slowly and regularly moving towards the destination. So if we have a human that is low energy, and spending most of their time indoors, they might get very uncomfortable at 125–130 °F. Medicine has figured out that humans that can tolerate higher temperature 165–170° for 30 min, that those humans don’t get tired as easy. Obviously the starting point is only a few minutes and degrees below—but regular stressing, and gently increasing the temperature and the time, the body begins to adapt. The skin will stop getting so prickly and itchy with heat exposure. The plasma volume will increase, tissue puffiness will decrease. Below is an example to keep track of a human’s desensitization to heat. Sauna Desensitization: This is an arbitrary listing of the movement between days and temperatures, and there is no need to rush or keep to the exact listing of this schedule. If any step is not tolerated simply repeat the previous steps for anywhere between 2–5 times before trying again.

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Goal: 30 min, 170 F 65 C Temp Day

130 F

1

5 min

3

10 min

140 F

5

5 min

7

7 min

9

10 min

150 F

11

5 min

13

7 min

15

10 min

17

12 min

20

15 min

160 F

23

10 min

27

15 min

30

20 min

170 F

33

10 min

36

15 min

40

20 min

43

20 min

46

25 min

49

25 min

52

30 min

12.16 What About Cooling the Body? One of the only known ways that any human can increase their basal metabolic rate, is by subjecting their body to colder temperatures. Makes sense, correct? Less environmental heat energy, the more the body needs to make its own heat energy. While some of the commercial ice baths are very cold, I do not recommend water below 15 °C, or about 60 °F. The key indicator here is involuntary muscle movement, I.E. shivering. Once the muscles of the body have started to shiver—it means that the autonomic nervous system is activated and trying to heat up the body. The use of water here is very necessary, as water temperature has a very different effect on the body than air temperature. Once shivering has started, no more than

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5 min should be spent in the cold bath. Cold showering is effective as well, however it may be difficult to stand in a shower once the body starts shivering.

12.17 Taking Away the Blame I have not tried to practice medicine in this work, nor have I really put forth any type of new idea. Over the time I spent with humans, I have come to both appreciate and admire every last one. The human mind and the human body are not separate compartments as I have listed, nor are the mast cells of the human body. If any fellow human read this much, I am grateful. Maybe it was helpful to look at the Earth from the perspective of a mast cell, perhaps even a little funny. The last message is not something that I want to give, it is something I wish to take away. There have been true geniuses in this time, and in history that have transformed the planet Earth—no human has ever got it perfectly right. Even the legendary scientists that have pushed vaccines, prophesized disaster, or just explained that stress can hurt a body, none of them got it done perfect. The immune system is balanced and capable, but is also imperfectly protecting every last human on the planet. So then, whenever self-blame, doubt, guilt, or any feeling of not belonging on this planet creep into a human’s brain, know that every single human that has ever lived has also had those exact feelings, and we welcome you with open arms for a consensual 20 s hug.

Index

A Acetylcholine, 45 Adaptive immunity, 28, 29, 32, 34 Adaptive process, vii Air-conditioning, 9 Air pollution, 112 Air quality, outdoor, 105–117 Airway inflammation, 117 Algae, 68, 69, 72 Allergens, 33, 34 Allergic reactions, vii Allergotherapy, 58 Allergy, 2, 9 Allergy drop, 167 Allergy shots, 161 American College of Rheumatology, 30 American Thoracic Society, 59 Amino acid alphabet, 30 Amino acids, 30, 83, 84 Anaphylaxis, 154, 155, 158 Antibiotics, 32, 51, 63, 65, 66, 69–72, 83 Antibodies, 19, 20, 30 Anti-histamines, 151 Anti-inflammatory diet, 77, 88 Anti-vax movement, 26 Apology, 125–127, 131 Aspartame, 77 Asthma, 50, 51, 56–59, 118 Atrophy, 10, 11, 13 Auto-brewery syndrome, 71 Autoimmune conditions, 42 Autoimmune disease, 16 Autoimmunity, 30, 34, 43, 113

Autonomic nerve connection, 96 Autonomic nervous system, 43–47, 76, 92, 151 B Bacteria, 62–70, 83 Bacterial toxins, 41 Bacterial vaccine, 31 Bad habits, 6 Barrier immunity, 40, 41, 47 Belief, 16 Bias, 5 Binge watching, 122 Biologic process, 115 Biologic system, 8 Booster vaccination, 22 Brain, 120, 123 body temperature, 137, 138 emotion, 136, 137 environmental stress, 133 hibernation to conserve energy, 141, 142 immune adaptive mechanisms, 133 measuring autonomic function heart rate variability, 146 pupillary constriction, 145 thermal acclimation, 145, 146 vagal tone, 145, 146 SAD, 134, 135 shivering to warm, 141, 142 sleep disorder, 143 12-step program, 134 Brain development, 73

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Lichtenberger, Allergic to Life, https://doi.org/10.1007/978-3-031-46026-5

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176 B-toxin, 44 Bubble Boy, 2 C Carbohydrate intolerance, 163 Carbon dioxide, 39, 113 Carbon monoxide, 113 Cardano, Gerolamo, 49, 50 CD4+ cells, 44 Celiac disease, 25 Chemical sensitivity, 40 Chewing, 95, 96, 102 Chicken pox, 19 Chlorella, 166 Chronic illness, 4 Chronic inflammation, 57 Clostridium difficile, 65, 72 Cocaine, 13 Code of life, 125 Conservation, 6 Constant feeding, 93 Conversation, 24 Corticotropin releasing hormone (CRH), 153 Cough, 110 COVID19, 16, 122 Creativity, 136 Cross reactivity, 21 Cysteine protease, 51 D Danger signals, 95 Deer in the headlights, 37 Defensive system, 3 Denial, 5 Der p 1, 51, 59 Desensitization, 58, 59, 159–162, 167, 169–171, 173 basal metabolic rate, 172 carbohydrate intolerance, 163 eating poison, 163 elimination diet, 164, 165 food inclusion, 165, 166 food protein triggered inflammation, 163 key indicator, 172 neurologic hypersensitivity, 162 physical contact, 167 reinforcing, polarizing, 168, 169 rest and digest mode, 166 self-perpetuating, 168, 169 type I hypersensitivity, 162 Developmental process, 13

Index Diabetes, 80 Diencephalon, 123 Digestion, 93, 95, 96, 98–103 Digestive system, 98, 99 Diversity, 69 DNA, 22, 61, 63, 65, 124, 125 D-norepinephrine, 85 Dopamine, 13 Drinking water, 68 Dust mites, 55 allergy avoidance, 49 allergy symptoms, 51 avoidance measures, 57 history of medicine, 49 humans as food, 51–53 inflammation, 55, 56 innate defense, 57 killing methods, 56 long-term inflammatory changes, 57 memory response, 55 modern house-style, 55 molds for growth, 53 parasitic relationship, 50 things to live, 51 pumping iron, 54 sensitivity, 56 sensitization, 58, 59 symptomatic management, 57 therapeutic treatment, 59 timeline, 50 use of antibiotics, 51 vaccination, 50 yeast fixins, 53, 54 E Ecosystem, 15, 66, 67 Eczema, 50, 57 Efficiency, 33, 138, 144 Elimination diet, 165 Emotion, 123, 129, 136, 137 Energy conservation, 141 Energy efficiency, 91 Enterotoxin B, 44 Enviromental stress, 12 Environment, v–vii, 10 Environmental protection agency, 108, 112 Environmental stress, 11 Evidence based medicine (EBM), 22 F Fatigue, 141

Index Fight/flight, 92, 100, 101 Fleming, Arthur Sr., 62, 63 Food, 92–94, 101 Food allergy, 5 Food consumption, 101 Food insecurity, 74 Functional MRI, 13 Fungal spores, 117 Fungus, 117 G Garbage, 110, 111, 113 Gastric emptying study, 93 Glyphosate, 85–88 Glyphosphate, 86 Good and bad concept, 24, 25 Good bacteria, 65, 70 Gut-associated lymphoid tissues (GALT), 67 H Harm, 50 Healthcare system, 106, 107 Health effect, 109 Health Insurance Industry, 106 Health issue, 31 Health problem, 17, 39, 156, 157 Health science, 8 Heart rate, 44, 146 Heart rate variability, 146, 147 Heat balance, 141 Herbicides, 85 Herpes virus, 19, 22, 26 Hibernation, 141 High fructose corn syrup, 13 Histamine, 43, 45, 127, 129, 151, 155 Home environment, 7 House dust mites, see Dust mites Human brain, 13 Human ecosystem, 61–71 Human-environmental interaction, 31 Human genetics, 61, 64 Human genome project, 125 Human nature, 31 Humans, 10 Hyper-media, 121 Hypersensitivity, 128, 162 Hypersensitivity reactions, 33 Hypersensitivity syndromes, 2 Hypertension, 15 Hypertrophy, 10, 11, 13

177 I IgE mediated hypersensitivity, 162 IL-6, 99 Illness, 14, 17 Immediate type hypersensitivity, 33 Immune deficiency syndromes, 2 Immune system, 3, 4, 21–23, 27, 29, 30, 32, 33, 39, 40, 43, 44, 46, 47, 73, 74, 81, 92, 99, 149, 150, 173 Immunitas, 20 Immunity, 20, 21, 32, 40 Immunodeficiency, 2 Immunology, 2, 19, 20, 27, 124 Immunotherapy, 58, 162, 170 Inaction, 106 Indoor air quality (IAQ), 105–117 Indoor environment, 14, 15 Infant formula, 73, 74 Infection, 41 Inflammation, 4, 32, 38, 55, 56, 93, 97, 99, 102, 103, 112, 150, 153, 156–158, 160, 163 Inflammatory reactions, 25 Influenza vaccine, 31 Innate immune system, 41 Innate immunity, 24, 28, 34 Internal adaptation, 43 Internet, 114 Intrinsic factor, 77 J Jenner’s vaccine, 21 Joint fever, 32 L Laughter, 124, 131 Learning, 136, 137, 140, 147 Leishmaniasis, 23 Light, 143–145 L-norepinephrine, 87 Long-term effects, vi, 7 Low carbohydrate, 93 L-tyrosine, 85 Lymphedema, 99 Lymphomania, 142 M Macroeconomics, 106 Mammary gland, 74 Mast cell activation syndrome(MCAS), 156

178 Mast cells, vii, 41–43, 46–48, 52, 64, 75, 85, 87, 97, 111, 113–115, 117, 127, 129, 134, 137, 139, 140, 149–157 activation, 59, 162 activation cycle, 46 autonomic nervous system to the immune system, 45, 46 CRH, 153 signal molecules, 152 Mastocytosis, 155 Medication, 107 Medium chain triglyceride (MCT), 99, 100, 103 Melatonin, 127, 135, 144–146 Mental health, 122 Metaphors, 38 Methicillin resistant Staph aureus (MRSA), 63, 64, 69 Microbiome, 15, 54, 66, 68, 69, 71, 72 Microplastics, 114 Milkmaids, 20 Minimal inhibitory concentration (MIC), 69 Mistaken identity, 21 Mold spore, 117 Molecular mimicry, 21 Mucosal barrier, 75, 113 Mucous membrane, 40, 47 Multiple sclerosis, 68 Muscle cramp, 93 Mutation pressures, 64 N Natural environment, 7 Natural response, 2 Negative emotions, 124 Nerve impulse, 13 Neuroimmune system, 38 Neurotransmitter, 45, 46, 84, 85 Nitrosamine, 7 O Obesity, 139, 140, 147 Osteoporosis, 27 Oxygen, 39 Ozone, 116, 118 P Pack of human, 130, 131 Papain, 51 Parasite, 33, 40, 42, 48, 50, 169, 170

Index Parasitosis, 48 Parasympathetic, 98, 102, 103 Particulates, 108–110, 112 Pattern recognition receptors, 55 Penicillin, 62, 63 Penicillium notum, 62 Pernicious anemia, 79–82, 88 Photosynthesis, 39 Physical barriers, 66 Physical health, 122 Physical injury, 2 Placebo effect, 16 Plagues, 4 Plant reproduction, 115 Plasma volume, 141 Plastics, 114, 115 Pollen, 115, 116 Pollution, 110, 112, 118 Possibility, 7 Prevention, 32 Primordial soup, 39 Protease, 51, 58 Protective system, 111 Protein, 164 Psychologic stress, 97 Public health measures, 21 R RAGE, 126 Ranitidine, 6, 7 Reactivation, 22 Rejection mechanism autonomic nervous system, 43–47 barrier immunity, 40, 41 deer in the headlights, 37 defense becomes offense, 41–43 environment, externally respond, 43 evolutionary existence, 38 functional ability, 38 health problems, 39 heightened senses, 38 human body, internal adaptation, 43 immune system, 39, 40, 46, 47 medical students team, 37 metaphors, 38 neurotransmitters, 45, 46 stress signals, 45 Rest and digest, 100, 101 R-factor, 77 Rheumatic fever, 32 Rhinitis Medicamentosa, 107 Root cause, vi, vii, 3, 7

Index

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S Sauna, 141, 171 Sauna desensitization, 171 Scarcity, 94 Science fiction, 1, 2, 58, 63, 122 Scurvy, 79, 80, 88 Search engine, 169 Seasonal affect disorder (SAD), 134, 135, 141, 146 Self-blame, 15 Self-medicating, 134 Selye, Hans, 133, 146 Sensitivity, 56 Sensitization, 56–59, 128 Sexual tension, 122 Shock, 37 Skeletal muscle, 10 Skin, 64, 66, 69–71 Sleep, 143 Smallpox, 20, 22 Smallpox vaccination, 30 Social dePrograming, 169 Social environment, 120 Social interaction, 119–131 Social media, 120, 121, 128, 131 Socialization, 120 Society, 17 Spores, 117 Staph aureus, 62–64 Starch, 165 Stress, 133, 134, 140 Stress response, 150, 151, 153, 158 Sucrose, 13 Superantigens, 64 Symbiosis, 40, 48 Sympathetic nervous system, 98

Threat, 43 Thyroid disease, 80 Tobacco smoking, 106 Tom Joad, 151, 152, 158 Toxin, 42, 46, 82, 83 Tradition, 130, 131 Triggered aggression, 119, 131 Trimethylamine (TMA), 67, 72 Tryptase, 154 Tryptophan, 86 Tyrosine, 87

T Temperature regulation, 146 Thoracic duct, 99, 103

Z Zone, 92

U United States Healthcare System, 16 Unnatural environment, 1, 2, 14 V Vaccine, 19–21, 23, 24, 26, 31, 33, 105 Vagus nerve, 76, 77, 88, 96–98 Variables, 8 Villous atrophy, 93 Viral vaccine, 31 Vitamin B12, 77, 78 Vitamin C, 77–80 W Weaponized guilt, 5 World Health Organization (WHO), 50, 73, 109 Y Yeast, 63