2018 Article 193

Khatami Clin Trans Med (2018) 7:20
https://doi.org/10.1186/s40169-018-0193-6
PERSPECTIVE Open Access
Cancer; an induced disease of twentieth

century! Induction of tolerance, increased
entropy and ‘Dark Energy’: loss of biorhythms
(Anabolism v. Catabolism)
Mahin Khatami*
Abstract
Maintenance of health involves a synchronized network of catabolic and anabolic signals among organs/tissues/
cells that requires differential bioenergetics from mitochondria and glycolysis (biological laws or biorhythms). We
defined biological circadian rhythms as Yin (tumoricidal) and Yang (tumorigenic) arms of acute inflammation (effec-
tive immunity) involving immune and non-immune systems. Role of pathogens in altering immunity and inducing
diseases and cancer has been documented for over a century. However, in 1955s decision makers in cancer/medical
establishment allowed public (current baby boomers) to consume million doses of virus-contaminated polio vac-
cines. The risk of cancer incidence and mortality sharply rose from 5% (rate of hereditary/genetic or innate disease)
in 1900s, to its current scary status of 33% or 50% among women and men, respectively. Despite better hygiene,
modern detection technologies and discovery of antibiotics, baby boomers and subsequent 2–3 generations are
sicker than previous generations at same age. American health status ranks last among other developed nations while
America invests highest amount of resources for healthcare. In this perspective we present evidence that cancer is
an induced disease of twentieth century, facilitated by a great deception of cancer/medical establishment for huge
corporate profits. Unlike popularized opinions that cancer is 100, 200 or 1000 diseases, we demonstrate that cancer is
only one disease; the severe disturbances in biorhythms (differential bioenergetics) or loss of balance in Yin and Yang
of effective immunity. Cancer projects that are promoted and funded by decision makers are reductionist approaches,
wrong and unethical and resulted in loss of millions of precious lives and financial toxicity to society. Public vaccina-
tion with pathogen-specific vaccines (e.g., flu, hepatitis, HPV, meningitis, measles) weakens, not promotes, immunity.
Results of irresponsible projects on cancer sciences or vaccines are increased population of drug-dependent sick
society. Outcome failure rates of claimed ‘targeted’ drugs, ‘precision’ or ‘personalized’ medicine are 90% (± 5) for solid
tumors. We demonstrate that aging, frequent exposures to environmental hazards, infections and pathogen-specific
vaccines and ingredients are ‘antigen overload’ for immune system, skewing the Yin and Yang response profiles and
leading to induction of ‘mild’, ‘moderate’ or ‘severe’ immune disorders. Induction of decoy or pattern recognition
receptors (e.g., PRRs), such as IRAK-M or IL-1dRs (‘designer’ molecules) and associated genomic instability and over-
expression of growth promoting factors (e.g., pyruvate kinases, mTOR and PI3Ks, histamine, PGE2, VEGF) could lead to
immune tolerance, facilitating cancer cells to hijack anabolic machinery of immunity (Yang) for their increased growth
requirements. Expression of constituent embryonic factors would negatively regulate differentiation of tumor cells
through epithelial–mesenchymal-transition and create “dual negative feedback loop” that influence tissue metabolism
under hypoxic conditions. It is further hypothesized that induction of tolerance creates ‘dark energy’ and increased
*Correspondence: [email protected]
Inflammation, Aging and Cancer, National Cancer Institute (NCI), National
Institutes of Health (NIH), Bethesda, MD, USA
© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.
Khatami Clin Trans Med (2018) 7:20 Page 2 of 31
entropy and temperature in cancer microenvironment allowing disorderly cancer proliferation and mitosis along with
increased glucose metabolism via Crabtree and Pasteur Effects, under mitophagy and ribophagy, conditions that are
toxic to host survival. Effective translational medicine into treatment requires systematic and logical studies of com-
plex interactions of tumor cells with host environment that dictate clinical outcomes. Promoting effective immunity
(biological circadian rhythms) are fundamental steps in correcting host differential bioenergetics and controlling
cancer growth, preventing or delaying onset of diseases and maintaining public health. The author urges independ-
ent professionals and policy makers to take a closer look at cancer dilemma and stop the ‘scientific/medical ponzi
schemes’ of a powerful group that control a drug-dependent sick society before all hopes for promoting public health
evaporate.
Keywords: Accidental discoveries, Aging, Autophagy, Biological circadian rhythms, Biorhythms, Cancer biology,
Cancer establishment, Conjunctiva, Constituent receptors, Crabtree effect, Dark energy, Decoy receptors, Effective
immunity, Entropy, Environment, Epithelial–mesenchymal, Fatigue, Fetus orderly growth, Gastrointestinal, Growth-
arrest, Growth-promote, Glycolysis, HPV vaccines, Hypoxia, Hypersensitivity, Immune intolerance, Immune-privileged,
Immune-responsive, Immune suppression, Induced disease, Infection, Inflammation, PI3 Kinase, IRAK-M, Longevity,
Mitochondria, Mitophagy, mTOR, Ocular tissues, Oxidative stress, Pasteur effect, P53, Personalized or precision medicine,
Pyruvate metabolism, Pyruvate kinases, Pyruvate-shuttle, Phosphatases, Ribophagy, Ribosome, Targeted therapy, TNF-α,
TNFRs, Viruses, Virus-like particles, Virus-contaminated polio vaccines, Yin and Yang of acute inflammation
Introduction between inflammation and time-course kinetics of induc-

tion of identifiable altered phases of immune response
The world will not be destroyed by those who do evil,
profiles toward multistep tumorigenesis and angiogenesis
but by those who watch and do nothing. Albert Ein-
(see below) [5].
stein.
These and related fundamental observations and dis-
Maintenance of human health is the result of an amaz- coveries that stood the test of time have been practically
ingly harmonious, synchronized and autonomous neuro- ignored and minimized or rejected by the decision mak-
physiological status of body. Health of an adult depends ers in cancer/medical establishment.1 In this perspective,
on the reciprocal interactions of positive and negative the author attempted to analyze, integrate data and iden-
biological feedback control mechanisms (biological tify relevant knowledge gaps on diverse topics of cancer
clocks, circadian biorhythms) between and among the sciences toward a roadmap. The goal was to briefly pre-
immune-vascular-metabolic-genomic-hormonal-neu- sent evidence that cancer is an induced disease of the
ronal (sympathetic and parasympathetic) pathways that twentieth century, facilitated by medical/cancer estab-
constitute effective immunity (biological laws) for pre- lishment for huge corporate profits ever since the Ameri-
venting diseases including cancer. As early as the nine- can public was allowed to consume virus-contaminated
teenth century, Paul Ehrlich using the newly invented polio vaccines in 1955s/1960s. Weakened immunity of
microscope made fundamental observations that cancer public has been reinforced by other pathogen-specific
cells are destroyed by immune/inflammatory cells [1]. vaccines (e.g., Swine flu, hepatitis B or C, measles,
Furthermore, over a century ago, Peyton Rous through anthrax, meningitis, HPV or even BCG) including vac-
a series of careful and pioneering studies demonstrated cines ingredients/adjuvants (e.g., mercury, aluminum,
that filterable viruses induce cancer; thus the establish- L-histidine, recombinant DNA, embryonic serum), which
ment of the field of virology [2]. Later on in 1957, Sir are ‘antigen overload’ for the immune system to clear. In
McFarland Burnet conceptualized the important theory the last few decades, public has additionally been exposed
of immune surveillance, the protection of body against to a wide range of environmental hazards [e.g., smoking,
all unwanted elements including the control of cancer
growth [3]. Burnet theory was based on evaluation and 1
Cancer/Medical establishment is referred to the most powerful decision
integration of a wide range of available data on cellular making group within the Government (NIH/NCI-FDA-CDC-DHHS), Big
pharma, major organizations (AACR, ACS, ASCO, AMA), cancer research
and molecular biology, embryology and pathology [3]. and treatment centers, major medical schools. Members of establishment
In 1986, Dvorak proposed that tumors are wounds that (5–10 × 103) with carrier longevity of 35–65 years are decision makers
do not heal [4]. Furthermore, the analyses of accidental in charge of research directions, publicity and funding. The temporary or
permanent handlers of establishment (directors of institutes, divisions or
discoveries that Khatami et al. established in 1980s on departments, deputies and staff (30–100 × 103) and the world’s largest lob-
experimental models of ocular inflammatory diseases, bying group (3–5 × 106) carry out the directions of members of establish-
are the only series of direct evidence for an association ment. War on cancer has been made as an imaginary problem that cannot
be solved for over six decades [5, 7, 16].
pesticides, genetically modified organisms (GMOs) and pigs from highly sensitized animals developed strong
preserved foods, electronic gadgets, low level carcino- clinical reactions upon 1st or 2nd challenge with antigen
gens] and other immune disruptors whose cumulative suggesting antibody transfer and genetic predisposition
effects adversely influence immunity [5–25].2, 3, 4 in newly born animals [8, 28, 29, 31]. Mixing antigen with
tumor-promoting agents shifted the induction of tumo-
Accidental discoveries in 1980s: time course rigenesis and angiogenesis to earlier time course, com-
kinetics of inflammation-induced developmental pared with using antigen alone, suggesting involvement
phases of immune dysfunction toward multistep of growth promoting kinases. Presence of circulating
tumorigenesis and angiogenesis IgE antibodies did not necessarily correlated with strong
In 1980s, we established experimental models of acute acute reactions, suggesting sensitization of local and dis-
and chronic ocular inflammatory diseases using guinea tal MCs including the lung airways or the fetus tissues [8,
pigs conjunctival-associated lymphoid tissues (CALTs). 26, 31]. In 2014, further analyses and integration of origi-
Systematic analyses of a series of reported data suggested nal data led to the first report on interactions and syner-
the first and only evidence for direct association between gies between host/local immune and non-immune cells
inflammation and time course kinetics of developmen- (e.g., mast cells, mucus-secreting goblet cells, epithelium,
tal phases of immune dysfunction (acute, intermediate B/plasma cells) and the recruitment and infiltration of
and chronic phases) in the direction of tumorigenesis activated immune cells (e.g., eosinophils, tumor associ-
and angiogenesis (‘accidental’ discoveries) [5–8, 26–41]. ated macrophages/TAM-M2) via activation of vascula-
Briefly, in the acute phase (immediate hypersensitivity ture toward tumorigenesis and angiogenesis at different
responses), early clinical and histopathological findings stages of immune dysfunction [38].
included strong or weak type 1 ocular reactions, tear- These are the earliest and only series of systematic
ing, activation and degranulation of mast cells (MCs), studies that produced evidence on the role of repeated
vascular hyperpermeability reactions and tissue edema. exposures to immune disruptors (antigen) in the induc-
The release of histamine and prostaglandins (PGF-1α) tion of multistep tumorigenesis and angiogenesis. These
were reported as primary and secondary mediators of accidental discoveries on direct role of inflammation in
immune responses in acute phase reactions. Animals alterations of immune dynamics toward tumorigenesis
with strong acute ocular reactions also demonstrated and angiogenesis deserve to be further studied, validated,
wheezing suggestive of MCs sensitization and activation confirmed and compared with other experimental mod-
in lung airways [8, 26, 30, 31]. The intermediate phase els of inflammatory diseases, other tissues [e.g., lung-
(down-regulation phenomena) responses were associated associated lymphoid tissues (LALTs), gut-associated
with minimum clinical responses, increased degranu- lymphoid tissues (GALTs)] or other tissues with different
lated MCs, heavy infiltration of eosinophils in ocular cell compositions (e.g., liver, breast, colorectal).
secretions and goblet cells, induction of neovasculari- As detailed elsewhere ([5–7, 38, 39], Khatami, NCI/NIH
zation and tissue atrophy [27, 31]. In the chronic phase records and legal documents since 1998), author’s chal-
responses, clinical appearance of tumor-like lesions in lenging efforts to promote the important role of inflam-
upper and lower bulbar conjunctiva, extensive angio- mation in cancer research, diagnosis and therapy initially
genesis and massive hyperplastic tissues were reported. met with serious oppositions and denials by members of
Histopathological studies demonstrated loss of capsular establishment who rejected the submitted concepts and
integrity in lymphoid tissue, increased presence of vari- comprehensive proposals that were extension of author’s
ous size lymphocytes (proliferation), lymphatic channels, original discoveries. However, in recent years, it seems
necrosis and growth in epithelial tissues, activated MΦs that Khatami’s efforts awakened the entire cancer com-
and presence of histiocytes (activated DCs?). Antibody munity within and outside NCI/NIH, on the important
assays of hyperplastic tissues showed changes in local role of inflammation in cancer science. In the last 2 dec-
IgGs biosynthesis (IgG1/IgG2 ratios). New born guinea ades, professionals enjoy significant increased in funding
on fragmented submitted ideas in the fields of OMICS
(e.g., proteomics, genomics, metabolomics, lipidom-
2
Health Impact News December 10, 2017—reported from World Mercury ics, proteo-genomics) or immunotherapy, using highly
Project Team—Anthrax Vaccine: Safety Concerns-‘Pilots Would Rather expensive specific technologies and experimental models
Leave the Military than be Forced to get Anthrax Vaccine’.
3 [e.g., genetically or chemically-induced (e.g., comination
US Senator Grassley Investigates Vaccine Corruption in Unsanctioned
Experimental Herpes Vaccine: Human Research. Health Impact News, Jan- of azoxymethane (AOM) and dextran sodium sulfate)] of
uary 12, 2018. tumors and organizing networking and symposia, with
4
Wagstaff A, Culyer AJ. Four decades of health economics through a bibli- no end in sight [5–7, 38–43]. However, the outcomes of
ometric lens. J Health Econ. 2012;31:406–39. https://doi.org/10.1016/j.jheal
eco.2012.03.002.
reductionist approaches on identification of hundreds of
molecular entities that are used for drug development and low level carcinogens that made young and old in Amer-
claimed as ‘targeted’ therapy or ‘personalized’ or ‘preci- ica sick and drug-dependent.
sion’ medicine have been very disappointing, extremely Analyses of related data suggest that nearly all diseases,
costly and dangerous for patients and society. Majority of to varying degrees, are the results of altered effective
expensive projects in cancer research and therapy focus immunity or loss of biological circadian rhythms (on–off
on identification of too many defective molecular species switches) that adversely influence tissue bioenergetics
in the landscape of cancer molecular tsunami with little/ (mitochondria), the principal generator of energy and elec-
no efforts to understand what initiate altered immune tricity (proton pumping) in organ systems [5, 7, 35–90].
response profiles that lead to multistep tumorigenesis. It is also noteworthy that the special or shared bio-
The initial immune response alterations were suggested to logical/medical features of full-blown diseases that often
be correctable, reversible or drugable [5, 7, 16, 39–43]. determine the outcomes of nearly all age-associated
Ongoing debates, controversies, misinformation and chronic conditions fall into the following three major
confusions regarding the role of inflammation, whether it categories, as interdependent defects in immune surveil-
is protective in preventing cancer or it is a cause of can- lance (biorhythms) associated with varying degrees of
cer are among serious factors in failing patients when loss of bioenergetics in affected tissues [5, 39]:
clinical trials are decided [5–8].5
(a) Vascular and lymphatic channels disorders.
Categories of human diseases (b) Tissue necrosis.
To better understand the biology of cancer, we first define (c) Tissue growth.
that, in general, all diseases are the outcomes of one or
combination of interdependent biological defects that are Manifestations of organ-specific diseases that are
medically/clinically categorized as the following: known as distinct pathological and clinical complications
such as polyps, pre-cancer, cancer metastasis and angio-
1. Congenital. genesis, or neurodegenerative and autoimmune diseases,
2. Hereditary. diabetes and cardiovascular complications, are generally
3. Neonatal. the outcomes of cumulative damages in the immune-
4. Induced. responsive tissues (e.g., epithelial, endothelial, mucus
secreting goblet cells, stroma) or immune-privileged tis-
In the following sections, attempts were made to dem- sues (e.g., CNS, BBB, neuroretina, cornea, reproductive
onstrate and suggest that cancer is a symptom of accu- system) and/or insulin-dependent (e.g., muscle, adipose
mulated violations of time-controlled biorhythms whose tissue, liver) and insulin-independent tissues (e.g., vascu-
disorderly proliferation and mitosis are facilitated by lature, neuronal and endothelial cells, fibroblasts) for glu-
altered mitochondrial bioenergetics, increased glucose cose transport and metabolism [5–8].
utilization and entropy and generation of ‘dark energy’, Overview and integration of data on diverse experi-
conditions that are toxic to normal cells. Unlike the pop- mental models of chronic illnesses or cancer research
ularized notion that cancer is 100, 200 or 1000 diseases!, and clinical studies suggest that all diseases share features
the author shows that cancer cells are body’s defective of one or more defects in innate (intrinsic, constituent)
cells whose disorderly growth are the results of loss of and/or adoptive (extrinsic or induced) pathways includ-
natural biphasic properties of Yin (tumoricidal) and Yang ing cellular [e.g., genomic/chromosomal (DNA/RNA,
(tumorigenic) of inflammation, associated with loss of epigenetic modifications), cell mediated or humoral
differential bioenergetics (anabolic vs catabolic) in tis- immunity (CMI/HI), hormonal, metabolic, neuronal
sues. Evidence is presented that over the last six decades, (sympathetic and parasympathetic)] activities that con-
decision makers in cancer establishment has gradually tribute to the complex signal communications of altered
weakened and manipulated the autonomic biological cir- immunity and manifest in different tissues as different
cadian rhythms, the Yin and Yang of effective immunity, diseases [5–8, 34–80]. We proposed that effective immu-
by introducing the public to various pathogen-specific nity (synchronized biorhythms, sympathetic and para-
vaccines and ingredients, in addition to exposures to sympathetic, or Yin and Yang of acute inflammation) is
exposures to a wide range of environmental hazards and responsible for protection of body against all intrinsic
(e.g., defective cancerous cells, useless proteins/peptides/
lipids, accumulated oxidized materials, lymphocyte-
5
Khatami M (2016) Book review: Safety concerns for HPV vaccination of derived clonal complexes, abnormal repair mechanisms
young generation, paid by Obamacare and V.P. Biden Moonshot initiative. in chromosomal-histone proteins-genetics, DNA/RNA
Global Vaccines and Immunology, ISSN: 2397-575X, 2016 https://oatex
t.com/pdf/GVI-1-118.pdf.
mutations, or hypo/hyper epigenetic modifications) or
extrinsic elements (e.g., pathogens/microbiomes, aller- destruction of foreign entity and the injured/infected
gen/antigens, low level carcinogens) that are perceived target tissue, the activated cells simultaneously signal for
harmful to individual’s survival [5–8, 20, 35–39]. polarization of immune cells (e.g., M2 or TAMs pheno-
types, degranulated MCs) that would automatically shut-
Bioenergetics of effective immunity: biological down mitochondria, allowing regeneration of TCA cycle
circadian rhythms via biphasic-synchronized Yin intermediates (e.g., succinate–fumarate–oxaloacetate)
and Yang of acute inflammation and numerous other important mitochondrial activities
As detailed elsewhere [5–8, 35–40], effective immunity fol- [e.g., pyruvate-shuttle, pyruvate carrier proteins, synthe-
lows complex and precise rules of molecular engagements sis of enzymes (e.g., SODs, cytochromes), metabolism
and require development of differential bioenergetics for of branched amino acids (leucine, valine, isoleucine)
body’s defense and survival after birth. Effective immu- and synthesis of structural proteins and maintenance of
nity was defined as a highly regulated signal transductions mDNA synthesis] that are required for mitochondrial
between 2 biologically opposing arms, termed Yin (tumori- function. Yang (tumorigenic, post-inflammatory) events
cidal) and Yang (tumorigenic) that intimately engage the involve polarization of immune cells and non-immune
activities of immune-metabolic–vasculature–hormonal– pathways for expression of growth promoting mediators
neuronal (sympathetic and parasympathetic) systems. and decoy receptors [e.g., VEGF, IL-dRs, cortisol, epi-
In an acute inflammation, autonomic crosstalk between nephrine, superoxide dismutases (SODs), MMPs, PGE2,
innate and adaptive immune cells and non-immune PI3 Kinases, mTOR, MAPK] to neutralize and remove
pathways has a 2-fold mission with differential energy the toxicities that are generated during Yin and to repair,
requirements from mitochondria and cytosol as outlined reconstruct or remodel the target host tissue and termi-
below [5, 35–40]. nate inflammation. Switching from oxidative phospho-
rylation in mitochondria, under hypoxic conditions and
A. Catabolic (Dressed to Kill!), Yin (tumoricidal arm): low energy utilization from glycolytic pathways are fun-
high energy consuming events utilizing oxidative damental events that require differential bioenergetics
phosphorylation from mitochondria (high-low energy switches from mitochondria to cytosol)
Yin events are involved in encountering/sensing (rec- for maintenance of effective immunity. The Yang pro-
ognizing), processing or digesting and eliminating the cesses are required not only for revival and repair mecha-
intrinsic or extrinsic foreign elements (e.g., allergen, path- nisms of injured tissue, but for mitochondrial recovery
ogens/microbiota, cancerous cells, oxidized metabolites, and biosynthesis of TCA cycle intermediates to gener-
senescent cells or lymphocyte complexes) and the injured ate efficient energy. Therefore, Yang events are naturally
host tissue. Yin (apoptotic, pro-inflammatory) events anabolic (low energy) and possess regenerative (growth)
require burst of energy (ATP hydrolysis) from mitochon- features of effective immunity, and function under low
drial oxidative phosphorylation (OxPhos) for activation of oxygen tension (hypoxia) for wound healing purposes.
innate and adoptive immune cells [e.g., MCs degranula- Simply described, in an acute inflammation, apoptotic
tion, MΦs (M1 phenotype), DCs, NKs or T and B/plasma arm or Yin responses are catabolic processes requiring
cells], as well as activation of non-immune systems (vas- high energy consumption from mitochondrial OxPhos
culature, metabolism, neuronal, hormonal) for generation to express death signals, oxidants, enzymes and recep-
of required toxins, oxidants and apoptotic factors. Path- tor molecules for destruction of both the enemy and the
ogen-specific induction of danger molecules and expres- injured/infected host cells. In contrast, the wound heal-
sion of specific pro-inflammatory mediators and receptor ing or Yang responses are anabolic processes and require
molecules (e.g., TLRs, vasoactive histamine, TNF, ILs, simultaneous polarization of immune and non-immune
ROS, NO, complement cascades) as well as, secretory lys- cells for generation of growth promoting factors to coun-
osomal activities, membrane fusion, exocytosis, ion fluxes teract and neutralize the toxicity of injured tissue. Yang
and vascular hyperpermeability responses facilitate the responses follow mitochondrial shutdown and switch to
destruction of foreign elements and injured host tissue. cytosolic low energy utilization from glycolysis (Warburg
Yin events require genomic activation of specific tumori- effect) to resolve inflammation.
cidal factors (above examples) [5–8, 35–39]. The major outcomes of an acute inflammation are lym-
phocyte-derived clonal expansion, increased synthesis
B. Anabolic (revival of target tissue), Yang (tumorigenic of pathogen-, or allergen-specific antibodies and plasma
arm): low energy consuming events-utilizing glycolysis and memory T and B cells that would prepare the body to
(Warburg effect) defend and unleash appropriate responses such as anti-
Following the release of oxidants toxins and utiliza- gen-specific antibody release when tissue is exposed to
tion of high energy from mitochondrial OxPhos during the same hazardous agents [5–7, 35–40].
The author’s original definitions of biphasic roles trophoblasts that anchor embryo and during fetus
of Yin (tumoricidal) and Yang (tumorigenic) of effec- growth under limited oxygen tension (hypoxic con-
tive immunity [35] present much larger applications for dition). Angiogenesis and organogenesis, including
understanding the synchronized biorhythms and neuro- development of lymphoid organs and generation of
metabolic responses of sympathetic and parasympathetic naïve pluriepotent stem cells or mesenchymal stem
systems that guard human health [5–7, 35–39]. cells (MSC) require growth factors and metabolism,
primarily using glycolysis for energy requirements.
Bird’s eye view on differential energy requirements The energy production for growth involves constitu-
throughout life: violations of biological rhythms ent growth pathways such as expression of pyruvate
(laws) and induction of immune tolerance kinases, aspartyl-asparginyl β-hydroxylases (ASPH
in tumorigenesis and angiogenesis or HAAH), mTOR/PI3Ks, insulin and insulin-like
The crosstalk in Yin and Yang of effective immunity growth factor (IGF) [5, 39, 69–76]. The author pro-
occurs continuously and simultaneously between and posed that the protection of fetus growth must occur
among cells, tissues, organs and glands (e.g., skin, liver, in the absence of fully functional mitochondria and
kidney, eyes, lung, heart, thymus, lymphoid organs, vas- limited Yin (tumoricidal, growth-arrest) pathways
culature, neuronal, and gastrointestinal tract) for mainte- to avoid necrosis that is dangerous to fetus survival
nance of health. In 2016, we proposed a working model and could lead to abortion [5, 39]. Thus, fetus orderly
for differential bioenergetics requirements of Yin and growth is practically established by anabolic path-
Yang pathways from fetus orderly growth, after birth and ways (Fig. 1). The growth-promoting events (Yang)
all the way to adulthood, aging process and development are also required after birth for wound healing path-
of chronic diseases and cancer [39]. The following sec- ways and establishment of effective immunity. The
tions briefly reflect further extension of the recently pro- overall features of fetus orderly growth include.
posed model on analyses and integration of a large body
of valuable scattered data pertaining to basic and clini- a. The earliest features in fetus growth are vasculo-
cal studies on developmental biology, immunity, aging, genesis and organogenesis, events that are com-
hormonal, metabolic and neuronal activities, to better pleted and functional after birth [5, 39]. In the
appreciate induction of immune tolerance and cancer process of fetus growth, naïve or undifferentiated
bioenergetics [5–7, 35–190]: immune T and B cells are transported from pla-
centa through fetus circulation to develop lym-
1. The body is a dynamic and energy consuming sys- phoid organs. Being in the protective environ-
tem involving highly complex interactions between ment of placenta, fetus is not directly exposed to
and among multi-organs whose function continually the atmospheric oxygen and is not challenged by
evolves, from conception, placentation, embryonic the environmental hazards. The hypoxic condi-
and fetal growth, after birth, puberty and adulthood tions of placenta provide fetus natural/constitu-
and aging or disease processes. The anabolic (regen- ent tolerance. Therefore, there is no need for an
eration, tumorigenesis or Yang) and catabolic (apop- effective immune surveillance (Yin and Yang),
tosis, tumoricidal or Yin) arms of effective immu- nor for functional mitochondria.
nity follow highly organized biological circadian b. Majority of the required fetus constituent
rhythms (biorhythms) requiring on–off switches of growth factors, receptors and enzymes (e.g.,
immune and non-immune responses that constitute pyruvate Kinases, mTORs, hormones) also share
the human health. Insufficient circadian rhythms features of wound healing, tolerance or tumo-
(skewed biological clocks or loss of sympathetic or rigenic (Yang) arm of effective immunity after
parasympathetic activities) are perhaps the result of birth.
one or more mutations or deficiencies in the circa- c. Features of rapid aging and maturation in pre-
dian clock genes that influence the amazingly syn- natal-embryonic tissues and postnatal develop-
chronized and interdependent features of biological ment of childhood cancers [e.g., neuroblastoma,
oscillators in Yin–Yang or ‘effective acquisition time’ B-lineage infant acute lymphoblastic leukemia
of immunity [5, 7, 39]. (ALL), mixed lineage leukemia (MLL), myeloid
2. Growth requirements of embryo-fetus develop- leukemia-Downe syndrome-ML-DS or medul-
ment are orderly processes (basically a one-way loblastoma] have been reported [5, 39, 73–76].
growth) occurring under protected environment of The rapid childhood aging are associated with
placenta during embryonic development involving increased and progressive genomic muta-
expression of constituent receptors, projected from tions and instability and fusion, as evidenced
Interplay of Oxida!ve Stress and Bioenerge!cs at Different Stages of

Life: Anabolic (Yang) v Catabolic (Yin) -Biorhythms
• Placenta-Embryo-Fetus Exchange • Environment
O2
O2
• Orderly Growth-Glycolysis, • Atmospheric O2
• Gherin, HA, • Anabolic/Catabolic
• HO-1, CYP1A1/CP450 • Mito Develop
• IGF/ASPH-Notch-1 Fetus Birth • Pyr-Mito. Shu#le
• PKs, Const-Ind Rs • Yin –Yang Develop
Vasculogenesis Adapta!on-O2
• HIF-1β/HIF-1α Tension-K+
Organogenesis
Channels, MSC Reprogramming
Anabolic (Yang) >> Hypoxia/mTOR
Organ Develop Cons!tuent-Induced Rs
Catabolic (Yin) Mo!lity-Notch
TLRs-IRAK-M;
Disorderly Growth mTOR/PI3K
Mito Dysfunc!on Aging Puberty -
OxPh v Glycolysis
Glycolysis Adulthood
Induced Rs
Tear-Wear Adapta!on
Tolerance,… Senescence Reproduc!ve • Environment
Cancer Cycle • Immunity
• Yin < Yang Angiogenesis Differen!a!on • Yin =Yang
• Skewed Immunity, • mTOR-Oxida!ve
• Oxida!ve Stress, mTOR-IRAK-M Stress, Infec!ons
Fig. 1 Schematic representation of Yin and Yang of immunity that parallels differential bioenergetics at various stages of life. It depicts that fetal
orderly growth primarily utilizes glycolysis and constituent growth factors (e.g., IGF, mTOR) under low O2 and in the absence of mitochondrial
development. After birth and exposure to atmospheric oxygen, major adaptation and reprogramming of organ systems including development
of mitochondria and effective immunity (Yin–Yang) are required. Aging and oxidative stress is depicted to skew effective immunity including mito-
chondrial dysfunction, induction of tolerance and hypoxia that resemble anabolic conditions of fetal orderly growth, that could lead to disorderly
growth of cancer cells (Yin <Yang). See text
by embryonic hyperplastic cell growth patterns a. Completion of mitochondria, the double mem-
that favor abnormal proliferations of cell sur- brane-bound organelles, for establishing the
vival under hypoxic conditions. Over expression many biological events for production of energy
of several genetically identified mutated growth and maintenance of bioenergetics. Among major
factors (e.g., MYC, PI3K, MAPK, erythropoietin pathways in mitochondrial development are the
receptor-B cell factor-1-EBCR1 or BCR, Notch1, establishment of pyruvate-shuttle between cyto-
Notch2, FBXW7 and polymerases) or perhaps sol-mitochondria, induction of pyruvate-carrier
low level histamine [e.g., independent from proteins, development of TCA cycle enzymes
MCs activation (‘leaky’ MCs), or in the absence and generation of ROS that are byproducts
of functional MCs] that trigger oncogenesis in of routine tissue metabolism (wear and tear),
childhood cancers are characteristics of adult metabolism of essential branched amino acids
cancers [5, 39, 73–76, 89]. (e.g., leu, isol, val) for biosynthesis of structural
proteins and ribosomal recycling activities or
3. After birth and during infancy the most pronounced perhaps chromatin remodeling-related events.
biological changes and reprogramming relate to It was proposed that biosynthesis of structural
newborn’s exposure and adaptation to atmospheric proteins after birth are required for maintaining
O2 and completion of organs development. It is pro- architectural integrities and boundaries among
posed that independent life of individual after birth and between cells and tissues (e.g., cell–cell-con-
requires the following major biological changes, tact inhibition, vascular tight junctions, inhibi-
adaptations and reprogramming (Figs. 1, 2). tion of epithelial–mesenchymal transition). Fully
functional mitochondria have the capability for
Ontology : Fetus and Lymphocytes Interac!ons

Mitochondria and Yin and Yang of Immunity a"er Birth
Fetus Growth (Placenta)
Vaculogenesis –Organogenesis
Naïve T cell Low Oxygen-Glycolysis B cell
Yin < Yang (Mito Not Func!onal)
Birth: Adapta!on to O2 Pressure, Mito.
Matura!on/Differen!a!on (Thymus) Matura!on/Differen!a!on (Bone marrow)

Bone Marrow
[Environment]
Migra!on, Interac!on with An!gens/Allergen in Secondary Lymphoid Tissues
Danger Molecule, Cytokine/Chemokine/Receptor, An!body
Mitochondrial Func!on and CMI-HI Immunity [Yin = Yang]

Interac!ons with Vascular, Hormonal, Metabolic, Neuronal Components
Effec!ve Immunity
Fig. 2 Schematic representation of ontology of fetal growth, showing vasculogenesis and organogenesis, under placenta’s limited oxygen tension.
It depicts that fetus growth occur primarily in the absence of functional mitochondria and Yin (tumoricidal, high energy) arm of effective immunity.
After birth and exposure to atmospheric oxygen and environmental hazards, adaptation, reprogramming and completion of organ development,
formation of lymphoid organs, immune cell maturation and migration in thymus and bone marrow are required, for functionality of mitochondria
and effective immunity (Yin–Yang). As depicted, requirements for differential bioenergetics and effective immunity, cell mediated or humoral
immunity (CMI, HI), to defend body against harmful elements throughout life occur after birth. See text
production of high energy (burst of ATPase enzymes, epigenetic modifications, activation

hydrolysis) that are required by Yin events (e.g., or protection of histone proteins and chromatin,
activation of MCs, DCs, MΦs or T and B lym- recycling pathways in ribosomes, mucosal–flora
phocytes) at moment notice to combat foreign interactions in gastrointestinal tract, matura-
elements [5, 7, 39, 70–77, 82–119]. tion of immune and non-immune systems (bio-
b. Exposure of newborn to outside environment rhythms)] are not fully activated during orderly
and independent living demand establishment of fetus growth. The molecular/cellular and sub-
fully functional biological circadian rhythms or cellular adaptation and reprogramming could
the catabolic and anabolic responses in tissues. occur simultaneously after birth and at the
How the effective immunity and signal trans- interface between host and environment. The
duction between and among immune and non- fact that during the first few months after birth,
immune pathways are completed after birth are newborn limited immunity depends on mother’s
among crucial knowledge gaps that deserve sys- immunity supports the above suggestions.
tematic, insightful and integrated understand- c. After birth, the complex establishment of effec-
ing. It is likely that completion of many organs tive immunity (fully functional Yin and Yang)
(e.g., lungs, heart, brain or gastrointestinal and mitochondrial-related cellular functions are
tract) functionality and reprogramming of tis- likely to take a few months to be completed. It
sues, cellular and subcellular components [e.g., is possible that the majority of components that
mitochondria and TCA cycle, mucosal barriers contribute to catabolic pathways are genetically
(e.g., aryl hydrocarbon), transcriptional factors (innately) present as constituent elements but
for numerous receptors and surface molecules, they are not functional or not expressed until
after birth. Potential examples of such constitutive membrane potential or pH gradient (proton
ent pathways are structurally naïve immune and pumping) across the extracellular or intracellular
none immune cells, sympathetic and parasym- membranes that would skew signal transductions
pathetic neuronal systems, inactive/inhibited and auto-regulatory processes of cellular biorhythms
apoptotic factors and components of double [5, 7, 15, 20, 36–39, 45, 82, 83, 89, 140, 151, 179–185].
membrane in mitochondria. Examples of con- 7. Innocuous substances and occasional exposures to
stituent components that are likely to be func- a wide range of foreign elements are ordinarily and
tional after birth include immature or naïve lym- differentially ignored by tissues that are immune-
phocytes, oxidases, pro-inflammatory cytokines, responsive or immune-privileged (natural immune
toxins, pyruvate-shuttle, pyruvate carrier pro- tolerance). The immune-privileged tissues (e.g.,
teins, TCA cycle proteins/enzymes, metabolic CNS, BBB, avascular cornea, neuroretina, reproduc-
pathways of essential amino acids (e.g., leu, ileu, tive organs) are highly sensitive toward oxidative
val) and biosynthesis of structural proteins for damage. These tissues possess special anatomical
cell–cell contact inhibition and vasculature tight or molecular features to minimize response to oxi-
junctions, components of epigenetic modifica- dative damage [5, 7, 36–40, 89]. These tissues pre-
tions, hypo- or hypermethylated genomic mate- sent higher levels of tolerance compared with the
rials. immune-response tissues (e.g., epithelium, endothe-
lium, mucus-secreting goblet cells). However, the
4. It is noteworthy that biological development and levels of immune tolerance are limited in both types
reprogramming and responding to environmental of tissues [5, 36, 37]. Persistent tissue stimulation
conditions continue through puberty for hormonal and exposure to potent pathogens or treatment of
regulations and reproductive cycles and adulthood; patients with combination of radiation and chemo-
many of which processes decline or change during therapy that are claimed as ‘targeted’ therapy, ‘per-
aging process (senescence). sonalized’ or precision’ medicine, using potent apop-
5. Continued proton pumping and generation of elec- totic factors, monoclonal antibodies against specific
tricity across the membrane, are crucial for estab- growth factors, are deemed hazardous (biological ter-
lishing pH gradients and differential acidity among rorists) to the immunity. These conditions stimulate a
extra-, and intra-cellular membrane components and wide range of immune responses causing ‘mild’, ‘mod-
cytoplasm for numerous routine biological activities erate’ or ‘severe’ acute or delayed hypersensitivity reac-
[e.g., transport of solutes/osmolytes and nutrients, tions (immune disorders) that could lead to manifesta-
stimuli-induced expression of danger signals and tion of different diseases, organ dysfunction, multiple
activation of immune cells, degradation and growth- organ failures (MOFs) or death [5, 7, 35–39, 43, 89].
arrest of defective cells (e.g., cancerous cells), inap- 8. Oxidative stress and alterations of Yin and Yang
propriate synthesis of proteins and mutated DNAs/ properties of effective immunity often differentially
RNAs, detection and destruction of pathogen’s facilitate growth promotion (anabolism) or growth
structural components, immune cell recognition and arrest (catabolism) in different tissues. The processes
activation, proliferation, wound healing and growth, are natural/inherent properties of immunity (bio-
lysosomal activities for digestion and recycling of rhythms) to resolve inflammation. Potential adverse
proteins and lipids] as well as, numerous biosyn- influence of extensive oxidative stress in immune-
thetic pathways in mitochondria. It is likely that the responsive tissues includes epithelial–mesenchy-
extent of proton pumping provided through vascu- mal transition (EMT), changes in extra- and intra-
lar or cellular membrane by ATPases or exchang- cellular membrane matrix [e.g., MMPs, IV collagen
ers (e.g., Na+/H+ exchanger, Ca2+/ATPase) alter, to biosynthesis, cellular transport activities, aqueous
varying degrees, from the time of fetus growth, after charges (altered H bonds)] further affecting cellular
birth, during reproductive period and adulthood, in hydrophobicity or hydrophilicity, protein foldings
aging or disease processes (e.g., neurodegenerative and cellular function. Extensive oxidative stress is
and autoimmune complications or carcinogenesis). the results of exaggerated expression and co-expres-
6. Intrinsic or extrinsic components that are recog- sion of growth and apoptotic factors that result in
nized as foreign agents (e.g., pathogens, allergen, immunological chaos (immune tsunami) that could
cancerous and defective cells, useless proteins, lipids, damage the tissue integrity at multiple levels of bio-
low level carcinogens or pathogen-specific vaccines logical, mechanical, physical and bioenergetics. Seri-
and ingredients/adjuvants), as well as, aging process, ous damages in immune-responsive tissues lead to
could temporarily or permanently disturb the effec- changes in bioenergetics and metabolism and pro-
ton pumping in the direction of initiation of tissue wound healing processes. Continued activities of
growth, neoplasia, precancer-polyps, invasive cancer Yang (tumorigenic) are associated with mitochon-
growth and angiogenesis. In immune-privileged tis- drial dysfunction (mitophagy) causing damages to
sues, exaggerated expression of tumoricidal media- tissue recycling processes and ribosomal activities
tors (catabolic or apoptotic factors) causes necrosis (autophagy) that are features of skewed immune
and local immune responsiveness in tissues in the responses or immune suppression (Figs. 1, 2, 3).
direction of neurodegenerative and autoimmune dis- 12. In immune-responsive tissues, enzymes or other fac-
eases (e.g., Alzheimers, Parkinson’s, multiple sclero- tors that modulate senescence negatively regulate
sis, atherosclerosis). differentiation of tumor cells (mitosis) through epi-
9. Glucose toxicity-induced changes in immune thelial–mesenchymal-transition (EMT) often involv-
response dynamics could additionally and adversely ing polarization, unscheduled or immature synthe-
influence tissues that are insulin-dependent (e.g., sis and activation of immune cells, or expression of
muscle, liver, adipocytes) or insulin-independent factors and receptors [e.g., TGFβ-R1, peroxidasin
(e.g., vasculature, BBB, retina, cornea, kidneys) for (PXDN), collagen IV], selective membrane catalysis of
glucose transport, metabolism or growth as contrib- sulfimine or changes in H bonds with protein struc-
uting factors in the induction of tolerance and initia- tures that create “dual negative feedback loop” and
tion of chronic diseases such as diabetes and cardio- further influence tissue metabolism, fibrosis or cancer.
vascular complications, hypertension, stroke, as well 13. During EMT, polarized immune cells are capable
as increased risk of carcinogenesis [5]. of expression of a panel of growth-promoting fac-
10. Aging processes (immunosenescence) induce tors and decoy receptor molecules that are immune
minor or major alterations in immune function suppressive and signal for mitochondrial shutdown,
[e.g., changes in age-induced cell death (AICD) and inhibiting pro-inflammatory responses, leading to
damage-induced cell death (DICD)] and enhance tolerance in favor of tumorigenesis and enhanced
the vulnerability of host tissue toward loss of balance activities of cytosolic glycolysis.
between apoptosis and wound healing processes, 14. Stimuli-induced activation and polarization of
increased memory B or T cells, clonal expansion immune cells are accompanied by activation of sev-
and increased hypersensitivity of humoral or cellular eral other metabolic pathways and expression of fac-
responses toward new or old stimuli (e.g., histamine tors [e.g., carbonic anhydrase 2 (CA2), constituent or
intolerance, autoimmunity), additionally contribut- induced pyruvate kinases (PKM1, M2), phsospho-
ing to the mitochondrial and ribosomal dysfunction enol pyruvate (PEP), PEP carboxy kinase (PEPCK)]
(mitophagy, autophagy) [5, 7, 35–39, 52, 53, 59–61, with potential different bioenergetics requirements
65–68, 83, 88, 89, 109]. Longevity and continuous that could influence cellular function. For example,
exposures to microbiota or pathogen-specific vac- changes in PKM1 and PEP in red blood cells, whose
cines and adjuvants/ingredients (e.g., mercury, alu- principal energy source is from glycolysis could
minum phosphate, aluminum hydroxide, L-histidine, lead to altered hemoglobin metabolism, anemia,
embryo serum) to varying degrees, could induce hemophilia, hemolysis, cardiovascular complica-
polarization of immune cells (e.g., MΦs, MCs, DCs, tions, jaundice (bilirubin) and blood-related diseases
T or B cells) and direct expression of wound healing including cancers (e.g., hepatocellular carcinoma)
factors, decoy or pattern recognition receptors [e.g., or severity of Guillian–Barre syndrome ([5], manu-
IL-1dRs, IRAK-M), surface molecules (e.g., CD-11, script in preparation);
CD-73), low level circulating histamine (independ-
ent from antigen-specific MCs IgE-fcεR aggregation In summary, disturbance of the well orchestrated
and degranulation)] ([5, 7, 35–39], manuscript in crosstalk in effective immunity by frequent exposures
preparation). to immune disruptors and aging processes cause minor
11. As noted above, the growth promoting events often or major degrees of retardation in immune response
occur under hypoxic conditions and low energy con- dynamics that could increase the risks of initiation and
sumption from glycolysis. The conditions are char- progression of a wide range of ‘mild’, ‘moderate’ or ‘severe’
acteristics of Yang pathways during normal fetus immune disorders in susceptible tissues. Low level cir-
growth or wound healing events and neovasculari- culating histamine was proposed as a blueprint in the
zation as well as, cancer growth and angiogenesis. induction of tolerance leading to diverse immune disor-
Therefore, induction of tolerance, while a feature of ders and alterations of acid–base balance and tissue bio-
effective immunity (Yang, anabolic or growth-pro- energetics [5, 39]. Cancer was hypothesized as a ‘severe’
moting), under oxidative stress represents extended accumulation of delayed hypersensitivity responses
Induced Tolerance and Cancer Entropy

Loss of Differen"al Bioenerge"cs
Aging
Senescence
Immune-Response Tissue
Vasculature Loss of Yin & Yang [Biorhythms]
Prolifera"on EMT-Polariza"on [CMI]
Leaky Junc"on [Induced Embryonic Growth] Hypoxia-Glysolysis
PEP, PKM2,Lactate
VEGF-HIF Mito-OxPhos [ATP], ER, Recycling
[Pyr-Shu#le, TCA] Extra-, Intra-cell Ions,
Channels
Branched –Aroma"c AAs
MMPs, dRs, PRRs,
mTOR/PI3Ks
Cancer Mass Entropy Tolerance
Prolifera"on, Temp
Angiogenesis
Cell-Cell Contact
Fig. 3 Schematic representation that aging (senescence) and oxidative stress lead to immune tolerance, associated with loss of differential
bioenergetics (oxidative phosphorylation in mitochondria and Yin/tumoricidal arm of immunity), increased glycolysis, angiogenesis and hypoxia
result in increased cancer cell growth and entropy. It depicts that in immune-responsive tissue loss of biorhythms (Yin–Yang) induces activation of
embryonic (constituent) growth in epithelial cells and polarization of epithelium-mesenchymal transition. The events are accompanied by impaired
pyruvate-shuttle and biosynthesis of structural proteins from branched or aromatic amino acids, increased IRAK-M and growth pathways (Yang,
tumorigenic arm) such as mTOR/PI3Ks, VEGF, increased glycolysis to satisfy lawless growth of cancer cells, under hypoxic conditions and loss of cell–
cell contact inhibition. See text
in tissues. Oxidative stress-induced skewed biologi- of Golgi complex, delivery of vesicles, as well as active
cal circadian rhythms and dysfunction of mitochondria transport of solutes/osmolytes and nutrients (e.g., glu-
(mitophagy), peculiarly provide opportunities for cancer- cose, Ca2+, ascorbate, myo-inositol), enzymatic processes
ous cells to utilize enhanced activities of cytosolic glyco- (e.g., oxidases, kinases, lipases, hydrolases), protein bio-
lysis pathways for consumption of energy from Crabtree synthesis and other physiological pathways, and physical,
or Pasteur Effects (induction of ’dark energy’), conditions mechanical or locomotion and architectural integrity of
that are toxic to normal cell survival, but facilitate can- cells/tissues/organs (Figs. 2, 3) [5, 7, 35–39, 78, 82, 83, 89,
cer cells lawless proliferation and increased entropy (see 101, 139, 140, 142–150, 178–220].
below). Mitochondrial dysfunction (mitophagy) has been
linked to a number of age-associated and chronic health
Differential mitochondrial bioenergetics problems, including migraine, cardiovascular and neuro-
requirements in Yin–Yang of immunity: oxidative degenerative diseases, sarcopenia, infertility, kidney and
stress-induced chronic diseases and cancer liver diseases, cancer, drug toxicities and other illnesses
The principal free energy source that is required for all that often accompany fatigue syndrome [5, 7, 35–39,
body’s biochemical pathways is the universally known 91, 142–150, 178–190]. Observations on the association
molecule of ATP. In general, the normal function of between defects in energy metabolism of cancer cells
organ system uses ATP as both an intracellular energy and effective respiration (oxidative phosphorylation) and
source and an extracellular messenger for energy requir- the abnormal rates of aerobic glycolysis for ATP synthe-
ing transmission of signals in CNS or optic nerve or other sis that was originally reported by Otto Warburg, led to
immune and non-immune cells for exocytosis, formation mitochondrial injury/damage and concept of mitophagy
[5, 40, 53–55, 91, 184–190]. It is now well documented These and related metabolic pathways, if studied sys-
that cancer cells are capable of converting glucose into tematically, should provide unique opportunities and
lactate and pyruvate. Synthesis and diffusion of lactate challenges to efficiently target and control the growth
create acidic conditions in the extracellular matrix (e.g., of cancer cells.
MMPs) and change the integrity of membranes (e.g., b. Pasteur Effect As originally described by Otto War-
IV collagen biosynthesis or receptor molecules) as con- gurg, the tumor cells are able of inducing glucose
tributing factors that alter tissue metabolism and bio- utilization and conversion to lactate in the presence
energetics during growth of cancer mass, invasion and of oxygen, a phenomenon called Pasteur Effect that
metastasis. These and other important observations on diminishes glycolytic metabolism in yeast [5, 39, 55,
the metabolism of cancer cells and the role that mito- 92, 189]. The utilization of glucose oxidation and
chondrial dysfunction play in cancer growth evolved in conversion to lactate perhaps play important roles
two hypotheses of survivability and adaption of cancer in metastasis (diffusion to extracellular matrix and
cells as ‘Crabtree Effect’ and ‘Pasteur Effect’, the glucose acidity) and enhanced proliferation. The above obser-
triggering mechanisms for cancer proliferation as out- vations and concepts argue that cancer cells have
lined below [5, 39, 185–190]. higher rates of consumption for either or both oxy-
gen or glucose. That means when concentration of
a. Crabtree Effect Tumor cells and normal proliferating either nutrient is reduced in the microenvironment
cells or pathogens (e.g., bacteria or yeast) have limited of cancerous tissue, cancer cells can thrive, while
respiration in the presence of high glucose concentra- normal cells cannot. Factors that are toxic to normal
tion. The phenomenon is known as Crabtree Effect. cell survival but facilitate metabolic adaptability of
Under such conditions, cancer cells are able to trig- cancer cells to microenvironment include the follow-
ger the competitive inhibition of oxidative phospho- ings [5, 47, 48, 53–55, 90, 189]:
rylation (respiration) for using phosphate groups (Pi, i. Increased mutations or damage in mitochondrial
inorganic phosphate) and ADP, through glycolysis for DNA and altered pyruvate-shuttle or pyruvate car-
their enhanced growth requirements, conditions that rier proteins.
are toxic to normal cells. An excellent publication by ii. Elevation of hexokinase (1,6 phosphofructo kinase)
Hammad et al. [189] explains the Crabtree and War- activities.
burg Effects and the roles that glucose and rate-limit- iii. Lysis or loss of mitochondrial cristae structures and
ing steps in constituent kinases (e.g., pyruvate kinases, altered mitochondrial protein and lipid content.
phosphofructokinase) play in regulation and uptake of iv. Increased acidity (lower pH) in extra-, or intracel-
substrates within and outside mitochondria for control lular environments (presence of lactate) and altered
of ATP production and mitochondrial intermediates. hydrophilic or hydrophobic properties of channels
While detailed mechanisms of the effects are debatable, for transport of cationic or anionic molecules and
it seems that the abundant presence of glucose, perhaps proteins and aquaporins.
including hyperglycemia of diabetes, impair mitochon- v. Potential utilization of mitochondrial cardiolipin as
drial normal function at several levels (e.g., inhibition additional sources of energy.
of energy requiring steps in pyruvate-shuttle and sub- vi. Loss of cell–cell contact inhibition.
sequent events in carrier proteins and enzymes that are vii.Induction of local entropy and higher temperature in
needed for biosynthesis of TCA cycle intermediates) cancer masses compared with surrounding tissue.
and energy production. The availability and activation
of other factors (e.g., adenosine, histamine) or changes Detailed analyses of related data suggest that cancer
in acid–base homeostasis during production of lactate oncogenes mutations and growth dysregulation, along
and dissipation of energy could be interdependent con- with associated enhanced expression of PI3K/Akt and
tributing factors in slow-down of mitochondrial func- altered balance in c-MYC, HIF or p53 pathways, adversely
tion. While enhanced glycolysis and glucose uptake influence transport and metabolism of glucose, amino
by cancer cells favor promotion of lawless growth of acids, ions or water channels (aquaporins) of the sur-
cancer masses, the conditions could create differential rounding normal tissues that impair extra- and intracel-
entropy that adversely affect the surrounding tissues lular components (e.g., mitochondria, ER, nucleus). For
(see below) [5, 7, 38, 39, 184–189]. It is suggested that example, loss or leak of cardiolipin, a key mitochondrial
Crabtree Effects initially share some features of Yang lipid, located in the inner membrane of mitochondria has
arm of immunity during normal wound healing or dur- been demonstrated in damaged mitochondria in cancer
ing orderly growth of fetus that occur under hypoxic environment [5–8, 39, 53–55, 60, 81–84, 102, 143, 144,
conditions; when mitochondria are not fully functional. 152, 166, 174, 178–191]. Cardiolipin is among several
other necessary components that are needed for efficient activation of lysosomal exocytosis and Ca2+ flux from the
cellular respiration and maintenance of chemiosmosis stored-operated Ca2+ channels as part of effector function
(aquaporin channel). While details of the role of mito- of MCs. Use of antihistamine or anti-allergic agents (e.g.,
chondria and inflammation in diseases of aging are not oxatomide, astemizole, olopatadine) in the in vitro models
well understood, it is likely that acute inflammation ini- of allergies or basophilic leukemia cells (RBL-2H3) seem
tially causes a burst of energy (ATP hydrolysis) in mito- to suppress one or a combination of interdependent MCs
chondria of activated immune cells to generate sufficient responses such as inhibition of AA pathways, cytokines
energy for induction of oxidants and toxins during apop- (e.g., IL-4) or Ca2+ influx through receptor-operated
tosis (Yin). In the process, cardiolipin molecules oscillate/ channels (ROC), phosphorylation of P38 mitogen-acti-
move from the inner to outer mitochondrial membrane vated protein kinase (MAPK) and c-Jun NH2-terminal
and signal to facilitate termination of inflammation during kinase, pathways that are involved in IL-4 gene expression
wound healing (Yang) events and to preserve regeneration and tumorigenesis (anabolic pathways?).
and function of mitochondrial TCA cycle intermediates. Inflammatory conditions such as potent pathogen-
induced severe immune reactions (e.g., sepsis, meningi-
Exocytosis, Ca2+ fluxes and recycling activities tis, pneumonia, anaphylaxis), major trauma as well as, the
in lysosomes: anabolic and catabolic energy claimed cancer ‘targeted’ drugs, ‘personalized’ or ‘preci-
requiring events sion’ medicine (in combination with partial or total body
Induction and completion of acute of acute inflamma- radiation) that are potent apoptotic factors or monoclonal
tory responses always require participation of lysosomes antibodies induce a vicious cycle of immune cell activation
and proper recycling of proteins and lipids of phagocyt- (immune tsunami or cytokine storm) [5–8, 39, 43]. Potent
ised materials, expression of lysosomal hydrolases and immune disruptors require high energy demands not only
proteases during autophagy. Among numerous biological from local tissue mitochondria, but they also cause induc-
alterations that occur under oxidative stress and aging, tion of systemic or intraperitoneal exaggerated expression
the body’s ‘self-eating’ processes of lysosomes and asso- of pro-inflammatory cytokines and toxins such as ROS,
ciated impaired activities in mitochondria or Golgi play caspases, oxidases, damage-associated molecular pat-
crucial roles in homeostasis of immunity or immunose- tern (DAMP), increased C-reactive protein (CRP), altered
nescence, chronic diseases or cancer [5, 39, 88, 89, 126, muscle F-actin filaments and high-mobility group box 1
184, 220]. For example, the early events in stimuli-induced (HMGB1). Drug-induced accumulation of inflammatory
activation of MCs via receptor (FcεR) aggregation and responses often cause serious damages to the function and
degranulation (pharmacological effects) require mem- integrity of tissues and multiple organ failures (MOFs) in
brane fusion for exocytosis of granules. The processes muscle, liver, kidney, lung, brain and heart and patient’s
involve secretory lysosomal activities and expression of death. Therefore, stimuli-induced frequent expression and
several protein receptor molecules, at different stages of co-expression of growth-arresting (Yin, tumoricidal) and
membrane fusion and require ATP hydrolysis and mobi- growth promoting (Yang, tumorigenic) cytokines such as
lization of Ca2+ from intracellular stores. Lysosomal exo- TNF-α, ROS, interleukins (e.g., IL-4, IL-6, IL-8, IL-10, IL-
cytic activities are triggered following an increase in free 12,IL-18), monocyte chemoattractant protein 1 (MCP-1),
Ca2+ (cation) concentration, acidified by H+/ATPase CXCR3, neutrophil extracellular traps (NETs), abnormal
hydrolysis for fusion and flux at the plasma membrane expression of vasculature components (e.g., P- and E-selec-
level [5, 39, 88, 89, 184, 220]. The complex pathways tins, ICAM-1, VCAM-1) damage mitochondrial oxidative
during degradation, clearance and recycling of proteins metabolism and DNA [5–8, 35–43, 169–175, 178–194].
require energy-dependent biosynthesis of a number of
acidic hydrolases or proteases and surface molecule, Definitions of constituent (Innate) and induced
signaling within lysosomes, endoplasmic reticulum (ER), (‘Designer’) pattern recognition receptors (PRRs)
Golgi apparatus and mitochondria [5, 38, 39, 88, 89, 92, in health and diseases
143, 144, 150, 152, 169, 171, 180–184, 192]. These inter- Pattern recognition receptors (PRRs) and surface mole-
dependent catabolic and anabolic activities are universal cules play crucial roles in signal transduction mechanisms
in living cells and influenced by aging and disease pro- and contribute to all aspects of cells/tissues functions such
cesses. Data using inhibitors of MCs degranulation, anti- as visual transduction, bone and lipid biosynthesis, bioen-
histamine agents, oxidative phosphorylation or glycolytic ergetics, cellular trafficking and infiltration, differentiation
pathways (e.g., glucose or pyruvate oxidation), under a and growth, nuclear/chromosomal or chromatin activities,
wide range of immune dysfunction or carcinogenesis sug- neuronal pathways, tissue necrosis or growth in immune
gest that MCs activation and release of histamine and and non-immune systems for maintenance of health or
other preformed or newly synthesized mediators, require induction of diseases [5–8, 35–39, 191–202]. Discussion
on the time course kinetics and mechanisms of actions of adaptation to gene-environment interactions and inter-
receptor molecules presents a complex molecular universe dependent shifts or synergies with induced receptor mol-
with unique or shared features that is beyond the scope ecules for maintenance of health or induction of diseases.
of this perspective. Suffice to note that defining only the
roles that insulin receptors play in health or induction of Induced, ‘Designer’ or pattern recognition receptors (PRRs)
major diseases such as diabetes and cardiovascular com- and surface molecules
plications or carcinogenesis is a huge topic and yet to be ‘Designer’ or induced receptors often present transient
fully understood [5–8, 39, 89, 202–207]. Analyses of a functions when tissue is exposed to specific stimuli (e.g.,
wide range of receptors or pattern recognition molecules allergen, pathogens, certain foods, carcinogens, bio-
(‘biological signatures’) that were defined as constituent or logical, chemical or environmental hazards) [5, 39].
designer receptor molecules [5] are outlined below to bet- Stimuli-induced specific toll-like receptor molecules
ter appreciate the crucial roles that these molecules play (TLRs-1-9) that signal for expression of specific cytokine
in maintenance of health or induction of tolerance in car- and chemokine receptors or antibody bindings (e.g., IgE-
cinogenesis: [5, 39, 126, 174, 202–208, 212–215]. fcεR, IgGγRs, IgARs) and related surface molecules are
examples of ‘designer’ or induced receptor or surface mol-
Constituent: innate and adoptive receptors and surface ecules during sensitization or activation of immune cells.
molecules Receptors with short half-lives may fit the profile of either
Constituent receptors and surface molecules are essential or both constituents and induced. These receptors include
(innate) members of the embryonic growth and devel- a wide range of molecules for ion channels, including acti-
opment. They are also synthesized and/or regenerated vation-induced enhanced Ca2+ permeability, expression
after birth for routine maintenance of enormous biologi- of receptor potential channels such as transient receptor
cal activities and molecular schedules of organs/tissues potential cation channel, subfamily 4 (TRPM4), TRPC 5,
functions throughout life. Constituent receptor molecules in combination with STIM1 and CRACM1 that contrib-
are involved in extracellular and intracellular signaling, ute to FcεRI-induced Ca2+ influx during MCs degranula-
actions of hormones, metabolites, cytoplasm or nuclear tion [5, 39, 99, 101, 151, 157, 158, 171, 182].
and genomic transporters/enzymes, mitochondrial mem-
brane trafficking, carrier proteins, neuronal transporters, Pattern recognition receptors (PRRs) and induction
or related surface molecules that routinely contribute of immune tolerance in multistep carcinogenesis
to the physiology of immune or non-immune systems. Initiation of immune responses in antigen presenting
Examples of such constituent pattern recognition recep- cells (APCs) toward microbials/pathogens or defective
tors are the various insulin receptors for glucose transport cancerous cells (foreign elements) is mediated through
or metabolism in insulin-dependent (e.g., muscle, adipo- a number of pathogen recognition molecules or recep-
cytes or liver) or insulin-independent tissues (e.g., vas- tors including specialized toll-like receptors-TLRs (e.g.,
culature, brain, neuronal tissues, retina, kidneys). These TLR1-9). Stimuli-induced expression of TLRs contributes
receptors are required during fetus growth and organ to the differential recognition of molecular structures or
development and for maintenance of health throughout sub-structures of pathogens for specific sensitization and
life [5, 7, 39, 125, 126, 130, 151, 157, 158, 171, 202–207]. activation of APCs and appropriate response. The impor-
After birth, each of the genetically-determined recep- tant roles that TLRs, decoy (dRs) or pattern recognition
tor molecules are strongly influenced by the signals they receptor molecules (PRRs) play in defense of body for
receive from the environment and become adaptable or activation of innate or adaptive immune or non-immune
programmable to the quality of nutrition (initiated from pathways for generation of death factors, pro-, and anti-
mother’s milk or consumed baby formula) and exposures inflammatory responses for human development or
to a variety of bioactive agents, microorganisms, environ- initiation or termination of acute or chronic inflamma-
mental chemical and biological hazards. Modifications of tory processes, immune tolerance and cancer have been
constituent receptor molecules that occur after birth seem extensively studied [5, 7, 39, 67, 72, 79, 157–162, 191,
to parallel the development of mitochondria and Yin–Yang 194–207, 210–217].
of effective immunity as infant becomes independent Decoy receptor molecules are agonist-binding proteins
from the protective environment of placenta and requires that sequester inflammatory cytokines and signaling
adaptation and reprogramming to the atmospheric oxy- receptor components during termination of acute inflam-
gen (see above). Major changes in constituent receptors mation (Yang). Structurally, decoy receptors are incapable
occur in the gastrointestinal and upper respiratory tracks, of participating in signaling receptor complexes. Decoy
skin or perhaps ocular tissues. Therefore, constituent/ receptors act as promoters or inhibitors of proliferation
innate receptor molecules are capable of maturation or of immune and non-immune cells and contribute to host
immune homeostasis or induction of ‘tolerance’ or ‘intol- major histocompatibility complexes (MHC I and II) and
erance’ in ‘mild’, ‘moderate’ or ‘severe’ immune disorders co-stimulatory surface molecules. The actions are fol-
or multistep carcinogenesis [5, 39]. The cytokine receptor lowed by expression of other pro-inflammatory cytokines
dual function (decoy behavior) was originally defined for and chemokines for destruction of microbial (Yin, catab-
IL-1 (IL-1dR) and IL-2 (IL-2dR) receptors. Briefly, decoy olism). The actions require high energy production from
or specialized receptors and related surface molecules are OxPhos in mitochondria. Stimuli-induced expression of
involved in a wide range of biological activities such as TLRs is associated with induction of IL-1R that form a
binding to immunoglobulins/antibodies (e.g., MCs-IgE- group of superfamily regulatory proteins with shared
FcεR; MΦRs, IgM Rs or IgGRs, mucus-secreting IgARs), and special features for signaling to intracellular domains
histamine (HRs) or surface molecules (e.g., CD 11, CD22, to induce expression of other cytokines at extra-, and
CD40,CD80, CD83, CD86), CD86, CAIX, integrin, TNF- intra-cellular levels and for recruiting adaptor molecule
Rs, IL-1Rs, indolamine 2,3 dioxygenase, CAMs, ECM). response such as myeloid differentiation (MY 88 gene)
Other receptor molecules that are able to sequester and formation of receptor-adaptor complex domains for
ligands and participate in termination of inflammation or proper immune responses [5, 35–39, 83, 201, 212–215].
proliferation of immune or non-immune cells or cancer Review of data on bacterial or viral infections on mod-
growth and angiogenesis include receptor molecules for els of liver injury or influenza infection-induced lung
MCSF, iNO, PGE2 and/or low level histamine [5, 7, 39]. tissue damage and lysis of epithelial cells shows exagger-
Some decoy receptors such as IL-1dRs have been iden- ated immune cell activation and increased expression
tified for regulation of other cytokines such as IL-8, a of interleukin (IL) receptor-associated kinase M (IRAK-
member of the IL-1 family, and TNFR superfamily (e.g., M) to protect tissue damage [5, 35–39, 190–201]. These
osteoprotegerin) [5, 39, 79, 191–196, 209–217]. and related data suggest the limited immunopathology
An extensively studied cytokine and decoy receptor protection of IRAK-M in tissue without influencing or
function that is involved in inflammation and multistep decreasing the viral clearance. Therefore, it seems that
carcinogenesis is tumor necrosis factor-alpha (TNF-α), a expression of IRAK-M protects, to some degrees, damag-
cysteine-rich cytokine and its receptor molecules (TNFR- ing the lung, or perhaps other epithelial tissues, and pre-
1, TNF-Rp55, TNF-Rp75). The TNFRs act as transponders venting complications of asthma. Expression of IRAK-M
of TNF by receiving and transmitting signals and are able also limits neutrophil-induced damage to tissue while
to trigger several biologically different functions during Yin improve tissue remodeling. Data on TLR7-induced MΦs
and Yang of acute inflammation (circadian biorhythms) for activation (Yin, M1 phenotype?) and tolerance (Yang,
maintenance of tissue homeostasis and elimination of host M2, TAM phenotype?) seem to accompany an elevated
cells with damaged DNA. A wide range of immune dis- expression of IRAK-M, decreased expression of TNF-α,
ruptors, extrinsic/exogenous or intrinsic/endogenous are followed by expression of NF-κB, p38 and stress-acti-
able to induce synthesis and production of TNF-α and its vated protein kinase (SAPK) within the protein family of
receptor molecules in a variety of cell types [e.g., MΦs, T mitogen-activated protein kinases (MAPKs).
cells (Th1, Th2), DCs, MCs or keratinocytes]. TNFRs also Induction of tolerance involves increased expression of
have proliferative capabilities for growth of fibroblasts or IRAK-M and sulfhydryl domain-(SH2) containing protein-
thymocytes and induction of expression of mitochondrial tyrosine phosphatase (SHP-1) activities and 2 subgroup
or cytoplasmic superoxide dismutases (SODs) to termi- of MAPKs, c-Jun-NH(2) N-terminal kinase (JNK) and
nate acute inflammation (Yang) during wound healing [5, p38 MAPK pathways that signal for immune suppression.
39, 126, 191, 194, 196, 209–211]. Depending on the extent of oxidative stress these events
Toll-like receptors (e.g., TLR1 and TLR2) are known to that signal for wound healing are potentially involved in
recognize and bind to ligands of specific molecular pat- temporary or permanent dysfunction of mitochondria
terns of microbioms such as the tri-acyl lipopeptides, to avoid oxidative damage to tissues [5, 39, 190–200].
lipoarabinomannan or bacterial wall peptidoglycan Involvement of SH-containing proteins in IRAK-M activ-
(PGN) and lipoteichoic acid (LTA), and phospholipo- ity, acting as anti-oxidants and scavengers of free radi-
mannan of the bacteria (e.g., mycobacterium tuberculo- cals (oxidants), supports mechanisms of termination of
sis, Staphylococcus aureus). For example, LPS-induced inflammation (Yang events) that we described for acute
expression of TLRs leads to activation of immature DCs inflammation [5, 36–40]. Lagler et al. [198] demonstrated
and differentiation and migration of appropriate phe- that activation of TREM-1 during the early Streptococcus
notypes from peripheral tissues to lymphoid organs to pneumonia infection resulted in a decreased expression of
activate naïve T cells (T0) and upregulate expression of lung IRAK-M and elevated pro-inflammatory cytokines,
suggesting that low expression of IRAK-M is mediated numerous other neurological and autoimmune diseases
by TREM-1 to promote efficient early bacterial clearance. sharply increased [5, 7, 16, 39, 79, 89, 175, 176, 219, 222–
Therefore, ‘tolerization’ and the associated expression of 224]. In 2013 (six decades after initial consumption of con-
IRAK-M may act to prevent liver cell death. LPS-induced taminate vaccines), the American Association for Cancer
expression of TNF-α was associated with a lack of IRAK- Research (AACR) announced that 1/3 (33%) of all women
M induction in liver cirrhotic lymphocytes [196]. and 1/2 (50%) of all men develop cancer in their life time;
Similar reports demonstrate that the mannose recep- that is up to 10 folds increase in the deadly incidence of
tors and C-type lectin-induced DCs’ specific intercellular cancer in the last six decades! [5, 7, 16, 20]. In 1955, deci-
adhesion molecule-3-grabbing non-integrin (DC-SIGN) sion makers in medical/cancer established ignored the
binds to Mycobacterium tuberculosis cell wall com- existing data that viruses cause cancer. They also down-
ponents called mannose-capped lipoarabinomannans played the serious safety concerns and warnings of a com-
(Man-LAMs) [213]. Furthermore, Man-LAMs inhibit petent and devoted professional at NIH (Bernice Eddy,
LPS-induced IL-12 p40 production, NF-κB activation MD, microbiologist) who discovered that Sabin polio vac-
and IRAK-1-TRAF6 interactions. cines (prepared in monkeys’ kidneys) were contaminated
The action is accompanied by increased IRAK-M with live viruses [e.g., simian virus (SV-40) and other filter-
expression [5, 79, 213]. able viruses]. This American tragedy significantly damaged
The author suggested that the molecular complexes the health of the last 3 generations in America and to lesser
associated with immune suppression for induction of extent, health of other developed nations who consumed
tolerance via IRAK-M, if not the same as decoy recep- the contaminated vaccines [5, 7, 11, 13, 14, 16]. Since the
tors (e.g., ILdR) that are expressed during polarization of 1955s, the immunity of old and young have been further
immune cells (Yang pathways), they operate on similar or weakened by heavy publicity to inoculate the individuals
complementary regulatory processes and follow similar with other pathogen-specific vaccines and their unhealthy
biological principals for maintenance of health or initia- ingredients and adjuvants (e.g., Swine flu, HPV, hepatitis B
tion of diseases [5]. or C, measles, meningitis, EBOLA, herpes) or even BCG,
whether or not the vaccines are contaminated with live
Cancer; an induced disease of twentieth pathogens. The younger generations who are also exposed
century facilitated by decision makers! Role to a wide range of biological and environmental hazards or
of virus-contaminated polio vaccines and sharp low level carcinogens suffer from a wide range of immuno-
increased in cancer incidence and mortality logical disorders (e.g., allergies, asthma, neurological and
and other diseases. Creation of a sick autoimmune diseases), conditions that are features of age-
drug-dependent society for corporate profit associated chronic illnesses [5, 7, 11, 12, 15–25, 74, 78, 89,
In this section, it is important to first remember that the 155, 202, 223–225, 246].6, 7, 8, 9 While the decision makers
role of pathogens (viruses, parasites and bacteria) in the insist that cigarette smoking is the major factor in the
induction of acute or chronic inflammatory and infectious increased risk of cancers, several studies suggest that not
diseases or cancer has been documented for over a century all smokers, even heavy smokers develop lung cancers.
[2, 5, 7, 10, 20–24, 39, 40, 56, 122, 123, 128, 155, 169, 216]. Reports on none-smokers or never smokers who develop
Secondly, while in the last century advances in develop- lung cancer suggest that such data overlook other more
ment of antibiotics, better hygiene and modern technolo- important contributing factors, particularly infective
gies improved longevity, the aging populations in America agents or pathogen-specific vaccines in the development
(current baby boomers) and the younger generations are of asthma, tuberculosis, lung and other site-specific
not healthier compared with the previous generations at
the same age [5, 7, 16, 20, 39, 175, 176, 219, 222–224]. In
1900s, the estimated risk of cancer was one in every 20
6
individuals (5%). The rate coincided with the normal low Tom Valentine: Polio vaccine spreads cancer. Dark Politricks. Part II,
SHOAH, June 21, 2011.
risk of cancer as a hereditary disease in the general popula- 7
Brian Shilhavy. The Truth About Vaccines: DocuSeries with 60 Top Health
tion. Furthermore, in 1940s (four decades later), before Experts Reveal What is Censored in Mainstream Media, Jan 13, 2018; U.S.
vaccinating the American public with virus-contaminated Government continues to pay out millions to victims injured by the flu shot.
polio vaccines, 1/16 individuals (approximately 6%) devel- Reflects report from Department of Justice (DOJ) on cases settled for vaccine
injuries and death mandated by National Vaccine Injury Compensation Pro-
oped cancer (1% increase in cancer incidence over 4 dec- gram (NVICP), March 8, 2018.
ades), according to available statistics. However, since 8
Daily Mail-UK Media Publication.”HPV vaccine destroying the lives of
1955s/1960s after public (current baby boomers) con- ‘Thousands’ of girls”, Accessed from Health Impact News, Sept. 28, 2017.
sumed virus-contaminated polio vaccines (injection or 9
Gordon Duff. Is American medicine a war crime? Veterans Today, July 3,
2012. http://www.veteranstoday.com/2012/07/03/is-american-medicine-a-
‘sugar pills’), the cancer incidence and mortality and war-crime/.
cancers [5, 7].10 American health status ranks last among organizations [5, 7, 16, 39, 43, 79, 227–235, 237].13, 14. 15,
16
other healthy nations, despite the fact that USA invests the Decision makers in cancer/medical community con-
highest amount of resources for healthcare [7, 16, 20, 219, tinue to fraudulently use wrong approaches (‘molecular
222]. false flags’, based on false foundations) in cancer research
In the last six decades significant increased in soft and clinical trials. Endless genetic mutations have been
tissue B cell-derived lymphomas (e.g., aggressive or identified in the molecular tsunami of site specific can-
non-aggressive forms of acute leukemia, lymphocytic cers for drug development that at best postpone death-
leukemia, Burkett’s’ lymphoma, myelocytic leukemia, sentence of patients for short durations [5, 7, 20, 45]. In
EBV-positive large B cell lymphoma in elderly, germinal such projects little regards are given to consider the seri-
center lymphoma or Kaposi sarcoma-associated herpes ous compensatory immune mechanisms when such
virus-encoded proteins in lymphoma) as well as solid drugs (poisons) cause cancer relapse, cachexia, thrombo-
tumors (e.g., liver, lung, breast, prostate, thyroid, pan- embolisms, metastasis and multiple organ failures that
creas, colon, ovarian) have been reported [5, 7, 13, 16, 20, kill patients (Fig. 4) [5–7, 16, 38, 39, 43].
67, 72, 89, 101, 175, 223]. A great deal of taxpayers funding are directed on detailed
In describing cancer, every few years, cancer decision mechanisms of structures and substructures or potencies
makers come up with some number and story and state of tens of thousands of evolving microorganisms (viruses,
that cancer is ‘too complex’; cancer is too many diseases bacteria, parasites) or chemical and biological carcinogens
(100 or 200 diseases). Recently, cancer was claimed to be and environmentally hazardous agents, as well as end-
1000 diseases to legitimize spending funding on data less mutated genes of growth factors or enzymes in the
sharing and aggregates!11 It seems that finding too many molecular tsunami of cancer environment. However, little/
pieces of broken molecules in the cancer immune tsu- no efforts have been invested to understand what initiates
nami make decision makers to claim that cancer is 1000 pathogen-induced alterations of immune response dynam-
diseases! What and how data sharing would help solving ics that lead to immune tolerance, loss of mitochondrial
cancer problems is another puzzule! All data that are bioenergetics (biological rhythms) and multistep carcino-
worthy (or not worthy) are published in various formats. genesis [5–8, 16, 39, 43, 79].
Computational biology and data aggregation have their Unlike the stories that are made up by decision mak-
limits to make sense of biological activities to solve can- ers in cancer community that cancer is 100 or 1000 dis-
cer problem or think about the solution. This is just eases which drag solving cancer problem, our accidental
another game to further postpone solving the mystery of discoveries on experimental models of acute and chronic
cancer that the cancer establishment created six decades inflammatory responses demonstrated systematic devel-
ago for maintaining control of a sick and drug-dependent opmental phases of immune dysfunction that resulted in
society. Cancer has been made as a myth (100 or 1000 tumorigenesis and angiogenesis. Analyses of related data
diseases) and money machine that cannot be solved. This and extension of these fundamental studies demonstrate
reminds us of Phillip Zelikow “The creation and mainte- that cancer is only ONE disease. Cancer is induced as the
nance of public myths exert a powerful influence” [7].12 results of loss of balance in tumoricidal (Yin) vs tumori-
The clinical features, morphologies and pathogenicities genic (Yang) properties of effective immunity (immune
of site-specific cancers and how to treat them, are the tolerance) or loss of differential bioenergetics to destroy
topics of numerous highly expensive clinical trials and cancerous cells (Fig. 4) [5–7, 20, 39, 43].
basic science investigations, using modern specific tech- Although recent attempts in immunotherapy seem
nologies and models of tumors [5, 7, 16, 20, 39, 76, 79, 80, more logical, the same reductionist views to target one
81, 90, 92–100, 115, 116, 119–134, 182, 226–243]. How- or two pathways [e.g., promote dendritic cells program
ever, the rates of failure in claimed ‘targeted’ drugs, ‘pre-
cision’ or ‘personalized’ medicine for solid tumors are
13
90% (± 5) according to governmental or private In February 2012, National Cancer Institute (NCI) Board meeting
(NCAB) report on cancer therapy, it was admitted that success rate being
15%; in March 2012, during Metabolon conference in Bethesda, Maryland,
10
Holtzman A: Dr. Leon Dmochowski and Dr. R. Lee Clark—Truth company professionals reported that 95% of cancer drugs that are developed
Tobacco Industry Documents.5-page Letter, to Paul D. Smith, VP and Gen- fail [7].
14
eral Counsel, Philip Morris Inc., January 06, 1965. https://industrydocumen June 1, 2012, E Berger (CNBC program) in an interview with then presi-
ts.library.ucsf.edu/tobacco/docs/[ID], Ness Motley Law Firm. https://indus dent of MD Anderson, DePinho confirmed that 95% of cancer drugs for
trydocuments.library.ucsf.edu/tobacco/docs/qymd0040—Bates Number: solid tumors fail—http://blog.chron.com/sciguy/2012/06/m-d-anderson-
10051001761005100180 [7]. president-goes-on-cnbc-extols-his-own-company.
11 15
The Cancer letter, “His six-month ‘listening tour’ almost over, Sharpless Brill S. (2013) Special Report, Bitter pill: Why medical bills are killing us.
discusses his vision for NCI”, February 23, 2018. Time (USA edition) March 4, 2013, 16-55.
12 16
Phillip Zelikow was one of the architects behind creation of war against Beil L. (2012) How much would you pay for 3 more months of life?
powerless nations. Newsweek, 9/3/2012. Vol. 160, Issue 10, 40-44.
Dynamics of Immunity in Aging and Carcinogenesis

Endless Muta!ons in Cancer Landscape for ‘Tergeted’ Therapy
Immune Disruptor Mul!step Carcinogenesis 1 2 , 3… Pre-neoplasia
Aging Polyps
Hyperplasia
Acute Inflamma!on Gene altera!ons
Telomere Shortening Cancer
‘Yin’ Yang’
Defec!ve Proteins Angiogenesis
Unresolved • Defec!ve Cell Muta!ons: (10, 2 0, 50, 100, 500s...)

Inflamma!on Func!on
Cancer Killing • Growth
1 (?) Ability Promote vs. Drugs 1, 2 ,3….
• Growth Arrest • ‘Targeted’
(Immune
Dysfunc!on) • Mitophagy Therapies
• Autophagy • Life-threatening
Cancer Killing • HA-Acid-Base Side Effects
(Immune Surveillance) • Bioenerge!cs • (Mul!ple Organ
Repair Mechanisms Failure)
Possible Correc!on/Preven!on Increased Risk—Loss of Yin-Yang Balance

Fig. 4 Schematic representation of complex dynamics of immunity in aging and carcinogenesis. It depicts that effective immunity or balance in Yin
and Yang of acute inflammation has the ability to kill cancerous cells; that initial stages of immune dysfunction could be corrected/reversed or pre-
vented. It depicts that unresolved inflammation and aging skew proper immune responses (immune dysfunction), associated with altered genomic
stability, expression and co-expression of pro-, and anti-inflammatory factors (unresolved inflammation), alterations in mitochondrial and ribosomal
functions and loss of acid–base balance in tissues that would increase risk of carcinogenesis. The complex scheme also depicts that development of
cancer drugs that are based on identification of numerous mutated/defective genes or growth expression products, at late stages of cancer (within
cancer molecular tsunami) are claimed as cancer ‘targeted’ therapy, ‘precision’ or ‘personalized’ medicine. Drug-induced life-threatening side effects
that cause multiple organ failures (MOFs) and patients’ death are also depicted. See text
death ligand 1 (PDL-1) or T cell receptors] failed patients Decoy receptors-IRAK-M and cancer immune
[5, 7, 20, 39, 43]. These expensive projects are not prop- tolerance: loss of biorhythms in increased entropy
erly designed, validated or evaluated by competent and and ‘Dark Energy’—toxicity to normal tissue
independent scientists. Recent data on computational biology or histobiologi-
Policy makers who appropriate funding for cancer cal experiments by West and colleagues [78] or Pitt [208]
research and therapy have no clue on how to assess wor- provide insightful information that cancer entropy and
thiness of the tremendously expensive projects that are higher temperature are the results of perturbations in
highly promoted by members of the cancer establish- mitosis, cell plasticity and aneuploidity in site-specific
ment. Such projects are considered ‘molecular false flags’, tissues. As detailed above, dysfunction of mitochon-
based on false foundations that destroy the precious lives drial bioenergetics parallels loss of effectiveness in Yin
of patients and drain resources to create huge corporate (tumoricidal) and Yang (tumorigenic) properties of acute
profits for the establishment (Fig. 4) [5, 7, 16, 20, 39, 40, inflammation leading to polarization of immune and non-
79, 95, 96, 175, 176, 226–235, 237–241]. immune systems in favor of growth promotion pathways.
Milton Friedman best described the situation “If the The increased utilization of glucose by Crabtree and/
government is put in charge of Sub Sahara, in 5 years or Pasteur Effects promotes disorderly growth of cancer
there will be a shortage of sands”.17 masses, conditions that are toxic to normal cell survival
[5, 55, 79, 92, 139, 185, 188, 189]. Abnormal cell division/
17
Milton Friedman, Nobel Laureate in Economic Sciences (1976), for his proliferation (mitosis), aneuploidity and increased phe-
achievements in the field of consumption analyses, monetary history and
theory and demonstration of the complexity of stabilization policy. Source: notype plasticity in cancer are associated with genomic
The Nobel Foundation. instability, increased entropy and temperature, compared
with surrounding tissue [5, 39, 78, 79, 208]. It is suggested Role of mTOR/PI3K, decoy receptors and IRAK-M
that disturbance in the synchronized biological circadian in induction of tolerance in carcinogenesis
rhythms of tissues could increase entropy (chaos) and The mammalian or mechanistic target of rapamycin
temperature and create ‘dark energy’ for enhanced growth (mTOR) is a serine/threonine kinase (also known as
of cancer masses. Induction of ‘dark energy’ and entropy DRAK2) and member of the phosphoinositide 3-kinase
in cancer masses could draw energy from surrounding (PI3K)-family of kinases (PIKK). The super-family of
normal cells (starvation), a potentially important factor mTOR/PIKK pathways is directly and indirectly involved
in patients’ fatigue. The use of anti-inflammatory agents in regulation of a wide range of tissue activities; metab-
(e.g., aspirin) for correcting the cancer entropy or per- olism, proliferation, differentiation, membrane lipid
haps influencing stability of chromosomal function [5, biosynthesis, growth and development, autophagy and
7, 35–40, 78, 79, 208] is intriguing. Whether expression immune cell responses [5, 39, 79, 178, 201, 260–267]. The
of intrinsic factors [e.g., constituent or induced recep- two major constitutive (innate, embryonic) and induced
tors (PM1K, PM2K), mTOR/PI3K, IRAK-M, IL-1dRs, complexes of mTORC1 and mTORC2 seem to contrib-
CAMs, PGE2, indolamine 2,3-dioxygenase, NFkB] that ute to tissue function and longevity. Molecular defects
are anabolic during wound healing or induction of can- or immature biosynthesis of any members of these com-
cer growth act differently from those anti-inflammatory plex pathways have been involved in initiation of a wide
agents (e.g., aspirin) that are reported to improve or lower range of metabolic disorders (e.g., diabetes and cardio-
cancer entropy are among important knowledge gaps that vascular complications), infectious diseases (e.g., tuber-
deserve further study. The findings that NO donor mol- culosis, COPD), neurological problems (e.g., autism,
ecule (S-nitrosoglutathione-GSNO) induces IRAK-M in epilepsy, Alzheimer’s, Parkinson’s), site-specific cancers
LPS-activated monocytes in the presence of TNF-α are (e.g., breast, bladder, peritoneal metastasis) and other
also interesting and support our definitions of tumoricidal age-associated chronic illnesses. The pathways involv-
and tumorigenic arms acute inflammation [5, 7, 35–40, ing immune cell tolerance (immune suppression) are
79, 89, 92, 121, 175, 193–200, 209–211]. implicated in clinical trials such as allograft acceptance
These and related reports demonstrate elevated levels in transplanted host tissues in models of skin allograft,
of IRAK-M in blood monocytes of patients with chronic bone marrow or stem cell transplantation for chemother-
inflammatory bowel disease or myeloid leukemia and apy-treated soft tissue sarcoma [5, 39, 79–83, 89–100,
metastasis or models of influenza also support the wound 116, 129–133, 245, 247–249]. However, mechanism of
healing effects of IRAK-M [5, 39, 79, 89, 175, 191–201]. actions or usefulness of embryonic stem cell transfer for
The reports that monocytes co-cultured with tumor cancer therapy are debatable and yet to be understood or
cells or supernatant of tumor cells demonstrated signifi- confirmed.
cant decrease in expression of apoptotic factors such as In general, growth hormones (GHs) modulate glucose
TNF-α while increased expression of IRAK-M further uptake in insulin-dependent tissues (e.g., muscle, adipo-
support induction of immune suppression in carcino- cytes). The growth hormones promoting signals involve
genesis. Tumor inoculation studies of IRAK-M deficient IGF-1-independent pathways and mTORC1 complex
models showed resistant to melonoma and fibrosarcoma to activate Rag-GTPase family of enzymes and lipid
tumor growth suggesting enhanced anti-tumor function metabolism. Low levels of plasma lipid were suggested to
of effector lymphocytes in the absence of IRAK-M [5, promote insulin sensitivity and signaling of PI3K/AKT/
196, 198, 213, 214]. Tumor-derived factors such as acidic mTOR [5, 7, 39, 40, 79, 193, 201–207]. Furthermore, lon-
gangliosides (sialic acid-containing glycosphingolipids), gevity seems to be associated with altered activities of
hyaluronan, glycosaminoglycan or C-type lectin that are membrane-enzyme complex PI3k-AKT-mTOR pathways.
generated in the extracellular matrix or plasma mem- Integration of relevant data shows that PI3K/AKT
brane of different cell types (e.g., chondriocytes, MΦs or is a common signaling pathway for activation of onco-
DCs) are capable of stimulating expression of IRAK-M genes through hypoxia, a major stimulus for expres-
that would inhibit danger signals (e.g., TLRs) in mono- sion of VEGF. Several selective inhibitors of PI3Ks (e.g.,
cytes leading to immune suppression. LY294002, ZSTK474, idelalisib, rituximab, SAR405,
The following further summarizes insights into the VPS34-IN1) with different effects on genetic altera-
pathways that are involved in induction of tolerance and tions are being examined for control of inflammation
loss of bioenergetics in chronic diseases or cancer [5, 7, in COPD, other respiratory diseases or autoimmune
39, 79, 89, 125–133, 139–154, 168–170, 174, 178–201]: and neurodegenerative diseases, or for treating several
cancers (e.g., CLL, non-hodgkin’s lymphoma, follicular aging (senescence) lead to development of tolerance
lymphoma, breast cancer, osteoclast survival) [5, 43, 217, (e.g., expression of IRAK-M, IL-1dRs, TNFdRs, PGE2)
218, 233, 241–245, 249]. The diverse roles of these inhibi- and/or ‘intolerance’ (e.g., increased allergic responses to
tors have primarily been shown in HIF-1α and HIF-2α innocuous or self-components) as contributing factors
and endogenous VEGF response to hypoxia and suggest in skewed response network of effective immunity and
that the inhibitors of different classes of PI3Ks inhibit induction of autoimmune or neurodegenerative diseases
and induce synergistically the common oncogenes, while or cancer [5, 7, 36–40, 67, 75, 157–166, 218]. Numerous
basal hypoxia-inducible VEGF was partially inhibited. defects in cellular and membrane functions, biological
components and receptor molecules [e.g., histamine, hor-
Tolerance in gastrointestinal (GI) tract mones (e.g., insulin-resistance, resistin), enzymes (e.g.,
About 70% of body’s complex immune system is in the kinases, diamine oxidase, HNMT), mutated genes, hypo-,
crucial position of digestive/gastrointestinal track. The or hypermethylated epigenetic modifications, polarized
immune composition in gut-associated lymphoid tis- innate or adaptive immune cells and over-, or under-
sues (GALTs) shares some features with other tissues that expressed inflammatory factors (e.g., M-CSF, IL-1dR,
are responsible for confronting and combating external TNF) myeloid-derived suppressor cells, cells, impaired
harmful agents. Examples of such tissues are the skin, DNA repair pathways, autophagy or mitophagy] may be
respiratory lung-associated lymphoid tissues (LALTs) or considered factors for induction of tolerance or intoler-
conjunctival-associated lymphoid tissues (CALTs) that ance in the development of ‘mild’, ‘moderate’ (intermedi-
are targets for early sensitization and tolerance (induc- ate) or ‘severe’ immune disorders including cancers [5,
tion of Th2 phenotypes) against perennial allergens (e.g., 39, 58, 59, 69, 84, 88, 108, 109, 116, 126, 129, 153, 154,
dust mites, cat epithelium or certain environmental com- 156–158, 164, 201–203, 215, 229, 231, 249, 250]. In the
ponents) [5, 7, 8, 31, 36–41, 64, 69, 72, 79, 80, 83, 101, experimental models of acute and chronic ocular inflam-
106, 137, 156]. The special features of immunity and tol- matory diseases that we established in CALTs [5, 29, 31],
erization in GALTs (e.g., increased numbers of plasma whether the chronic stimulation of tissues that led to
cells lining of the gut epithelium for production of IgA tumorigenesis and angiogenesis involved induction of
and IgE, TLRs, enzymes and hormones) are required for tolerance by decoy receptors or IRAK-M during polari-
maintenance of homeostasis of gut microbiota (intrinsic zation of immune cells (e.g., TAM) are among important
foreign elements) and ingested foods. In the gastrointes- knowledge gaps that remain to be studied.
tinal tract, tolerance against various GI bacteria (GI flora) Nearly all age-associated chronic diseases such as
is likely due to several regulatory/inhibitory complex metabolic disorders [e.g., type 2 diabetes mellitus (adult
molecules with IRAK-M and related immune suppres- onset, T2-DM), cardiovascular complications, stroke] or
sive pathways (e.g., dILRs, TNFRs or surface molecules neurodegenerative and autoimmune diseases are features
receptors) [5–8, 36–41, 64, 69, 72, 79, 142]. Interestingly, of altered immunity involving polarization of immune
expression of regulatory receptor molecules (IRAK-M) cells and skewed expression of pro-inflammatory media-
in epithelial lung tissue of asthmatic patients suggests tors, receptors or surface molecules (e.g., IL-6, TNFRs,
induction of immune suppression also involves expres- M-CSF, CD11, CD34). In the case of diabetes mellitus,
sion of adenosine receptors (A2A) and surface molecules insulin-insensitivity are reported to increase the risk of
of CD4+ T lymphocytes that could signal for mitochon- several cancers, while it reduces risks of other cancers
drial shutdown to prevent damage to the tissue [5, 79, [5–7, 36, 202–207]. Whether accessibility of specific tis-
142]. sues to the released apoptotic factors cause reduced
An overall review of numerous reports on mechanisms risk of specific cancers in diabetes are among questions
of tolerance or ‘intolerance’ (e.g., histamine intolerance) that await future investigations. Related reports show
suggests that the initial immunity and tolerance occur that PI3K/AKT pathways are involved in glucose trans-
during embryonic-fetus growth in lymphatic-vascular porter-1 (GLUT-1) activities [5, 53–55, 81, 127, 175,
tissues, thymus, respiratory and gastrointestinal tracts 187–190]. Other kinases such as glycogen synthase
under the low oxygen tension for protection of orderly kinases (GSK-3α, GSK-3β) play dual roles (activation and
growth. Fetus immunological system, studied in cord deactivation) in diverse biological activities, for growth-
blood, has Th2 phenotypes; thus bases for protection of promoting and differentiation or growth-arresting (apop-
‘graft-versus-host’ reactions or ‘tolerization’ [5, 69–85, tosis), metabolism and neuronal function, embryonic
202]. After birth and during adulthood and aging pro- development or carcinogenesis. The mechanisms of
cess, tolerance develops toward commensal microbiota action of GSK-3 are additional examples of biorhythms
and certain endotoxins (e.g., LPS) or infective agents. or Yin–Yang of immunity, playing as tumor suppressor or
Review of related data suggests that oxidative stress and
tumor promoter and involving pathways of PI3K/PTEN/ insulin-insensitivity and hyperglycemia (glucose toxicity
Akt/mTOR, Ras/Raf/MEK/ERK [5, 39, 98–101, 127, 128]. and high circulating glucose levels) alter mTOR complexes
Use of diabetes drugs such as sulfonylurea and met- (mTORC1, mTORC2) and mediate several interdepend-
formin seems directly influence ATP-sensitive k+ chan- ent pathways of metabolism, ribosomal biogenesis and
nels for enhancing membrane depolarization of pancreatic autophagy. Whether caloric restriction (CR) and increased
beta cells and stimulating exocytosis of insulin granules [5, insulin sensitivity via decreased signaling in mTOR path-
54, 89, 180, 202–207, 253]. The suggested mechanisms and ways, promotes endocrine factors and lifespan are subjects
clinical values or efficacy and safety of such agents in diabe- of recent debates [5, 72, 79, 202–207].
tes are controversial. In general, these agents seem to sup- Therefore, it is logical to consider that PI3K/AKT/
port that cellular exocytosis is energy-dependent processes mTOR activities play crucial and interdependent roles
in immune and non-immune cells/tissues. Diabetes (hyper- in contributing to the induction of tolerance, growth and
glycemia) and related metabolic disorders are considered metabolism of tissues that would influence innate/intrin-
immune disorders that initially influence the metabolic sic pathways under hypoxic conditions and mitochon-
pathways for glucose transport and metabolism. Impaired drial dysfunction.
glucose transport and utilization in these metabolic disor-
ders, are associated with induction of Il-6, T cell activation Biology of IRAK-M and soluble hormones in immune
and generation of memory or regulatory cells (Treg), path- tolerance: violations of biological circadian rhythms
ways that require additional sources of energy from fatty in carcinogenesis
acid oxidation for glycolysis and glutaminolysis, as alterna- Effective immunity requires elaborate and precise com-
tive or compensatory mechanisms for impaired mitochon- munication with a variety of hormones [e.g., estrogen,
drial oxidative phosphorylation. Under these conditions, α-melanocyte-stimulating hormone (MSH), insulin,
cell surface ligation and activation of membrane phospho- TSH, cortisol, adiponectin] that are induced or secreted
lipases (e.g., PLC) or perhaps metabolism of arachidonic from tissues and organs (e.g., thyroid, neuro-endocrine,
acid (AA) and activation of cyclooxygenase/lipooxygenase liver, adrenal glands, adipocytes, breast, ovary, thymus)
pathways, as well as, release of low level histamine, would for routine maintenance of health throughout life [5, 7,
allow mobilization of intracellular Ca2+ under impaired ER 36, 39, 40, 71, 72, 202–207]. These hormones have anti-
and T cell-dependent plasma membrane influx of Ca+2 and inflammatory properties and are often involved in wound
other ion channels [e.g., calcium release-activated chan- healing (Yang) events. The actions of these hormones are
nels (CRAC), H+/Ca2+/K+ or Na+ exchangers] [5, 39, 47, regulated by a number of receptor molecules and inhibi-
81, 140–143, 179, 180, 184, 203, 239, 253]. Hyperglycemia tors and their role fluctuate at different stages of life [5,
of diabetes could differentially interfere with transport and 7, 39, 74, 75, 262]. For example, review of several elegant
metabolism of nutrients, amino acids or solutes/osmolytes, reports demonstrate that growth promoting factors such
(e.g., vitamin C, pyridoxine/pyridoxal phosphate, myo- as adiponectin, insulin or anti-infective mediators that
inositol, leu, ala, gly) in tissues that are insulin-dependent induce IRAK-M expression require activation of phos-
or insulin-independent for glucose transport and metabo- phatidyl inositol 3-kinase (PI3K), protein kinase B (AKT/
lism and could change extra-, intracellular structures (e.g., PKB/mTOR) or ERK pathways to induce macrophage
protein/lipid glycosylation, basement membrane collagen endotoxin tolerance and signal for wound healing and
synthesis) [5, 7, 36, 39, 79, 203–207, 221, 250–260]. Related immune suppression [5, 7, 36, 39, 178–182, 195–207].
data on obesity show low-grade inflammation and impair-
ment of insulin receptor signaling and insulin resistance Induction of ‘Dark Energy’ in cancer mitosis
are mediated through the complex and interdependent and proliferation: Fatigue syndrome, a working
stress kinases [e.g., p38, mitogen-activated protein kinase hypothesis
(MAPK), c-Jun NH2-terminal kinase (inhibitor of NF-kB As noted above, continued proton pumping and gen-
kinase-β-IKKβ), AMP-activated protein kinase, protein eration of electricity are required for numerous routine
kinase C, Rho-associated coiled-coil containing protein cellular activities such as transport of ion/solute and
kinase, RNA-activated protein kinase] to phosphorylate the metabolites, lysosomal digestion and protein recycling,
key regulators of glucose homeostasis in various tissues. degradation of pathogens’ structural proteins-lipids-
The phosphorylation of serine residues of insulin recep- genes for immune recognition, activation and cellular
tors (e.g., IRS-1) results in diminished enzymatic activity of proliferation. Proper functioning of mitochondria as
PI3K/Akt pathway, important mechanisms that contribute energy power plant is crucial for proton pumping during
to insulin resistance in type 2 diabetes mellitus or induc- routine metabolism or fighting against harmful elements
tion of cancer growth [5, 36, 52–54, 102, 178, 203–207, (intrinsic and extrinsic). Mitochondrial function depends
221]. Review of a number of reports also suggests that on presence and function of essential basic building
blocks (e.g., pyruvate-shuttle, pyruvate carrier proteins, In this comprehensive article, the author presented
TCA cycle mediators) to generate energy and main- sufficient evidence to suggest that cancer is an induced
tain crosstalk between cytoplasm and mitochondria, at disease of Twentieth century, facilitated by the decision
moment notice for production of high energy and oxi- makers in cancer/medical establishment when the public
dants to fight pathogens (Yin) and also during downtime was immunized by virus-contaminated polio vaccines in
(Yang) for biosynthesis of intermediates of TCA cycle 1955s, despite extensive evidence that viruses cause can-
and preservation of energy. cer. It was demonstrated that pathogen-specific vaccines
Loss of synchronized network of Yin and Yang of effec- and ingredients weaken/retard immunity, not promote it.
tive immunity is intimately entangled with energy drain Cancer was shown to be the symptom of the loss of dif-
and electronic charges of important proteins for integ- ferential bioenergetics of effective immunity (Yin–Yang)
rity of intra-, extra-cellular membrane structures. It is that is responsible for fighting and destroying cancerous
suggested that the altered (increased) entropy or tem- cells or any other intrinsic and extrinsic hazardous mate-
perature creates ‘dark energy’ around cancer masses rials. Under immune suppression cancerous cells slowly
and drain energy from neighboring normal tissues. The or aggressively take over the machinery of host for its
differential bioenergetics that are required for mainte- enhanced and lawless growth, under hypoxic conditions
nance of circadian rhythms in health could be shifted/ and mitochondrial dysfunction. The energy for abnormal
switched under oxidative stress, during the induction of growth of cancerous cells is supplied by increased glu-
tolerance and mitochondrial shutdown in exchange for cose uptake and altered tissue metabolism via glycolysis
increased glycolysis, enhanced growth of cancer cells and Crabtree and Pasteur Effects that create ‘dark energy’
and associated increase in entropy and temperature. and entropy, conditions that are toxic to normal cells.
The shifts in energy distribution and enhanced entropy Induction of ‘dark energy’ is characteristics of disorderly
around cancerous cells (‘dark energy’) could alter energy growth and proliferation of cancer cells that drain the
requiring events of protein electrical charges (e.g., nega- energy of neighboring normal cells, potentially contribut-
tive charges, H-bonds, hydrophobic/hydrophilic ratios) ing to the observed fatigues in patients.
for proper cellular functions. It is further suggested that It was hypothesized that mitochondria and Yin and
impaired electrical charges could adversely influence pro- Yang of effective immunity and biological reprogram-
tein folding that would alter a number of cellular activi- ming develop after birth when newborn is exposed to
ties (e.g., water, nutrient and ions channels, transporters, atmospheric pressure and environmental conditions.
structural proteins). Cumulatively, altered energy-requir- Longevity and unresolved inflammation were defined
ing biological activities could limit energy utilization in as alterations in immune and non-immune response
normal neighboring cells, a potential factor in symptom dynamics. Tardiness of immunity (loss of balance in
of fatigue observed in cancer patients. Enhanced ‘dark Yin and Yang) leads to induction of ‘mild’, ‘moderate’ or
energy’ and entropy create asymmetry that could force ‘severe’ immune disorders, conditions that are associated
the normal cells from oscillating at required energy (loss with altered mitochondrial function. Insufficient circa-
of biorhythms) for cell survival (Fig. 5) (manuscript in dian rhythms (skewed biological clocks) were suggested
preparation). The extent of progressive complex interac- to be the results of one or more mutations or deficiencies
tions between growth of tumor cells and host environ- in the circadian clock genes that influence the synchro-
ment could dictate and direct clinical response outcomes. nized communications among biological oscillators (pos-
Potential influence of oxidative stress in shifting the ratios itive and negative rhythms) or ‘effective acquisition time’
of innate/adaptive production of mTORC1/mTORC2 of immunity. Lawless growth of cancer cells is peculiarly
during induction of tolerance and activation of Crabtree comparable to the orderly (one way) growth of fetus that
and/or Pasteur Effects in creating differential entropy and involve activation of trophoblasts factors and constitu-
‘dark energy’ and disorderly growth of cancer masses are ent receptors that are required for fetus orderly growth
important topics that require systematic studies for effec- under hypoxic conditions (Fig. 5).
tive control of cancer cell growth. The current reductionist approaches to cancer science
and therapy are conducting numerous out-of-focus and
Summary and future directions fuzzy projects projects on identification of one or com-
bination of mutated genes or expression products using
While falsely-based science will not hide the scien-
expensive and specific technologies as bases for drug
tific truth at the end, it creates confusion and chaos
development. The outcome failure rates of such reduc-
that benefit those who gain control of public health
tionist, fraud and chaotic projects are 90% (± 5) that
at high cost to society.
destroyed the precious lives of millions, but generated
Epithelial-Mesenchymal Transi!on
Cons!tuent Receptors of Trophoblasts from Embryo to Cancer?
Placenta!on-Uterus
EMT Embryonic body
Cancer Vasculogenesis-
Organogenesis
MMPs Sexual
‘Dark Trophoblasts
Energy’ Asexual
Fetus Orderly
Cons!tuent
Crabtree Growth
Reservoir Stem Cells
Pasture Receptor-Enzymes
Glycolysis
Birth-Adulthood
Organ systems
Mito, Yin-Yang
Immunity
Fig. 5 Schematic representation of loss of biorhythms, expression of constituent receptors and induction of tolerance for epithelial–mesenchymal
transition (EMT) during cancer proliferation and growth. The scheme represents activation of trophoblasts growth factors that are required for pla-
centation during embryonic and orderly fetus growth (constituent) and receptors including pyruvate kinases receptors and hormones. Induction of
anabolic factors increase lawless growth of cancer cells and increase metabolism through glycolysis under mitochondrial dysfunction and hypoxia,
features resembling/mimicking aspects of orderly growth of fetus. Expression of embryonic growth factors facilitate increased glucose metabolism
through glycolysis, Pasteur and Crabtree effects and induction of immune tolerance creating ‘dark energy’ that enhance entropy, mitosis and prolif-
eration of cancer masses, conditions that are toxic for normal cell survival. See text
huge corporate profits for the cancer/medical establish- (a) What are the early changes in complex network of
ment (e.g., government, Big pharma, organizations and immune responses that lead to genetic instability,
largest lobbying group and ‘philanthropists’/business- loss of biorhythms, mitochondrial dysfunction and
men who support medical education programs) [5, 7, altered metabolism that lead to immune tolerance
20, 39, 43]. Again, targeting young and old population to toward multistep carcinogenesis and angiogenesis.
be vaccinated by pathogen-specific vaccines (e.g., HPV, (b) How to develop universal vaccines and prophylac-
flu, measles, meningitis) weaken (not promote) immu- tic agents that promote body’s natural immunity for
nity. The pathogen-specific vaccines and ingredients are maintaining the autonomous, sympathetic and para-
viewed as ‘antigen overload’ overwhelming or skewing sympathetic or Yin and Yang, biological circadian
immunity to clear and resolve immune/inflammatory rhythms that are required for improving public health
responses. Tardiness of immune responses is the bases and preventing majority of chronic diseases or cancer.
for induction of a wide range of health problems such as
asthma, autoimmune and neurodegenerative diseases or Future research directions require focusing on system-
cancers in old and young populations. atic and logical studies that are outlined in the following
After investing several trillions of dollars of taxpayers’ overall topics [5, 7, 20, 39, 72, 175]:
and private organizations funding for cancer research
and treatment, the decision makers have yet to seriously i. Time-course kinetics of immune response dynamics
consider the need for understanding the following scien- are fundamental and essential first steps in under-
tific common senses and logics: standing details of host interactions with stimuli
(infective agents, environmental and biological haz- us to extraordinary achievements in many biomedical
ards). The extent of damage that specific immune fields. Solving cancer problem is not an exception if the
disruptors impose on bioenergetics and architec- business of cancer did not overwhelm the search for sci-
tural integrity and function of affected tissues during entific facts and logics.
developmental phases of multistep disease processes
are among important topics that deserve detailed Concluding remarks
studies. Identification of shared or special features of For over six decades the reductionist approaches of deci-
early events during host–pathogen interactions that sion makers in cancer science popularized the notion that
alter immune response profiles are among important cancer is too many diseases (100, 200 or 1000); cancer is
knowledge gaps that require detailed studies. too complex to solve; that they have made ‘extraordinary
ii. Potential reversibility of early stages of inflammation- advances’ and need more money to further progress on
induced immune dysfunction including alterations the war against cancer. The decision makers now make up
in cellular chromosomal/genetic material that would other stories that they need to aggregate and share data
lead to cellular growth promotion and genesis of and require more resources and time to solve cancer mys-
hyperplasia, neoplasia/pre-cancer or cancer-malig- tery. The truth about claims of ‘targeted’ therapy based
nancy deserve detailed studies. on identification of endless defective molecular entities is
iii. The quality (nature) and quantity of initial acute that such mindless and chaotic approaches failed patients
immune responses (strong or weak) and the genera- at the rate of 90% (±5), costing the loss of millions of pre-
tion of histamine and other pro-, or post-inflamma- cious lives and financial toxicity to the society. All relevant
tory mediators could influence subsequent responses data are available in various medical and basic science
such as the extent of rejection or penetration of anti- disciplines. Integration of quality data on how cancer is
gen in subepithelial tissue, vascular hyperpermeabil- initiated has been practically ignored and its systematic
ity and tissue integrity during Yin and Yang activities investigations are not allowed when competent profes-
and clearance of antigen. sionals propose more logical and cost-effective studies
iv. It is important to understand the influence of mito- to help understand cancer biology and how to prevent
chondrial dysfunction and energy shifts during or treat it. As author presented in the last couple of dec-
increased glycolytic pathways that result in adaptation ades, analyses of data from her accidental discoveries on
of cancer cell growth and immune tolerance. Induction experimental models of ocular inflammatory diseases and
of tolerance could change mitochondrial-dependent extension of relevant data on multidisciplinary fields of
activities of cMyc, Alt/PTEN or p53 and related path- medical and immunological sciences suggest that cancer
ways and alter apoptosis (Yin) events leading to prolif- is only one disease. Disorderly growth of cancer cells is
eration and entropy or ‘dark energy’ in cancer mass. the results of loss of autonomic and synchronized balance
v. Understanding the thermodynamics and biological in tumoricidal (Yin) and tumorigenic (Yang) properties of
communications of high energy-consuming and volt- immunity to arrest cancer cells. Loss of differential bioen-
age-dependent pathways in apoptosis (Yin, tumori- ergetics in Yin (high energy, tumoricidal) and Yang (low
cidal) that are involved in destroying defective cancer energy, tumorigenic) pathways often leads to ‘mild’, ‘mod-
cells are important topics that are not fully under- erate’ or ‘severe’ immune disorders or cancer.
stood. The goal of this comprehensive perspective was to
vi. Stimuli-induced redox-sensitive mitochondrial tran- extend the design of a roadmap as comprehensive as
sition pore (MTP) that opens to the cytoplasm, fol- possible, by analyzing relevant data on major biological
lowed by depolarization, electron flux in the electron features at different stages of life. In the process of inte-
transport chain (ETC) during production of electron grating and connecting the informational dots, important
donors (NADH and FADH2) that would increase the knowledge gaps that are worthy of future investigation
level of reactive oxygen species (ROS) are crucial top- were revealed. Integrating and disseminating relevant
ics that require better systematic studies. information are important for broadening the scope of
intellectual understanding on the complex dynamics of
Minor or major heterogeneities in intrinsic biology and effective immunity that lead to effective promotion and
genetic makeup of individuals often lead to heterogenei- maintenance of health.
ties in response profiles toward different biological insults
After all ‘we may be intelligent, but if not able to
(immune disruptors). These confounding factors present
think and love well being of others, we use the intel-
unique challenges and opportunities to overcome in
ligence against humanity’ [?].
future research. However, the outcomes are expected to
be rewarding as the truth in science has always advanced
Abbreviations 8. Khatami M (2017) The eyes have it all! Inflammation aging and cancer.
AA: arachidonic acid; ASPH: aspartyl-asparginyl β-hydroxylase; CALTs: Springer, Cham, pp 175–212. https://doi.org/10.1007/978-3-319-66475
conjunctival-associated lymphoid tissues; CAM: cell adhesion molecule; -0_4
CRP: C-reactive protein; DAMP: damage-associated molecular pattern; ECM: 9. Day A (2009) ‘An American tragedy’, the cutter incident and its implica-
extracellular matrix; GSK-3α, GSK-3β: glycogen synthase kinases; GALTs: gut- tions for the Salk polio vaccine in New Zealand 1955–1960. Health Hist.
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virus; LALTs: lung-associated lymphoid tissues; LPS: lipopolysaccharide; LTA: present in AKR leukemic tissues with notes on a sarcoma produced by
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1; MOFs: multiple organ failures; NETs: neutrophil extracellular traps; PGN: (2005) Some oral poliovirus vaccines were contaminated with infec-
peptidoglycan; PI3K: phosphoinositide (phosphatidyl inositol) 3-kinase; PIKK: tious SV40 after 1961. Cancer Res 65(22):10273–10279
PI3K kinase; PRRs: pattern recognition receptors; PEP: phosphoenol pyruvate; 12. Sykes A, Gerhardt E, Tang L, Adderson EE (2017) The effectiveness of
ROC: Receptor-operated channel; SAPK: stress-activated protein kinase; TLRs: trivalent inactivated influenza vaccine in children with acute leukemia.
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VCAM: vascular CAM. virus vaccine and the risk of cancer—a review of the epidemiological
evidence. Dev Biol Stand 94:235–244
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The author read and approved the final manuscript. tumors in rats by tissue-culture preparations of SE polyoma virus. J Natl
Cancer Inst 22:161–171
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Khatami Clin Trans Med (2018) 7:20

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