A recent study published online in the journal
Fertility and Sterility in
September of 2017 systematically reviewed for the first time evidence
for the effect of two compounds, ionomycin and A23187 (also known as
calcimycin), on fertilization rates and pregnancy outcomes in infertile
couples undergoing an
in vitro fertilization procedure known as
intracytoplasmic sperm injection (ICSI) [1]. ICSI involves the direct
deposition of sperm into the oocyte cytoplasm, which typically leads to
high rates of fertilization. However, fertilization failure despite
repeated ICSI is likely caused by a failure of the oocyte to activate
[1]. Physiological oocyte activation is accomplished by the delivery of a
sperm-borne oocyte activating factor called phospholipase C zeta
(PLCζ). PLCζ activates human oocytes by inducing an intracellular
signaling cascade that ultimately results in increased calcium (Ca2+)
oscillations in the oocyte, which drives oocyte activation to completion
[1].
As oocyte activation is an indispensable prerequisite for
the creation of all human life, every human being alive today and any
human being that has ever lived began their existence as an activated
oocyte [2]. Ionomycin and A23187 increase the levels of
intracellular Ca2+ and are thus commonly known as Ca2+ ionophores [1].
The authors of the
Fertility and Sterility study showed that
over a total of 1,521 ICSI cycles, calcium ionophores including
ionomycin and A23187 led to a statistically significant improvement in
fertilization, cleavage, blastulation, implantation rates, overall
pregnancy, and live-birth rates [1]. Ionomycin and A23187 have also been
shown in several independent studies to effectively induce human oocyte
activation, leading to the birth of normal, healthy children [3,4].
Strikingly, as described further below, both ionomycin and
A23187 are antibiotics that are naturally produced by certain species
within the bacterial genus Streptomyces [5,6]. Other
structurally distinct compounds and methods have also been shown to
induce human oocyte activation, including ethanol, puromycin (an
antibiotic and protein synthesis inhibitor produced by
Streptomyces alboniger),
as well as mechanical manipulation and electrical stimulation, both of
with have been reported to result in the creation of normal children
[7-11]. Interestingly, as mouse oocytes are considered models for human
oocytes, ionomycin, A23187, anisomycin (an antibiotic and protein
synthesis inhibitor produced by
Streptomyces griseolus), mycophenolic acid (an immunosuppressant produced by the fungus
Penicillium brevicompactum), cycloheximide (a protein synthesis inhibitor produced by
Streptomyces griseus), carvacrol (a secondary plant metabolite produced by
Origanum vulgare{oregano}), and phorbol 12-myristate 13-acetate (PMA, a secondary plant metabolite produced by
Croton tiglium)
each induce activation of mouse oocytes [12-22]. Ionomycin, A23187,
PMA, and reactive oxygen species (ROS) also induce the acrosome reaction
in human sperm, a process characterized by the release of hydrolytic
enzymes from the head of sperm which is necessary for oocyte penetration
and thus indispensable for the creation of all human life outside of a
clinical setting (ICSI bypasses the need for oocyte penetration)
[23,24]. Additionally, although an over-production of ROS, similar to
Ca2+, may lead to deleterious effects including cell death/apoptosis,
low levels of ROS have been shown to act as signaling molecules and ROS
is significantly increased on or immediately following mouse oocyte
activation [25,26].
Furthermore, the master metabolic regulator AMPK is critical for
oocyte meiotic resumption and maturation (a process that precedes and is
essential for oocyte activation), is found located across the entire
acrosome in the head of human sperm, and is activated by increases in
ROS and Ca2+ [27-29]. Ionomycin, A23187, ethanol, puromycin, mechanical
force, electrical stimulation, anisomycin, mycophenolic acid, carvacrol,
and PMA also induce AMPK activation, indicating that a common mechanism
of action links chemically distinct compounds with the creation of
human life [30-39]. This common mechanism of action likely centers on
the induction of cellular stress, mediated by indirect increases in
intracellular Ca2+, ROS, and/or the AMP(ADP)/ATP ratio, etc. as I
originally proposed in 2016 [40]
. Because the bacterial-derived
antibiotics ionomycin and A23187 induce both the acrosome reaction in
human sperm and human oocyte activation, producing normal, healthy
children, it can be said that “non-human organisms have the power to
create human life or the power to end life.” As explained below, the
beneficial effects of cellular stress induction (i.e. a “shock”) crosses
species boundaries and may indeed play a role in facilitating natural
selection, a process that underlies and drives evolution.
A number of bacterial species residing within the genus
Streptomyces
have proven to be extremely important and medicinally valuable as
approximately 70% of clinically useful antibiotics are derived from
Streptomyces [41]. The antibiotics ionomycin and A23187 are naturally produced by
Streptomyces conglobatus and
Streptomyces chartreusensis, respectively [5,6]. Other important examples include the antibiotic tetracycline (produced by
Streptomyces aureofaciens), the immunosuppressant rapamycin (produced by
Streptomyces hygroscopicus), and the anti-helminthic avermectins (produced by
Streptomyces avermitilis) [42]. Many soil and aquatic-dwelling species of
Streptomyces
can be found in harsh environments and are characterized by a unique
life cycle, including spore germination followed by vegetative mycelium
production, aerial hyphae formation, sporulation (i.e. spore formation),
and antibiotic production [43,44]. Curiously, just as cellular stress
induction leads to the creation of human life and other beneficial
effects in human cells (see below), stress induction also promotes the
induction of aerial hyphae formation, sporulation, and antibiotic
production in many
Streptomyces species (spp.). Indeed, a
decrease in the levels of ATP and bacterial growth is associated with
sporulation, aerial hyphae formation, and antibiotic production
[42,45]. A reduction in glucose/nutritional deprivation, the preferred
sugar/carbon source for many
Streptomyces spp., also
significantly increases antibiotic production [46]. An increase in
intracellular ROS and Ca2+ is associated with spore germination, aerial
hyphae formation, and antibiotic production [47-49]. Other cellular
stressors, including heat shock and ethanol, also significantly increase
antibiotic production, provocatively indicating that the effects of
cellular stress crosses species boundaries, enhancing bacterial survival
and facilitating the creation of human life [50,51].
The beneficial effects of low-level cellular stress induction
also extends to plants, as many plants produce secondary metabolites
partly for the purpose of self-defense, analogous to antibiotics. Similar to the harsh, stressful environments often inhabited by
Streptomyces spp., the Great Basin Bristlecone Pine (
Pinus Longaeva),
considered the oldest living non-clonal organism on the planet (
>5000 years old), thrives in an exceptionally harsh environment,
characterized by increased elevations and exposure to UV radiation,
nutritionally-deprived soils, harsh temperatures, and mechanical stress
due to wind variances, leading early researchers to conclude that it’s
longevity is intimately associated with adversity [52-54]. Conversely,
Pinus Longaeva
species that are located in less stressful environments (i.e. lower
elevations) are strongly associated with younger age classes (<875
years) [55]. Similarly, the Creosote bush (
Larrea tridentate),
considered one of the oldest living clonal organisms on the planet
(>11,000 years old), also thrives in harsh environments including the
Mohave Desert [56]. AMPK, which increases lifespan and healthspan in
several model organisms, is the primary sensor of cellular stress in
eukaryotic organisms (e.g. plants and humans) and the plant AMPK
orthologue SnRK1 as well as Ca2+ and ROS are critical for seed
germination, fertilization, root gravitropism, and secondary metabolite
production [57-64]. The secondary plant metabolites PMA (which activates
mouse oocytes and promotes the acrosome reaction in human sperm) and
artemisinin (an anti-malarial drug) both activate AMPK and the
antibiotic A23187 also increases production of the secondary metabolite
resveratrol in grape cell cultures, again indicating that exposure to
low-level stressors may promote extension of lifespan and initiate the
creation of human life [17,23,39,65,66].
Organismal exposure to beneficial levels of stress may also play a critical role in evolution. As
first noted by Charles Darwin, evolution is driven by natural
selection, a process characterized by environmentally-induced phenotypic
changes that may lead to inheritable survival and reproductive
advantages [67]. From “On the Origin of Species by Means of
Natural Selection, or the Preservation of Favoured Races in the Struggle
for Life”, Darwin explained that “if there be, owing to the high
geometrical powers of increase of each species, at some age, season, or
year, a severe struggle for life, and this certainly cannot be
disputed;……But if variations useful to any organic being do occur,
assuredly individuals thus characterised will have the best chance of
being preserved in the struggle for life;” [67]. This “struggle for
life” Darwin spoke of is embodied by selective pressures which may be
abiotic (i.e. light, wind, temperature, etc.) or biotic (predation,
disease, competition, etc.) [68,69]. As alluded to above, such selective
pressures are indeed sources of cellular stress, sensed by both
prokaryotes and eukaryotes, that induce beneficial responses (at
appropriate levels), leading to the acquisition of phenotypes conducive
for continued survival. Both biotic (e.g. infection) and abiotic (e.g.
heat) stressors/selective pressures activate AMPK (which is
evolutionarily conserved among eukaryotes) in human cells [70,71]. A
phenomenon often cited as an example of natural selection on a readily
observable timescale is the development of bacterial resistance to
antibiotics, resulting in problematic mutant strains that may be
life-threatening for some individuals (i.e. the elderly and
immunocompromised) [72]. Intriguingly, lethal levels of bactericidal
antibiotics have been shown to kill microorganisms via the induction of
ROS, sub-lethal levels of bactericidal antibiotics however increase
mutagenesis and bacterial resistance via induction of lower levels of
ROS, and heat as well as nutritional stress increase bacterial
resistance to antibiotics, providing compelling evidence that continuous
exposure to low levels of stress likely plays a significant role in
natural selection and evolution [73-75].
Moreover, gravity itself likely functions as a cellular
stressor/selective pressure that has influenced the development of
organisms on Earth since the emergence of the very first lifeform. Gravity
exerts its effects on living organisms via the application of force,
which is experienced by human cells in the form of mechanical loading or
stress [76]. The application of force or a mechanical load has recently
been shown to activate AMPK and simulated microgravity (i.e. hind limb
unloading in mice) significantly decreases AMPK activation
[77,78]. Spaceflight also inhibits the activation of T cells (immune
cells essential for adaptive immunity), whereas the application of force
and AMPK activation promote T cell activation [79-81]. Interestingly,
spaceflight has recently been shown to decrease the levels of the master
antioxidant transcription factor Nrf2 and the heat shock-inducible
protein HSP90a but increase the levels of the growth-promoting kinase
mTOR in mice [82]. AMPK however inhibits mTOR but increases the
phosphorylation, nuclear retention, and transcriptional activity of Nrf2
[57,83,84]. Also, HSP90 interacts with and maintains AMPK activity and
HSP90 is necessary for progesterone-induced human sperm acrosome
reaction [85,86]. Interestingly, rapamycin, an immunosuppressant
produced by
Streptomyces hygroscopicus, extends lifespan in genetically heterogeneous mice, activates AMPK
in vivo
in normal aged mice, and increases human sperm motility
[42,87,88]. Simulated microgravity via the use of NASA-designed rotating
wall vessels (RWVs) however drastically reduces rapamycin production
(~90%) whereas the antibiotic gentamycin increases rapamycin production
by
Streptomyces hygroscopicus, providing further evidence that
cellular stress, in the form of mechanical loading induced by gravity,
is essential for development, function, and survival of Earth-bound
organisms [89,90].
The induction of cellular stress also links seemingly
dissimilar physiological and pathological states with the activation of
AMPK. As discussed above, both ionomycin and ROS activate AMPK
and promote oocyte meiotic resumption, a process that is AMPK-dependent
and is essential for efficient oocyte activation [27,30,91]. ROS is also
critical for ovulation, PMA and ionomycin both activate mouse oocytes,
and ionomycin is extensively used during ICSI procedures, creating
normal healthy children, suggesting that cellular stress-induced AMPK
activation is also essential for oocyte activation [3,4,12,17,92]. The
activation of oocytes and T cells share strikingly similar intracellular
signaling mechanisms (e.g. PLC-PIP2-DAG-PKC-IP3-Ca2+) and ionomycin
combined with PMA are extremely effective in activating T cells and are
often used as positive controls in HIV-1 latency reversal studies
[93-95]. Reactivating latent/dormant HIV-1 in CD4+ T cells, potentially
facilitating immune system detection and virus destruction, is currently
being pursued as a method for the potential eradication of HIV-1
(called the “shock and kill” approach) [96]. Similar to oocyte
activation, both Ca2+ and ROS are critical for T cell activation (and
hence latent HIV-1 reactivation) and other cellular stress-inducing
compounds, including NDGA derived from the Creosote bush, butyrate
derived from bacteria, as well as ROS and HSP90 have been shown to
reactivate latent HIV-1 [26,93,94,97-101]. Interestingly, AMPK
inhibition leads to cell death on T cell activation, knockdown of AMPK
significantly decreases HIV-1 replication, and metformin (a well-studied
AMPK activator derived from the French Lilac plant) increases butyrate
production in human diabetic patients [81,102,103]. Perhaps most
convincingly, early preliminary data showed that metformin significantly
reduced several markers preferentially associated with cells latently
infected with HIV-1 (e.g. PD-1, TIGIT, TIM-3) and also destabilized the
latent HIV-1 reservoir in chronically-infected HIV patients, indicating
that cellular-stress induced AMPK activation likely links the creation
of human life with the potential eradication of HIV-1, as I originally
proposed in 2016 [40,104,105].
AMPK activation may also link the disparate disease states of HIV-1 latency and Hutchinson-Gilford progeria syndrome (HGPS). HGPS is a genetic disorder caused by aberrant alternative splicing of the
LMNA
gene, generating a toxic protein called progerin that induces an
accelerated aging phenotype and premature death at approximately 14
years of age [106]. Excessive activity of the gene splicing factor SRSF1
has been shown to prevent reactivation of latent HIV-1 and contribute
to aberrant splicing of the
LMNA gene in HGPS [107-109].
Metformin however has recently been shown to ameliorate the accelerated
aging phenotype in cells derived from children with HGPS by reducing the
levels of both SRSF1 and progerin and activating AMPK, as I first
proposed in 2014 [110-112]. Interestingly, both Ca2+ and ROS induce
autophagy (a process of disposing of damaged/toxic proteins and
organelles) and rapamycin, which activates AMPK
in vivo and
increases intracellular Ca2+ levels, improves accelerated aging in
progeria cells by inducing autophagic degradation of progerin
[87,113-116]. Temsirolimus, an analog of rapamycin, also alleviated
accelerated aging defects in progeria cells but also increased the
levels of ROS and superoxide within the first hour of treatment
[117]. Such evidence strongly suggests that cellular stress-induced AMPK
activation links the reversal of HIV-1 latency and alleviation of
accelerated cellular aging defects in HGPS.
Cellular stress-induced AMPK activation also links the
potential elimination of cancer stem cells (CSCs) with HIV-1 latency
reversal and viral eradication. CSCs, which are largely
resistant to chemoradiation therapy, are a subpopulation of cancer cells
that exhibit characteristics similar to embryonic stem cells (ESCs),
including self-renewal, multi-lineage differentiation, & the ability
to initiate tumorigenesis [118,119]. Mechanisms that sustain quiescence
& promote self-renewal in adult stem cells (ASCs) & CSCs likely
also function to maintain latency of HIV-1 in CD4+ memory T
cells. Indeed, HIV-1 has been found to establish long-lasting latency in
a recently discovered subset of CD4+ T cells that exhibit stem
cell-like properties known as T memory stem (TSCM) cells and increases
in Ca2+, ROS, and AMPK activation have been shown to promote T cell
activation and ESC, ASC, and CSC differentiation
[119,120]. Additionally, A23187 and PMA have been shown to promote CSC
differentiation (causing CSCs to become more susceptible to
chemoradiation) and metformin induces CSC differentiation and/or
apoptosis in an AMPK-dependent manner in the deadliest of cancers,
including glioblastoma and pancreatic cancer, providing support for my
publication in 2017 in which I first proposed that CSC differentiation
and/or apoptosis and HIV-1 latency reversal/viral eradication may be
linked by cellular stress-induced AMPK activation [119,121-124].
In conclusion, the ability of non-human organisms including certain Streptomyces spp.
to initiate the creation of human life is predicated on the induction
of cellular stress, mediated by increases in intracellular ROS, Ca2+,
AMP(ADP)/ATP ratio increase, etc. The beneficial effects of
transient cellular stress induction, which may be likened to selective
pressures, crosses species boundaries and may indeed play a role in
facilitating natural selection, a process that underlies and drives
evolution, as evidenced by stress-induced increases in antibiotic
production by
Streptomyces spp. and stress-induced mutagenesis and antibiotic resistance in various bacterial strains.
Because
AMPK, a primary sensor of cellular stress in eukaryotic cells that
increases lifespan and healthspan, plays a critical role in oocyte
meiotic resumption/maturation, T cell activation, and stem cell
differentiation, the creation of human life, the potential eradication
of HIV-1, amelioration of accelerated aging in HGPS cells, and CSC
differentiation/apoptosis are likely linked by a “Shock to Live”, or a
“Shock to Kill”.
https://www.linkedin.com/pulse/antibiotics-produced-bacteria-activate-human-oocytes-creating-finley/
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