Charles Shang, MD
The gold standard in testing scientific theory requires multiple
independent prospective tests. This standard is applied to basic
acupuncture research. This article reviews the key results of basic
acupuncture research which meet the gold standards and discusses their
Literature search and review of publications in medline and Chinese
medical literature databases are combined with discussion with many
experts to identify and analyze the models in basic acupuncture research
which have predictions. These predictions are further checked for
independent confirmation by multiple research groups.
Initial literature screen identified more than 400 related articles.
Further analysis and discussion showed that the growth control model is
the only published model in basic acupuncture research which has met the
gold standard. It encompasses the neurophysiology model and suggests
that a macroscopic growth control system originates from a network of
organizers in embryogenesis. The activity of the growth control system
is important in the formation, maintenance and regulation of all the
physiological systems. Several phenomena of acupuncture such as the
distribution of auricular acupuncture points, the long term effects of
acupuncture and the effect of multimodal nonspecific stimulation at
acupuncture points are consistent with the growth control model. The
following predictions of the growth control model have been
independently confirmed by research results in both acupuncture and
conventional biomedical sciences: 1. Acupuncture has extensive growth
control effects. 2. Singular point and separatrix exist in
morphogenesis. 3. Organizers have high electric conductance, high
current density and high density of gap junctions. 4. A high density of
gap junctions is distributed as separatrices or boundaries at body
surface after early embryogenesis. 5. Many acupuncture points are
located at transition points or boundaries between different body
domains or muscles, coinciding with the connective tissue planes. 6.
Some morphogens and organizers continue to function after embryogenesis.
Conclusion: Current acupuncture research suggests a convergence of the
neurophysiology model, the connective tissue model and the growth
control model. The growth control model of acupuncture set the first
example of a biological model in integrative medicine with significant
prediction power across multiple disciplines. Basic acupuncture research
has met the gold standard of science with multiple independently
According to the World Health Organization (WHO),
a broad definition of acupuncture is the stimulation of certain points
on the body (acupuncture points) using needling, moxibustion,
electricity, laser, or acupressure for therapeutic purposes.1
The Standard Acupuncture Nomenclature published by the WHO listed about
400 acupuncture points and 20 meridians connecting most of the points.2
Results from randomized controlled trials (RCTs) have shown that
acupuncture is effective in treating dozens of disorders1
such as osteoarthritis 3, 4, 5 pelvic and back pain 6
neck pain 7 migraine and tension headache 8,9
nausea/vomiting 10 and inflammatory bowel disease.11
Mixed results widely exist in acupuncture research12 for
various reasons. Many neurohumoral 13, 14, 15, 16 mechanical
and growth control effects of acupuncture18 have been
observed. Several models of acupuncture mechanism have been proposed.
The focus of this article is on the biological models of acupuncture
which can meet the gold standard of science with multiple independently
The Observations from Acupuncture Research
In the mid-70s, the discovery of endorphin
induction in acupuncture analgesia and its blockade by naloxone was
instrumental in establishing the validity of acupuncture in modern
science.19, 20 In acupuncture analgesia, the peripheral
nervous system has been shown to be crucial in mediating the effect. The
analgesia can be abolished if the acupuncture site is affected by
postherpetic neuralgia21 or injection of local anesthetics.22
Different frequencies of electric stimulation in electroacupuncture lead
to release of different neuropeptides.13 Electroacupuncture
has been shown to release nociceptin and inhibit the reflex-induced
increases in blood pressure16 and increased the synthesis of
nitric oxide in mediating the protective effect on gastric mucosa.23
Since the 1950s, it has been discovered and
confirmed with refined techniques14 that many acupuncture
points and meridians have high electrical conductance24, 25, 26
though the results are sometimes mixed.27 High electric
conductance of acupuncture points have been successfully used for
locating acupuncture points in acupuncture therapy.28 The
high electric conductance at acupuncture points is further supported by
preliminary finding of high density of gap junctions at the epithelia of
the acupuncture points.29, 30, 31, 32 Gap junctions are
hexagonal protein complexes that form channels between adjacent cells.
It is well established in cell biology that gap junctions facilitate
intercellular communication and increase electric conductance. High
concentrations of nitric oxide and nitric oxide synthase have also been
observed at acupuncture points and meridians.33
Modern Biological Models of Acupuncture
In the 1970's, the relation between the nervous
system and acupuncture alteration of visceral function was explored by
examining the cortical evoked potentials, single unit discharges and
neurochemistry associated with acupuncture. These studies brought forth
the Meridian-Cortex-Viscera correlation hypothesis which states that: 1.
The meridian system is an independent system connected via the nervous
system to the cerebral cortex. 2. It acts through neurohumoral
mechanisms.34 A contending model claimed that the meridian
system as described in the classic acupuncture literature does not exist
and that all the effects of acupuncture are mediated through nervous
Another hypothesis suggested that the network of
acupuncture points and meridians is a signal transduction network formed
by interstitial connective tissue. Mapping of acupuncture points on
human arm showed an 80% correspondence between the sites of acupuncture
points and the location of intermuscular or intramuscular connective
tissue planes in postmortem tissue sections.37
Modern biological models of acupuncture are
confronted with the following puzzling facts:
- The distribution of acupuncture points: The
distribution of acupuncture points is different from the
distribution of nerves, blood vessels, lymphatics or connective
tissue. For example, an auricle has no important nerves or blood
vessels or lymphatics or complex connective tissue planes and no
significant physiological function other than sound collection.
While the vagus nerve has an auricular branch, this branch has no
known important function in modern neuroscience. A search of Medline
did not yield any article on the function of the auricular branch of
vagus nerve in the past 50 years. The auricle nevertheless has the
highest density of acupuncture points. According to the WHO, 43
auricular points have proven therapeutic value,2 which
consist of more than 10% of the acupuncture points of the entire
human body. Numerous RCTs have demonstrated the efficacy of
auricular acupuncture38, 39, 40, 41, 42, 43 while some
results are mixed.12
- The non-specific activation of acupuncture
points: Therapeutic effect of acupuncture has been achieved by a
variety of stimuli10,1 including needling, injection of
nonspecific chemicals, electricity, temperature variation, laser,
and pressure. No conventional nerve stimulation technique has such
diverse modalities of stimulation. Non-noxious stimuli such as
non-thermal low intensity laser irradiation, which does not cause
local nerve excitation44 or collagen fiber reorganization
at acupuncture points, can cause extensive systemic effects45
and stimulate local cellular calcium oscillation,45 cell
proliferation, release of basic fibroblast growth factor,
interleukins as well as other growth control effects.46
This suggests that another system other than nervous system mediates
the initial signal transduction in acupuncture.
- Transient acupuncture stimulation often
causes long lasting effect over weeks or months. For example, two
RCTs9,8 have shown that the relief of migraine headache
lasted 1 year after acupuncture treatment – thousands of times
longer than the physiological half life of endorphin47
and other common neurotransmitters. Similar long-term benefits of
acupuncture have been shown by RCTs on the treatment of shoulder
pain,48 chronic low back pain,49, 50 primary
dysmenorrhea,51 spinal cord injuries,42
urinary urgency41 and osteoarthritis.5, 52, 53
This long lasting effect is almost non-existent in conventional
therapy using transient mild peripheral nerve stimulation. In
conventional nerve stimulation, long lasting effects require long
term stimulation as observed in the effects of opioids, serotonin
reuptake inhibitors, sacral nerve stimulation,54 and
vagal nerve stimulation.55
- The existence of acupuncture points. i.e. why
do stimuli at many acupuncture points cause diverse systemic effects
without obvious benefit of survival for normal animals? For example,
stimulation at acupuncture points PC6 and ST36 which are at the
extremities increases the gastric motility in dogs.56
This is contrary to the fight or flight response and seems to offer
no survival benefit to animals. What is the intrinsic function of
acupuncture points? How did these acupuncture points come into
existence over the course of evolution?
In science, models or hypotheses capable of
successful prospective predictions are considered more convincing than
models solely based on retrospective explanations or accommodations.57,
58 The gold standard in testing a scientific theory is multiple
independent confirmations of its predictions. It is therefore important
to assess which theory in basic acupuncture research has met this gold
standard. A literature research in PubMed with full text (Medline) using
keywords acupuncture AND (predict* OR corollary) identified 101
articles. Similar search strategy in Chinese medical/scientific
literature databases including
http://www.chinainfobank.com/ identified over 300 articles. Further
review of the literature and discussion with more than a dozen experts
in this field narrowed down to two biological models59,18
which have independently confirmed prediction(s): The neurophysiology
model on the long term effects of acupuncture59 suggests: 1.
The trophic and anti-inflammatory effects of acupuncture are important
in mediating its long term effects. 2. Long term potentiation and long
term depression are likely involved in acupuncture signal transduction.
Its corollary on the peripheral anti-inflammatory effect of endorphin in
acupuncture has been confirmed.60 The growth control model
first published in the 1980s61 correctly predicted multiple
research results not only in acupuncture, but also in conventional
biomedical sciences. It also has shed light on the puzzling observations
mentioned above.62,18 This model encompasses the
neurophysiology of acupuncture18 and is supported by the
research results on connective tissue at acupuncture points.17,37
It is the only published model which has met the gold standard of
the multiple independent prospective tests.
The Origin and Function of Acupuncture Points
It is well known that all the physiological
systems, including nervous system, are derived from a system of
embryogenesis - a growth control system.63[Figure
1] In growth control, the fate of a larger region is frequently
controlled by a small group of cells, which is termed an organizing
center or organizer.64 A gradient of messenger molecules
called morphogens forms around organizers. Organizers have highest
(sources) or lowest (sinks) local concentration of morphogens64, 65
and therefore are macroscopic singular points of morphogen gradient
field. A singular point is a point of discontinuity. It indicates abrupt
transition from one state to another. Small, nonspecific perturbations
around singular points - organizers can have important systemic effect.66,
67 Several lines of evidence suggests that the bioelectric field
interacts with morphogens and growth factors, and guides morphogenesis.68,
69 The growth and migration of a variety of cells are sensitive to
electric fields of physiological strength.70, 71 Organizers
and acupuncture points share several common features: Both commonly
distribute at the extreme points of surface curvature18,61,62
and are activated by non-specific stimuli.67,61 Both are
associated with bioelectric field.18 The growth control model
therefore suggested that acupuncture points originate from organizers.18,61
Confirmed Predictions on Organizers and
Based on the connection between
acupuncture points and organizers, the growth control model predicted
that organizers have high electric conductance, high electric current
density and high density of gap junctions.18,61 These
predictions on organizers have been independently confirmed: Organizers
such as blastopore and zone of polarizing activity have high electric
conductance, high current density72 and high density of gap
junctions.73, 74, 75, 76 Multi-cellular organisms maintain
regular form and function despite constant replacement of cells,
intra-cellular components and extracellular matrix. Without growth
control, this constant regeneration is prone to structural
disintegration and degeneration into various tumors. The growth control
model predicted that organizers and morphogens partially retain their
regulatory function after embryogenesis.18,61 This prediction
has also been independently confirmed: Morphogens such as retinoic acid,
Wnt, bone morphogenetic protein and Hedgehog as well as some organizers
continue to exist and function in adult after embryogenesis.77, 78,
79, 80, 81
Confirmed Predictions on Acupuncture
One corollary from the growth control
model is that acupuncture has extensive growth control effects which
have been confirmed: Acupuncture has been shown to regulate various
growth factors and growth control genes. It can induce vascular
endothelial growth factor82 and basic fibroblast growth
factor83 during brain ischemia. It also induces glial cell
line-derived neurotrophic factor84 and expression of the c-fos
proto-oncogene.85, 86 Acupuncture regulates the expression of
Bcl-2,87 Bax, fas and FasL proteins which are involved in
apoptosis signaling. Acupuncture inhibits the apoptosis of intestinal
epithelial cells in inflammatory bowel disease of rats88 and
enhances proliferation of CD8+ lymphocytes,89 reduces nerve
growth factor in polycystic ovaries,90, 91reduces IL-6
expression and proliferation of osteoclasts.92 The
neuro-humoral factors induced by acupuncture such as endorphins, nitric
oxide and serotonin also have growth-control effects.92, 98, 94
In RCTs, acupuncture has shown efficacy in treating growth control
related disorders including spinal cord injuries38 and low
sperm quality.95, 96
Growth Control System as Foundation of
A growth control system originates from a
network of organizers.97 In embryogenesis, the development of
organizers precedes the development of other physiological systems.18,64
The formation, maintenance and regulation of all the physiological
systems are dependent on the activity of the growth control system.
Growth control is a primary function of all multi-cellular organisms.
The evolutionary origin of the growth control system likely preceded all
the other physiological systems. Its genetic blueprint served as a
template from which the newer systems evolved. Consequently, it overlaps
and interacts with other systems but is not merely part of the nervous
system, immune system or circulatory system. The growth control signal
transduction is embedded in the activity of the function-based
physiological systems: The regulation of many neural, circulatory,
immune processes and related disorders are mediated through growth
control mechanisms such as hypertrophy, hyperplasia, atrophy, apoptosis
with shared messenger molecules including morphogens98, 99, 77,81
and common signal transduction pathways involving growth control genes
such as proto-oncogenes.100, 101, 102
The Nonspecific Stimulation and the
Long Term Effects of Acupuncture
Based on the growth control model,
acupuncture points and organizers are singular points and therefore
prone to nonspecific perturbation. The long lasting systemic effects of
acupuncture can be achieved by nonspecific stimuli as mentioned above.
Similarly, long lasting growth control activities of organizers have
been induced by various stimuli such as mechanical injury and injection
of nonspecific chemicals.67 Based on the growth control
model, acupuncture effect is a byproduct of the growth control network.
Stimulating organizers – acupuncture points can not only cause transient
modulation of neurotransmission, but also alter the growth control
signal transduction in various systems - leading to long term effects.18
The Distribution of Acupuncture Points
Organizers are at the extreme points of
curvature on the body surface such as the locally most convex points
(e.g., apical ectodermal ridge and other growth tips) or concave or
saddle points (e.g., zone of polarizing activity).103, 18
Similarly, almost all the extreme points of the body surface curvature
are acupuncture points. For example, the convex points include EX-UE11
Shixuan (finger tips), EX-LE12 Qiduan (toe tips), ST17 Ruzhong (tip of
nipple), ST42 Chongyang, (the convex, palpable point of arteria dorsalis
pedis), GV25 Suliao (nose tip) ... The concave points include TE3
Zhongzhu (the concave point between the 4th and 5th metacarpal), KI1
Yongquan (at the concave point of the sole), GB20 Fengchi (the concave
point below occipital bone, between upper ends of sternocleidomastoid
and trapezius), BL40 Weizhong (midpoint of the transverse crease of the
popliteal fossa), HT1 Jiquan (the most concave point of axilla), BL1
Jingming (at the concave point above medial canthus), CV8 Shenque
(navel)... Based on growth control model, the extreme points of surface
curvature are associated with organizers – acupuncture points. The
auricle obviously has the most convoluted surface morphology of the
human body. Therefore it has the highest density of extreme points of
surface curvature and is expected to have the highest density of
organizers - acupuncture points. Auricle exemplifies the interconnection
of growth control: Auricular morphology is a sentinel of malformation in
other organs. Auricular malformation has been observed in numerous
malformation syndromes. It is recommended in a standard textbook of
pediatrics that any auricular anomaly should initiate a search for
malformations in other parts of the body.104
The Origin of Meridians
The growth control model suggests that
the discontinuity or abrupt transition in growth control not only exists
at organizers but also along boundaries.18,61 The growth
control boundaries or folds between different structures are also called
separatrices in mathematics and often connect singular points -
organizers. The model predicted that growth control boundaries have high
electric conductance and high density of gap junctions – just as the
meridians in acupuncture which likely originate from growth control
boundaries. These predictions have been confirmed: As embryogenesis
progresses, high density gap junctions become restricted at discrete
boundaries, leading to the subdivision of the embryo into communication
compartment domains.105, 106 Increasing or decreasing the gap
junctions can cause various developmental defects107 such as
spina bifida.108 These high electric conductance boundaries
are likely major pathways of bioelectric currents. Organizers are known
to locate at boundaries between different structures.109 The
growth control model suggests that meridians originate from separatrices
– boundaries in growth control and form an undifferentiated,18,61
interconnected cellular network that regulates growth and physiology. In
consistence with the prediction of under-differentiation of the meridian
system and growth control system, it has been observed that the most
apical part of folds of embryo remain undifferentiated in morphogenesis,110
including organizers such as apical ectodermal ridge.111 As
predicted by the growth control model, singular point and separatrix
have important roles in morphogenesis.112, 113 Growth control
boundaries/separatrices are similar to organizers in controlling growth
and pattern formation with morphogen gradient.114 Many
acupuncture points are located at boundaries between different body
domains or muscles, coinciding with the connective tissue planes which
connect adjacent body domains or muscles.17, 37, 115
Current acupuncture research suggests a
convergence of the neurophysiology model, the connective tissue model
and the growth control model. The growth control model of acupuncture
set the first example of a biological model in integrative medicine with
significant prediction power across multiple disciplines. It is the
first theory in basic acupuncture research which has met the gold
standard in testing scientific theory. The following predictions of the
growth control model have been independently confirmed by research
results in both acupuncture and conventional biomedical sciences: 1.
Acupuncture has extensive growth control effects. 2. Singular point and
separatrix have important roles in morphogenesis. 3. Organizers have
high electric conductance, high current density and high density of gap
junctions. 4. A high density of gap junctions is distributed as
separatrices or boundaries at body surface after early embryogenesis. 5.
Many acupuncture points are located at transition points or boundaries
between different body domains or muscles, coinciding with the
connective tissue planes. 6. Some morphogens and organizers continue to
function after embryogenesis. The growth control model has also shed
light on several puzzling phenomena of acupuncture such as the
distribution of auricular acupuncture points, the long term effects of
acupuncture and the effect of multimodal nonspecific stimulation at
- The structure and cell
differentiation at acupuncture points as well as the neurophysiology
and growth control signal transduction involved in different
modalities of acupuncture should be further delineated.
- Manipulating the singular points -
organizers of the growth control system may be a convenient way of
activating intrinsic stem cells as evident from the improvement of
sperm quality after acupuncture.95, 96
- As the growth control model predicts
the growth control activity at acupuncture points/extreme points of
surface (or interface) curvature after embryogenesis, residual
morphogen gradient may still exist at these points and may be
detectable by probing morphogen candidates such as Hedgehog, Wnt and
TGF-beta families. Certain morphogen gradient distributes along
boundaries.116 This pattern may persist after
embryogenesis into adulthood and coincides with meridians.
- Mapping of the growth control system
and the dynamics of its electromagnetic field with high resolution
techniques such as the superconducting quantum interference device
(SQUID) and atomic magnetometer :117 The growth control
model predicts that the singular points and separatrices of the
bioelectric field in growth control correlate with the acupuncture
points and meridians respectively.
- The growth control model suggests
that techniques involving the stimulation of the growth control
system such as acupuncture can activate the growth control activity
of an organism and improve its structure and function at a more
fundamental level than symptomatic relief.18 In growth
control, the change in electric field precedes morphologic change
and manipulation of the electric field can affect the change.70,
118 Development of the techniques of detecting and
manipulating the electric field may enable the diagnosis and
treatment of a pathologic process at the early signal transduction
stage prior to the anatomical or morphological change.
- The growth control model suggests
that apparently unrelated acupuncture points are not exactly
‘placebo’ points. The more acupuncture points are used as placebo
points in a RCT, the more likely that some systemic effects will be
resulted from the ‘placebo’ treatment. The self-regulatory effect of
acupuncture will be difficult to predict when the patients have
multiple comorbidities and many acupuncture points are used. Subtle,
‘sham’ stimulation at acupuncture points can be effective due to the
response of the acupuncture points to nonspecific stimuli. These
reasons may contribute to the mixed results in RCTs on acupuncture.
This model also suggests that acupuncture is mostly likely to
demonstrate its efficacy and advantage in a patient population with
few comorbidities, relatively good general health and
Vitality and a
regimen with efficient use of acupoints.
- The growth control model suggests
that the distribution of growth control system is related to both
internal and external structures. Acupuncture points which are not
at obvious extreme points of surface curvature or meridians which
are not at obvious surface boundaries may be vestigial or related to
interface between internal structures such as muscles and bones.
Intrinsic stem cells are likely part of the undifferentiated growth
control network. The germ cell is one of the least differentiated
cells and also a type of stem cell – similar to the embryonic stem
cell in its ability to differentiate into all three germ layers. The
distribution pattern of intrinsic germ cells can be deduced based on
the fact that the distribution pattern of primary tumors reflects
the distribution of their normal counterpart. The primary germ cell
tumors119 have a midline and para-axial distribution
pattern which spans from the sacrococcygeal region to pineal gland.
It appears to concentrate at 7 locations: sacrococcygeal region,
gonads, retroperitoneum, thymus, thyroid,120 suprasellar
region, and pineal gland. This pattern reflects the distribution
pattern of intrinsic germ cells which are likely to be highly
inter-connected in a normal state (e.g. via gap junctions121
) and provide important regulatory functions.122, 56 This
also suggests a hierarchy in the degree of cell differentiation and
function in the growth control system.
I thank Steven K.H. Aung, Zang-Hee Cho,
Yuenan Cui, Li Dingzhong, Maria do Desterro Leiros, Michael Levin,
Vitaly Napadow, Richard Nuccitelli, Stig Ollmar, Rosa N. Schnyer, San
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Department of Medicine
New England Baptist Hospital
Harvard Medical School
125 Parker Hill Ave.
Boston, MA 02120