Tcm model of system biology

1

Master Programme of TCMICBAS – University of Oporto

Heidelberg School of Chinese Medicine

Henry Johannes Greten MD, PhD

[email protected]

TCM as a Model of System Biology

New evidence by double blinding?

2

I. Functional diagnosis of Chin. Medicine

describes biological systems by a

mathematical language Heidelberg

Model of TCM

II. Double-blinded studies in acupuncture are

now possible, augmenting the level of

evidenceIII.

III.Acupuncture is more efficient if based on

such functional diagnosis

Three points, one conclusion

system biology of CM is relevant

3

Present „schematic“

acupuncture – No proof of efficacy

• Latest meta–analysis of 33 studies on acupuncture: „no specific effect“ (Linde 2009)

• No double blinding, no functional diagnosis

•No rational definition of diagnostic criteria

4

Mathematics in TCM (binary numbering of the I Ging: Leibniz

1643)

structural deficiency vs.

regulatory deficiency

constitution

path. factor„organ

pattern“ orbs

„What is the patients „inner

nature“

„What affected the patient?“

„Which signs and symptoms appear now?“

4x2guiding criteria

„snapshot of the actual functional

state“

+ + +

repletio/depletio„fullness“/

„emptiness“

calor/ algor„heat“/„cold“

extima/intima„exterior“/„interior“

yin/ yang

?

neurovegetative signs

humoro-veget. signs

neuro-immunolog. stages

rep

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ep

leti

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ca

lor

alg

or

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or I II III IV V

VI

F

W

H

M

EF

W

H

M

EF

W

H

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EF

W

H

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Defining the diagnosis: systemic approach

5

6

7

Binary Numbers formed of Yin and Yang

De-mystifying TCM - the Heidelberg model

8

SummerS

Fire

WaterN

Winter

W A

utumnS

prin

g E

Wo

od Metal

De-mystifying TCM - the Heidelberg model

9

10

SummerS

Heaven

EarthN

Winter

W A

utumnS

prin

g E

Hill

Lake

Thund

er

Wind

Fire

Water

11

Defining the Diagnosis: Periodicity of Regulation

37°C time

38°C

36°C

thermostatelectric heater

water basin

35°C

39°C

12

yin (depletion)

yang (repletion)

timeWATERMETALFIREWOOD

EARTH1

EARTH 3

EARTH 2

13

time

yin (depletion)

yang (repletion)

WATERMETALFIREWOOD

EARTH1

EARTH 3

EARTH 2

14

Hyper-dynamic

sympathetic parasympathetic

Cortisol

Adrenaline

Endorphines

enteric NS active

Hyper-tone

T3, T4

Hypo-tone

Hypo-dynamic

enteric NS inactive

enteric NS inactive

37°Ctime

38°C

36°C

Wood Metal WaterFire

15

Clinical manifestations of wood high content of energy,

upward movement

postulated transmitters, hormones/ metabolism:Sympathetic N.S., adrenaline, glycogenolysis, glucose, ACTHira, power of descision,

„the general“;stress-, fight-, territorial-, hierarchy and conflict-programms (limbic system)

sensory organ and body opening: eye;

sympathetic signs (tarsal- orbitalmuscles), tendency to high intra-occular pressure, mydriasis

voice character: shouting;tends to inspiratory posture, tongue and larynx go down and open with inspiration. „support“

„ascendant yang“

sensation of extended liver

splanchnic nerves (sympathetic n.s.) stimulate

the liver, contracting livercapsule, rising

pressure of the liver veins, leucozytosis,

glycogenolysis„hepatic orb rises upward and outward“;contraction of the physiological extensors, extension of the thorax with an inspiratory tendency

fist-clenching; flexor muscles of the arm are

„physiological extensor muscles“

perfection: nervusincreased neuromuscular excitability, hypertone patterns of movement

„flos“= blossom: nails;impaired microcirculation

(TCM: a „rough flow“ of qi and xue) leads to dystrophy

rising (blood) pressu

re

increasing heart rateswollen chest

Copyright Greten 2003

16

FIREWOOD

repletion

YANG YIN

time

depletion

WATERMETAL

HE

PA

TIC

TE

NU

INT

ES

TIN

AL

(“small

inte

stine”)

FE

LL

EA

L

CA

RD

IAL

PE

RIC

AR

DIA

L

TR

I-CA

LO

RIA

L

(triple

”bu

rner”)

PU

LM

ON

AR

Y

CR

AS

SIN

TE

ST

INA

L

RE

NA

L

VE

SIC

AL

PRINCIPAL

PROBLEM

OF

REGULATION

ORB

distrib

utio

n o

f flu

ids in

b

ack

an

d lo

wer b

urn

er

re - g

en

era

tion

bre

ath

, surfa

ce,

rhyth

m

surfa

ce o

f gu

ts, co

nd

uctio

n o

f n

ou

rishm

en

t

con

trol o

f “positive

d

rive”

shou

lder-, e

ar-a

che,

“em

otio

nal a

bd

om

en

”

distrib

utio

n o

f qi/fl

uid

s on

sides a

nd

bu

rners

con

trol o

f excita

tion

an

d fl

ow

, “stress”

sup

pre

ssed

imp

ulse

, am

biva

len

ce

con

trol o

f em

otio

nality

an

d a

ssocia

tivity

17

Earth: the principle of regulation 1) downregulation2) target value3) upregulation

time

yin (depletion)

yang (repletion)

“STOMACH”

“SPLEEN”

1

2

3

© Greten 2003

De-mystifying TCM - the Heidelberg model

18

Clinical manifestations of Earth

time

yin (depletion)

yang (repletion)

“STOMACH”

“SPLEEN”

1

2

3

Yin, tends towards depletionintimahorreal orb, transforms, brings the „clear“ upwards,disease like „postprandiale syndrome“clears humor, pituitasymbolizes metabolism „rises“„holds“ the flesh

Yang, tends towards repletionextimaaulic orbstores, transportsbrings the „turbid“ downwardsneeds to be moisturized---- symbolizes digestion„sedates“---

© Greten 2003

De-mystifying TCM - the Heidelberg model

19

Non-linear Aspects of Chinese

MedicineMathematics in TCM (binary numbering of the I Ging: Leibniz 1643)

constitution

path. factor„organ

pattern“ orbs

„What is the patients „inner

nature“

„What affected the patient?“

„Which signs and symptoms appear now?“

4x2guiding criteria

„snapshot of the actual functional

state“

+ + +

repletio/depletio„fullness“/

„emptiness“

calor/ algor„heat“/„cold“

extima/intima„exterior“/„interior“

yin/ yang

?

neurovegetative signs

humoro-veget. signs

neuro-immunolog. stages structural deficiency vs.

regulatory deficiency

rep

leti

od

ep

leti

o

ca

lor

alg

or

rep

leti

od

ep

leti

o

ca

lor

alg

or I II III IV V

VI

F

W

H

M

EF

W

H

M

EF

W

H

M

EF

W

H

M

E

20

thermostatelectric heater

37°Ctime

38°C

36°C

water basin

35°C

39°C

Weak yin – the effect of a decrease of water in the basin

Copyright Dr. Johannes Greten 2003HSCM, *49-6221-374546, fax 302035

Local: worse on pressure

MICROCIRCULATION INCREASED

Red tongue

Warm sensatio

n

Pre-inflammatory

state

Relative lack of fluids in

larger vessels

Systemic: changing

pain-location

Heart rate increases

Dry mouth, nose and

lung

Sparse, concentrated urine

Water saving

Dry, constipated stool

Pathophysiology of calor („heat“)

22

Mathematics in TCM (binary numbering of the I Ging: Leibniz

1643)

structural deficiency vs.

regulatory deficiency

constitution

path. factor„organ

pattern“ orbs

„What is the patients „inner

nature“

„What affected the patient?“

„Which signs and symptoms appear now?“

4x2guiding criteria

„snapshot of the actual functional

state“

+ + +

repletio/depletio„fullness“/

„emptiness“

calor/ algor„heat“/„cold“

extima/intima„exterior“/„interior“

yin/ yang

?

neurovegetative signs

humoro-veget. signs

neuro-immunolog. stages

rep

leti

od

ep

leti

o

ca

lor

alg

or

rep

leti

od

ep

leti

o

ca

lor

alg

or I II III IV V

VI

F

W

H

M

EF

W

H

M

EF

W

H

M

EF

W

H

M

E

Defining the diagnosis: systemic approach

23

Relevance of Classical Diagnosis

1. Is acupuncture more effective using the classical diagnosis ?

2. Can we perform double-blinding in acupuncture ?

24

Step 1

Diagnostic

TCM Diagnosis

Marking Points A, B, C

Step 1

Diagnostic

TCM Diagnosis

Marking Points A, B, C

Step 2

Therapist

Usage of points

Randomised order, ABC,

BAC, CAB

Step 2

Therapist

Usage of points

Randomised order, ABC,

BAC, CAB

Double-Blinding Acupuncture

Step 3

examiner

Step 3

examiner

blinding of patient

blinding of therapist

blinding of examiner

25

Objective Pain Evaluation (Flexion)

110

112

114

116

118

120

122

124

126

128

130

beforetreatment

immediatelyaftertreatment

7-days

Classical Ac, HM

Schematic Ac

Control Ac-

Kn

ee fl

exi

on,

deg

rees

0

26

Chin. Medicine-Based Acupuncture Superior to „Schematic“ Acupuncture

• Gonarthrosis pain + mobility: 2x better, n>100

• Pain after tonsillectomy: HM beats standard by

3xSertel et al., Archives of Otorhinolaryngology, in 2009

• Congestion of the nose: classical points beat

unsp. points Sertel et al. , American Journal of Rhinology, 2009

• Gait improvement in the elderly : classical

point significantly effective, sham acu no effect

27

Chin. Medicine-based Acupuncture superior to „schematic“ acupuncture

• Sternotomy induced pain: 78 % vs. 16,3% pain reduction (p< 0,001

lung function (IVC): + 360 ml vs. + 33ml (N=100, p <0,001) (Kick A et al.

2006)

• Walking distance in pAOD : 86,5 % vs. 40% (N= 34, p< 0,001) (Buhlmann E et al. AMSTCAR, Shanghai 2006)

• Capillary bloodflow (O2) in pAOD: 2-6 fold enhancement,

Effects reversible by „counter acupuncture“ (Greten J, Krug A, Kick A, Remppis A,

Diehm C, in preparation )

• Polyneuropathy: 76% of the patients show enhanced nerve

conductivitySchröder S et. al. European Journal of Neurology)

• Congestive Heart failure: HM better than standard points

Journal of Acupunture and Tuina Sciences, 2008

• Pharmacotherapy:

– Inhibition of macrophages by coptis through NFkB blockade comparable to Western pharmacology

– CaCo (Cancer-of-Colon) cells: inhibition of NFkB by coptis and scrophularia

– Curcumin: apoptotic effect in neuroblastoma cells– Scrophularia: inhibition of proinflammatory NFkB– C. elegans model: anti-oxidant effect of Chinese

herbs– Hesperitine („orange juice“): HERG blockade– EGCG (green tee) electrophysiologically active

Application in pharmacology

29

I. functional diagnosis of Chin. Medicine

describes biological systems by a

mathematical language Heidelberg

Model of TCM

II. Double-blinded studies in acupuncture are

now possible, augmenting the level of

evidenceIII.

III.Acupuncture is more efficient if based on

such functional diagnosis

Three points, one conclusion

system biology of CM is relevant

30

Subjective Pain Evaluation (WOMAC)

treatment after treatment

0

8

9

10

11

12

13

14

15

16

17

18

19

before immediately 3-days 7-days

Classical Ac (HM)

Schematic Ac

Control Ac-

WO

MA

C p

ain

scor

e

31

12 studies showing specific effects

• Cho ZH, Chung SC, Jones JP, Park JB, Park HJ, Lee HJ, Wong EK, Min BINew findings of the correlation between acupoints and corresponding brain cortices using functional MRIProc Natl Acad Sci U S A. 1998 Mar 3;95(5):2670-3.

• Ernst M, Lee MHSympathetic effects of manual and electrical acupuncture of the Tsusanli knee point: comparison with the Hoku hand point sympathetic effects. Exp Neurol. 1986 Oct;94(1):1-10.

• Huang ST, Chen GY, Lo HM, Lin JG, Lee YS, Kuo CDIncrease in the vagal modulation by acupuncture at neiguan point in the healthy subjects. Am J Chin Med. 2005;33(1):157-64.

• Kim MR, Kim SJ, Lyu YS, Kim SH, Lee YK, Kim TH, Shim I, Zhao R, Golden GT, Yang CHEffect of acupuncture on behavioral hyperactivity and dopamine release in the nucleus accumbens in rats sensitized to morphine. Neurosci Lett. 2005 Oct 14;387(1):17-21.

• Kim YK, Lim HH, Song YK, Lee HH, Lim S, Han SM, Kim CJEffect of acupuncture on 6-hydroxydopamine-induced nigrostratal dopaminergic neuronal cell death in rats. Neurosci Lett. 2005 Aug 12-19;384(1-2):133-8.Lee DC, Lee MO, Clifford DHCardiovascular effects of acupuncture in anesthetized dogs. Am J Chin Med (Gard City N Y). 1974 Jul;2(3):271-82.

• Lee DC, Lee MO, Clifford DHModification of cardiovascular function in dogs by acupuncture: a review. Am J Chin Med (Gard City N Y). 1976 WINTER;4(4):333-46.

• Lee JH, Beitz AJ The distribution of brain-stem and spinal cord nuclei associated with different frequencies of electroacupuncture analgesia. Pain. 1993 Jan;52(1):11-28.

• Lee MY, Lee DC, Kim S, Clifford DHCardiovascular effects of acupuncture at Tsu San Li (St-36) in dogs. J Surg Res. 1975 Jan;18(1):51-63

• Lee SC, Yin SJ, Lee ML, Tsai WJ, Sim CBEffects of acupuncture on serum cortisol level and dopamine beta-hydroxylase activity in normal Chinese. Am J Chin Med. 1982;10(1-4):62-9.

• Litscher G Computer-based quantification of traditional chinese-, ear- and Korean handacupuncture: needle-induced changes of regional cerebral blood flow velocity. Neurol Res. 2002 Jun;24(4):377-80.

• Park HJ, Lim S, Lee HS, Lee HJ, Yoo YM, Lee HJ, Kim SA, Yin CS, Seo JC, Chung JHAcupuncture enhances cell proliferation in dentate gyrus of maternally-separated rats. Neurosci Lett. 2002 Feb 22;319(3):153-6.

• Park HJ, Chae Y, Jang J, Shim I, Lee H, Lim SThe effect of acupuncture on anxiety and neuropeptide Y expression in the basolateral amygdala of maternally separated rats. Neurosci Lett. 2005 Apr 4;377(3):179-84. Epub 2005 Jan 6.Toda K, Ichioka, MElectroacupuncture: relations between forelimb afferent impulses and suppression of jaw-opening reflex in the rat. Exp Neurol. 1978 Sep 1;61(2):465-70. Toda K, Ichioka M, Suda H, Iriki A Effects of electroacupuncture on the somatosensory evoked response in rat. Exp Neurol. 1979 Mar;63(3):652-8. Toda K, Ichioka M, Iriki A, Suda H Electroacupuncture effects on the field potentials in the caudal part of the spinal trigeminal nucleus evoked by tooth pulp stimulation in rat. Exp Neurol. 1979 Jun;64(3):704-9. Toda K, Ichioka MAfferent nerve information underlying the effects of electroacupuncture in rat. Exp Neurol. 1979 Aug;65(2):457-61.Toda K, Ichioka M, Iriki A Effective conditions of electroacupuncture stimulation for suppressing toothpulp-evoked jaw-opening reflex in the rat. Bull Tokyo Med Dent Univ. 1980 Jun;27(2):111-9. Toda K, Suda H, Ichioka M, Iriki ALocal electrical stimulation: effective needling points for suppressing jaw opening reflex in rat.Pain. 1980 Oct;9(2):199-207.