The Jing-Mai System

in Vertebrate Development and Evolution

Rainer Machne

Bled, February 2004

Institute for Theoretical Chemistry and Structural Biology

Institute of Microbiology and Genetics

University of Vienna

not:

Outline

• The Multiscale Complexity of Biological Signaling Networks

• Developmental Models: Morphogenes and Gene Regulatory Networks

• The Jing-Mai System and Neurocristophathies

• Vertebrate Innovations: Neural Crest and Hyaluronan

Outline

• Jing-Mai Hypotheses

• The Biochemistry of Yin and Yang

• Fractal Rythms

• TCM: a translation problem

Biological Signaling Networks

proliferation vs. differentiation, migration vs. adhesion

putting together the pieces, beginning to unravel the net

Hanahan and Weinberg 2000

A migrating cell

cells are gels, not aqueous bags

Li 2002, Pollack 2003

SBML - exchanging and merging models

0.05 0.1 0.15 0.2 0.25 0.3time [s]

1

2

3

4

5

6

Con

cent

ratio

n

GLCiATPG6PADPF6PF16bPAMPDHAPGAPNADBPGNADHP3GP2GPEPPYRAcAldGLCoF26bPCO2EtOHGlycerolGlycogenTrehaloseSuccinatecompartment

Yeast Glycolysis

-10 0 10 20 30 40 50 60 70 80 90time

-20

-15

-10

-5

0

5

10

15

20

25

30

35

40

45

50xyzEmptySetatmosphere

Lorenz EN (1963) Deterministic nonperiodic flow. Journal of the Atmospheric Sciences

0 100time [h]

0

1

2

3

4

5

6

7

8

Con

cent

ratio

n

Circadian rythms, birythmic

0 10 20 30 40 50 60 70 80 90 100time [min]

0

0.2

0.4

Con

cent

ratio

n

Cell Cycle

www.sbml.org

Metabolic Network of Chlamydia trachomatis

ATPSYN__45__RXN

PROTON_periplasm Pi

ADP

PROTON

SUPEROX__45__DISMUT__45__RXN

2

DIHYDROPICRED__45__RXN

ACETYL__45__COA__45__CARBOXYLTRANSFER__45__RXN

CARBPSYN__45__RXN

WATER

ACONITATEHYDR__45__RXN

ADDALT__45__RXN

GDPMANMANHYDRO__45__RXN

LIPIDXSYNTHESIS__45__RXN

UGD__45__RXN

IMP__45__DEHYDROG__45__RXN

LEUCINE__45__DEHYDROGENASE__45__RXN

GMP__45__SYN__45__GLUT__45__RXN

FGAMSYN__45__RXN

CTPSYN__45__RXN

TETHYDPICSUCC__45__RXN

PEPSYNTH__45__RXN

PRPPAMIDOTRANS__45__RXN

PEPCARBOX__45__RXN

CITSYN__45__RXN

OHMETHYLBILANESYN__45__RXN

_6PGLUCONOLACT__45__RXN

PALMITOYL__45__COA__45__HYDROLASE__45__RXNPSERPHOSPHA__45__RXNF16BDEPHOS__45__RXN

GLUCOSE__45__1__45__PHOSPHAT__45__RXN

GPH__45__RXN

SUCCDIAMINOPIMDESUCC__45__RXN

ASPARAGHYD__45__RXN

FORMYLMETHIONINE__45__DEFORMYLASE__45__RXN

FORMYLTHFDEFORMYL__45__RXN

DIHYDROOROT__45__RXN

METHENYLTHFCYCLOHYDRO__45__RXN

ADENODEAMIN__45__RXN

IMPCYCLOHYDROLASE__45__RXN

CYTDEAM__45__RXN

GTP__45__CYCLOHYDRO__45__II__45__RXN

3

CYTIDEAM__45__RXNCYTIDEAM2__45__RXNDCTP__45__DEAM__45__RXN

AMP__45__NUCLEOSID__45__RXN

INORGPYROPHOSPHAT__45__RXN

DUTP__45__PYROP__45__RXN

ATP

DARABKIN__45__RXN

SUCCCOASYN__45__RXN

2

GMP__45__SYN__45__NH3__45__RXN

GLYRIBONUCSYN__45__RXN

FORMATETHFLIG__45__RXN

DALADALALIG__45__RXN

DIHYDROFOLATESYNTH__45__RXN

UDP__45__NACMURALA__45__GLU__45__LIG__45__RXN

UDP__45__NACMUR__45__ALA__45__LIG__45__RXN

SAICARSYN__45__RXN DETHIOBIOTIN__45__SYN__45__RXN

AIRS__45__RXN

_6PFRUCTPHOS__45__RXN

SHIKIMATE__45__KINASE__45__RXND__45__RIBULOKIN__45__RXN

RIBOKIN__45__RXN

GALACTOKIN__45__RXN

RIBOFLAVINKIN__45__RXN

GLUCONOKIN__45__RXN

PEPDEPHOS__45__RXN

GLYCEROL__45__KIN__45__RXN

MANNKIN__45__RXN

INOSINEKIN__45__RXN

PHOSGLYPHOS__45__RXN

ACETATEKIN__45__RXN

ASPARTATEKIN__45__RXN

GLUC1PADENYLTRANS__45__RXN

FADSYN__45__RXN

ARGININE__45__KINASE__45__RXN

H2PTERIDINEPYROPHOSPHOKIN__45__RXN

UMPKI__45__RXN

ADENYL__45__KIN__45__RXN

UDPKIN__45__RXN

CDPKIN__45__RXN

CMPKI__45__RXN

GUANYL__45__KIN__45__RXN

DADPKIN__45__RXN

GDPKIN__45__RXN

DCDPKIN__45__RXN

DUDPKIN__45__RXN

DGDPKIN__45__RXN

DTMPKI__45__RXN

DTDPKIN__45__RXN

GARTRANSFORMYL2__45__RXN

PEPCARBOXYKIN__45__RXN

URA__45__PHOSPH__45__RXN

ADENPHOSPHOR__45__RXN

INOPHOSPHOR__45__RXN

GAPOXNPHOSPHN__45__RXN

ASPARTATE__45__SEMIALDEHYDE__45__DEHYDROGENASE__45__RXN

PHOSACETYLTRANS__45__RXN

URPHOS__45__RXN

THYM__45__PHOSPH__45__RXN

DAHPSYN__45__RXN

DEOXY__45__RIBOSE__45__1P

URACIL

DEOXYURIDINE

DEOXYADENPHOSPHOR__45__RXN

DEOXYINOPHOSPHOR__45__RXN

D__45__PPENTOMUT__45__RXN

PSEUDOURIDYLATE__45__SYNTHASE__45__RXN

_2OXOGLUTARATEDEH__45__RXN

SUC__45__COA

CARBON__45__DIOXIDE

NADH

_2__45__KETOGLUTARATE

SUCCINYLDIAMINOPIMTRANS__45__RXN

ASPAMINOTRANS__45__RXN

CO__45__A

PYRUVDEH__45__RXN

ACETALD__45__DEHYDROG__45__RXN MALSYN__45__RXN

NAD

GCVMULTI__45__RXN

2

DLACTDEHYDROGNAD__45__RXN MALIC__45__NAD__45__RXNMALATE__45__DEH__45__RXNGLYCDEH__45__RXNMETHYLENETHFREDUCT__45__RXN

FORMATEDEHYDROG__45__RXN

ALCOHOL__45__DEHYDROG__45__RXN

_2TRANSKETO__45__RXN

FRUCTOSE__45__6P

GAP

ERYTHROSE__45__4P

XYLULOSE__45__5__45__PHOSPHATE

_1TRANSKETO__45__RXN

L__45__GLN__45__FRUCT__45__6__45__P__45__AMINOTRANS__45__RXN

_2__46__7__46__1__46__90__45__RXN

TRANSALDOL__45__RXN

TRIOSEPISOMERIZATION__45__RXN

threo__45__d__40__s__41____45__iso__45__citrate

CIS__45__ACONITATE

ISOCITDEH__45__RXN

ISOCIT__45__CLEAV__45__RXN

AMMONIA

DEOXYINOSINE

DEOXYADENOSINE

RIBOSE__45__1P

ADENINE

ADENOSINE

PPENTOMUT__45__RXN

ETOH

ACETALD

CYTIDINEKIN__45__RXN

CMP

GDP

CYTIDINE

GTP

ADENYLOSUCCINATE__45__SYNTHASE__45__RXN URKI__45__RXN

MANNPGUANYLTRANGDP__45__RXN

DARABALDOL__45__RXN

GLYCOLALDEHYDE DIHYDROXY__45__ACETONE__45__PHOSPHATE

D__45__RIBULOSE__45__1__45__P

RIBULOSE

HYPOXANTHINE

HYPXPRIBOSYLTRAN__45__RXN

DIOHBUTANONEPSYN__45__RXN

DIHYDROXY__45__BUTANONE__45__P FORMATE

RIBULOSE__45__5P

RIBULP3EPIM__45__RXN

PYRUVFORMLY__45__RXN

ACETYL__45__COA

PYRUVATE

DIHYDRODIPICSYN__45__RXN

GLUCOSAMINE1PACETYL__45__RXN

METHYLENE__45__THF

GLY

THF

DIHYDROFOLATEREDUCT__45__RXNGLYOHMETRANS__45__RXN

METHYLENETHFDEHYDROG__45__NADP__45__RXNTHYMIDYLATESYN__45__RXN

PHOSGLUCOSAMINEMUT__45__RXN

GLUCOSAMINE__45__1P

D__45__GLUCOSAMINE__45__6__45__P

MANNOSE

GDP__45__MANNOSE

GDPMANDEHYDRA__45__RXN

N__45__ACETYL__45__D__45__GLUCOSAMINE__45__1__45__P

NAG1P__45__URIDYLTRANS__45__RXN

PPI

IMP

PRPP

PRTRANS__45__RXN

ADENPRIBOSYLTRAN__45__RXN

URACIL__45__PRIBOSYLTRANS__45__RXN

OROPRIBTRANS__45__RXN

BISOHMYR__45__GLUCOSAMINYL__45__1P

UMP

OH__45__MYRISTOYL

INOSINE

GLUCDEHYDROG__45__RXN

GLC__45__D__45__LACTONE

NADPH

GLC

GLUCISOM__45__RXN

NADP

UDPNACETYLMURAMATEDEHYDROG__45__RXN_6PGLUCONDEHYDROG__45__RXN SHIKIMATE__45__5__45__DEHYDROGENASE__45__RXNMALIC__45__NADP__45__RXN

GLU6PDEHYDROG__45__RXN

HOMOSERDEHYDROG__45__RXN

GLYC3PDEHYDROG__45__RXN

FADH2

FAD

SUCC__45__FUM__45__OXRED__45__RXN

GLYCEROL__45__3P

2

UDP__45__GLUCURONATE

UDP__45__GLUCOSE

GALACTURIDYLYLTRANS__45__RXN UDPGLUCEPIM__45__RXN

UDP__45__ACETYL__45__CARBOXYVINYL__45__GLUCOSAMINE

UDP__45__N__45__ACETYLMURAMATE

_6__45__P__45__GLUCONATE

_3__45__DEHYDRO__45__SHIKIMATE

SHIKIMATE

D__45__LACTATE

MAL

FUMHYDR__45__RXN

D__45__6__45__P__45__GLUCONO__45__DELTA__45__LACTONE

GLC__45__6__45__P

PGLUCISOM__45__RXN

OXALACETIC_ACID

OXALODECARB__45__RXN

DIHYDROXYACETONE

GLYCEROL

L__45__ASPARTATE__45__SEMIALDEHYDE

HOMO__45__SER

XANTHOSINE__45__5__45__PHOSPHATE

CATAL__45__RXN

2

OXYGEN__45__MOLECULE

HYDROGEN__45__PEROXIDE

2

PROTOPORGENOXI__45__RXN

COPROGENOXI__45__RXNDIHYDROOROTOX__45__RXN

_5__45__METHYL__45__THF

HOMOCYSMETB12__45__RXN

SUPER__45__OXIDE

2

_5__44__10__45__methenyl__45__thf

DIHYDROFOLATE

_2K__45__4CH3__45__PENTANOATE

LEU

FUM

SUC

DELTA__123__1__125____45__PIPERIDEINE__45__2__45__6__45__DICARBOXYLATE

_2__44__3__45__dihydrodipicolinate

2

PROTOPORPHYRIN_IX

PROTOPORPHYRINOGEN

2

2

COPROPORPHYRINOGEN_III

OROTATE

DI__45__H__45__OROTATE

DPG

L__45__BETA__45__ASPARTYL__45__P

MALONYL__45__COA

HCO3

GLT

GMP

AMP

GLN

PABASYN__45__RXN

ANTHRANSYN__45__RXN

GLUTRACE__45__RXN

2

CARBAMOYL__45__P

ASPCARBTRANS__45__RXN

_5__45__PHOSPHORIBOSYL__45__N__45__FORMYLGLYCINEAMIDINE

_5__45__P__45__RIBOSYL__45__N__45__FORMYLGLYCINEAMIDE

ADENYLOSUCC

L__45__ASPARTATE

ASPARTASE__45__RXN

AMPSYN__45__RXN

_5__45__PHOSPHO__45__RIBOSYL__45__GLYCINEAMIDE

PRA

GART__45__RXN

_10__45__FORMYL__45__THF

AICARTRANSFORM__45__RXN

CTP

UTP

GLUC1PURIDYLTRANS__45__RXN

D__45__ALA__45__D__45__ALA

D__45__ALANINE

_7__44__8__45__dihydropteroate

UDP__45__AA__45__GLUTAMATE

D__45__GLT

UDP__45__ACETYLMURAMOYL__45__ALA

L__45__ALPHA__45__ALANINE

_7KAPSYN__45__RXN

P__45__RIBOSYL__45__4__45__SUCCCARB__45__AMINOIMIDAZOLE

PHOSPHORIBOSYL__45__CARBOXY__45__AMINOIMIDAZOLE

AICARSYN__45__RXN

DETHIOBIOTIN

DIAMINONONANOATE

_5__45__PHOSPHORIBOSYL__45__5__45__AMINOIMIDAZOLE

D__45__SEDOHEPTULOSE__45__7__45__P

RIBOSE__45__5P

RIB5PISOM__45__RXN

N__45__SUCCINYL__45__2__45__AMINO__45__6__45__KETOPIMELATE

_8__45__AMINO__45__7__45__OXONONANOATE

_6__45__CARBOXYHEXANOYL__45__COA

DAPASYN__45__RXN

ACETYL__45__P

n__45__succinylll__45__2__44__6__45__diaminopimelate

S__45__ADENOSYL__45__4__45__METHYLTHIO__45__2__45__OXOBUTANOATE

S__45__ADENOSYLMETHIONINE

PHOSPHO__45__ENOL__45__PYRUVATE

UDPNACETYLGLUCOSAMENOLPYRTRANS__45__RXN

_2__46__5__46__1__46__19__45__RXN

URIDINE

FRUCTOSE__45__16__45__DIPHOSPHATE

F16ALDOLASE__45__RXN

SHIKIMATE__45__5P

RIBOSE

GALACTOSE__45__1P

GALACTOSE

FMN

RIBOFLAVIN

GLUCONATE

MANNOSE__45__6P

MANNPISOM__45__RXN

G3P

_3PGAREARR__45__RXN

ACET

UDP__45__N__45__ACETYL__45__D__45__GLUCOSAMINE

MANNOSE__45__1P

PHOSMANMUT__45__RXN

GLC__45__1__45__P

PHOSPHOGLUCMUT__45__RXN

ADP__45__D__45__GLUCOSE

UDP__45__GLACTOSE

CPD__45__493

ARG

DIHYDROPTERIN__45__CH2OH__45__PP

AMINO__45__OH__45__HYDROXYMETHYL__45__DIHYDROPTERIDINE

H2PTEROATESYNTH__45__RXN

UDPCDP

DATP

DADP

DCTP

DCDP

DUTP

DUDP

DGTP

DGDP

TDP

TMP

TTP

_3__45__ENOLPYRUVYL__45__SHIKIMATE__45__5P

CHORISMATE__45__SYNTHASE__45__RXN

RIBOFLAVIN__45__SYN__45__RXN

RIBITYLAMINO__45__AMINO__45__DIHYDROXY__45__PYR

DIMETHYL__45__D__45__RIBITYL__45__LUMAZINE

2

P__45__AMINO__45__BENZOATE

PHOSPHORIBOSYL__45__FORMAMIDO__45__CARBOXAMIDE

AICAR

SER

TRYPSYN__45__RXN

CARBAMYUL__45__L__45__ASPARTATE

DUMP

MET

HOMO__45__CYS OROTIDINE__45__5__45__PHOSPHATE

OROTPDECARB__45__RXN

THYMINE

THYMIDINE

N__45____40__5__45__PHOSPHORIBOSYL__41____45__ANTHRANILATE

ANTHRANILATE

PRAISOM__45__RXN

DIAMINOPIMEPIM__45__RXN

MESO__45__DIAMINOPIMELATE

LL__45__DIAMINOPIMELATE

DIAMINOPIMDECARB__45__RXN

GSAAMINOTRANS__45__RXN

_5__45__AMINO__45__LEVULINATE

GLUTAMATE__45__1__45__SEMIALDEHYDE

PORPHOBILSYNTH__45__RXN

2

_2__45__PG

_2PGADEHYDRAT__45__RXN

DEOXY__45__RIBOSE__45__5P

DEOXYRIBOSE__45__P__45__ALD__45__RXN

DARABISOM__45__RXN

D__45__ARABINOSE

FRU

CARBOXYPHENYLAMINO__45__DEOXYRIBULOSE__45__P

IGPSYN__45__RXN

ADCLY__45__RXN

_4__45__AMINO__45__4__45__DEOXYCHORISMATE

UROGENDECARBOX__45__RXN

4

UROPORPHYRINOGEN__45__III

LYS

LYSDECARBOX__45__RXN

INDOLE__45__3__45__GLYCEROL__45__P

CADAVERINE

CHORISMATE

GLYOX

CIT

ACONITATEDEHYDR__45__RXN

_3__45__DEOXY__45__D__45__ARABINO__45__HEPTULOSONATE__45__7__45__P

_3__45__DEHYDROQUINATE__45__SYNTHASE__45__RXN

H2NEOPTERINALDOL__45__RXN

DIHYDRO__45__NEO__45__PTERIN

UROGENIIISYN__45__RXN

HYDROXYMETHYLBILANE

TRP

_3__45__DEHYDROQUINATE__45__DEHYDRATASE__45__RXN

DEHYDROQUINATE

PSEUDOURIDINE__45__5__45__P

2

PORPHOBILINOGEN

4

GDP__45__4__45__DEHYDRO__45__6__45__DEOXY__45__D__45__MANNOSE

2

4

PALMITATE

PALMITYL__45__COA_3__45__P__45__SERINE

GLYCOLLATE

CPD__45__67ASN

N__45__FORMYLMETHIONINE

CYTOSINE

DIAMINO__45__OH__45__PHOSPHORIBOSYLAMINO__45__PYR

DEOXYCYTIDINE

2

metabolic networks: long known and well understood

Krieger 2004

Emergent Properties of BSN

MAPK_p

H10

H11

A5

MAPK_pp

H12

H2

E8

MAPK

H9

MAPKK_pp

MKP1

MAPKK

H5

MAPKK_p

H6

H7

H8

GTP_Ras_Raf_p

PP2A

Raf

H1

Raf_p

H3

H13

Raf_pp

H4

PKC_a

GTP_Ras

B4

B6

GDP_Ras

B7 B8 B9 A6

SHC_a

A4 A9

SHC

A7

SOS

A2

SOS_p

A3A10

GEF

B10 B11B12 B13

GEF_p

B2

GEF_ip

B1

GAP

B5

GAP_p

B3

PDE1

C13

C18

PDE

C12

C16

PDE_p

C15C17

AC2

C4 C8

AC2_p

C7 C10

C11

Ga_GDP

D10

Ga_GTP

D6

Gs_alpha

PIP2_PLA2

E12

Ca_PLA2

E5 E6

E13

DAG_Ca_PLA2

E10

PLA2_p

E2E7

Ca_PLA2_p

E9

PLA2_cyto

E3

E4

PIP2_Ca_PLA2

E11

PLCg

F1

PLCg_p

F2

Ca_PLCg

F4

F5

Ca_PLCg_p

F3F6

PLC

G1 G2

Gq_PLC

G5

Ca_PLC

G3

G8

Ca_Gq_PLC

G4 G9

Gq

G_GDP

CaMKII

I1

I6

CaMKII_ip

I5

CaMKII_T286p

I2

I7

I10 I12

I13

I14 I15

CaMKII_pp

I3

I8

PKC_i

K1

K3

K5

K7

Ca_PKC

K2

K4

K10

DAG_PKC

K6

AA_DAG_PKC

K8

DAG_Ca_PKC

K9

M5

M10

IP3R

L1

IP3R_a

L7

Ca_transp

L2

Ca2_Ca_transp

L3

Cap_channel

L6

Cap_channel_a

L5

CaM

M1

M4

Ca2_CaM

M2 N5

Ca3_CaM

M3 N4

Ca4_CaM

N3

C6

Ng

Ng_p

M6

M7

M8

M9

PP2B

N1

Ca2_PP2B

N2

Ca4_PP2B

O8

Il

O4

Il_p

O1

O5

O6

O7

O9

PP1

I4

PP1_a

EGF_EGFR

A8

EGF_EGFR_internal

SOS_GBR2

SHC_a_SOS_GRB2

SOS_p_GRB2

Gbg_GEFCaM_GEF

Gs_AC2

C9

Gs_AC2_p

C3

Gs_AC1u8

C1

Ca4_CaM_AC1u8

C2

Ca4_CaM_PDE1

C14

Glu_R

D9

Gabg_Glu_R_GTP

D8

Gbg

Gabg

D3D5

Gabg_R

D2

Gabg_Glu_R

D7

CaM_CaMKII

I9

I11

CaM_CaMKII_T286p

R2C2

J1

cAMP_R2C2

J2

cAMP2_R2C2

J3

cAMP3_R2C2

J4

cAMP4_R2C2

J5

cAMP4_R2C

J6

cAMP4_R2

PKA_inhib_PKA

Ng_CaM

Ca4_CaM_Ca4_PP2B

O12

Ca3_CaM_Ca4_PP2B

O11

Ca2_CaM_Ca4_PP2B

O10

Il_p_PP1

O2

Il_PP1

O3

Ca

L4

G6

PC

DAG

G7

Inositol

IP3

PIP2

E1

APC

AA

PIP2_p

D1

Glu

Synapse

D4

RGTP

GDP

PKA

A1

EGFEGFR

GRB2

cAMP

PKA_a

J7

PKA_inhib

Ca_stores

L9_Leak_stores

Ca_pumpCa_ext

L8_Leak_ext

ATP

PKC

C5

AC1u8

Gsalpha

AMP

a tiny fraction of the whole signaling network

Bhalla, Iyengar 1999

bioLogic: Inhibition-Activation scheme

PDGF

PDGFR

b

SHC

b+p

internalization

Grb2

b

SOS

b

Ras

GDPexchange

PKC

GEF

p

GAP

p

Raf

p GDPexchange GTPhydrolysis

GTPhydrolysis

b

ubiquitination

MKP1

deg

MEK

2p

ERK

p

transc 2p

PLA2

p

PP2A

2dep

2dep

dep

2p

2dep

MKP2

2dep

APC

lip

AA

lip

Ca

b

b

DAG

b

b

PIP2

b

b

abstraction of Bhalla, Ram, Iyengar 2001

⇒ intermingled feedback loops : switches and oscillators

Block diagram of the ’Hub’ protein p53 in Kohn notation

combinatorial complexity constrains conventional modelling approaches

Kohn 1999, Maimon 2001, Kitano 2002

‘Conceptual Biology’ : Biology as Literature Science

1950 1960 1970 1980 1990 2000 2010Year

0

5000

10000

15000

20000

Publ

icat

ions

in P

ubM

ed

MAPKhyaluronanmiRNAsiRNA

* Conceptual Continuity ⇒ integrating diverse data and knowledge

from atoms to medicine - from genes to society?

* Multiscale Complexity ⇒ compound graph

every edge/node is a complex network itself

* Dangerous Small World property ⇒ find your own ‘conspiracy’ theory

Blagosklonny 2002

Models of Sea Urchin Development

N

N

N

N

N N

N

N

N

N

N

N

N

N

N

N

NN

N

N

N

N

NN

N

N

N

N

N

N

N N

N

N

NN

N

N

N

N

N

N

N

N

N

N

N

N

NN

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

NN

N

N

N

N

N

N

N

N

NN

N

N

N

N

N

N

N

N

N N

N

N

Beck 2004, Davidson 2002

Incomplete Phylogenetic Tree

cephalochordata vertebrata

eukaryotes

plants opisthokonts

fungi animals

protostomia deuterostomia

arthropoda mollusca echinodermata chordata

tunicata

The Jing-Mai System and Congenital Heart Diseases

Li-Ling 2001 and 2003

The Neural Crest Cells - ‘the’ Vertebrate Innovation

Knecht 2002, Gammill 2003, Srivastava 2000

Hyaluronan - another Vertebrate Innovation

Bio(electro)chemical properties:

⇒ long chains connected via hydrophobic interactions

⇒ forms a highly hydrated matrix

⇒ establishes diffusion and streaming potentials

⇒ conversion of mechanical force to potential difference and ionic current

Glycoforum, Toole 2001, Barrett 1975 and 1976

The third Polymer : Sugars

At CSLA11

At CSLA15

At CSLA10

At CSLA1

OsCSLA11At CSLA14

At CSLA3

At CSLA2Mt CSLA1I t CSLA2I t CSLA3At CSLA9OsCSLA2

OsCSLA4OsCSLA5

Os

CS

LA

7

At

CS

LA

7

Os

CSL

A3

OsC

SLA6

At CSLC8

At

CSL

C4

AtCSLC6

AtCSLC12

GmCSLG2

Mt

CS

LG

1

At CSLB3

At

CS

LB

2

AtC

SL

B4

AtCSLB1

AtCSLB5

AtCSLB6

AtCSLE1

MtCSLE3

OsCSLE2

OsCSLE1

LeCSLG1

MtCSLG4

AtCSLG1

AtCSLG2

AtCSLG3

OsCSLH1

OsCSLH2

AtCSLD2

OsCSLD2

AtCSLD3

PtrCSLD4

OsCSLD1

MtCSLD3

OsCSLD4

AtCSLD1

AtCSLD6

OsCSLF1

OsCSLF2

Os

CS

LF

4

Os

CS

LF

3

Os

CS

LF

6OsCSLF7

Mt

CE

SA

6Gm

CE

SA

3

Mt

CE

SA

1

At CESA10At CESA3At CESA2

At CESA9

At CESA6Br CESA1OsCESA9ZmCESA8OsCESA3PcCESA1Pt r CESA3EgCESA1

At CESA4Mt CESA2

OsCESA7

PyaO_HasSt u_HasSt ez_HasSt p_Has_

Ran_Has3Mm_Has3

Eqc_Has2Sus_Has2Bot _Has2Mm_Has2Ran_Has2

Hs_Has2

Dr _Has2

Dr _Has3

Mm_Has1

Ran_Has1

Hs_Has1

Xl _Has1

Rhgp_nodCRhe_nodC

Br I S_nac

Rhgb_nodC_

Mec_nac

Mem_nac

Me

l_

no

dC

Rhl

_n

od

c

Rh

t_nodC

Brj_nodC

Sim_nodC

Azc_nodC

Sut_Has

Luc_Chs1

Dm_Ch

s1

Trc_Chs2

Aea_Chs

Dm_Chs2

Di_Chs

Brm_Chs

Ex

d_

Ch

s4

Coi_Chs4

Tum_Chs

Glv_Chs

Nec_IV_Chs4Emn_VChsD_

Rmo_Chs3

Usm_IV_Chs5

Caa_III_Chs

Fin_Chs

Exd_VWdCHS5

Mag_VCsm1

Blg_VChs2

Asf_ChsE

Fuo_VChsV

Em

n_VChsD

Glg_VChsA

Co

p_

VCh

s7

Us

m_

VC

hs

6

Asf_VIChsD

Co

i_

VI

Ch

s

Exd_Chs2

Amq_ChsA

Emn_Chs1

Opn_ChsA

Scp_Chs1

Us

m_

Ch

s2

Phn_pChs

Ne

c_

Ch

s2

Exd_I I _Chs1

Coi _I I _Chs

Emn_ChsA

Sc_Chs2

Caa_I _Chs

Rmo_Chs2

Rmo_Chs1

Caa_Chs2Sc_Chs1

Pec_I I I _Chs

Emn_ChsBAsf _I I I _ChsGAr b_Chs2Exd_Chs3Nec_Chs3Ab_pChs

Sam_Chs

0.1

The 3 formgiving polysaccharides ?

Spicer 1998, Lee 2000

Some other Vertebrate Innovations and Hyaluronan

Heart: EMT into cavities, ECM expansion, eletrical environment in excitation?

Endothel: stimulated by fragments, migration in angiogenesis

Dynamic Epidermis: thick HA layer, high turnover rate, wound repair

Adaptive Immunity: stimulated by fragments, transport to lymph nodes, carrier of antigens?

Endoskeleton: condensation, major compound of cartilage, synovial fluid and connective

tissue

⇒ strongly hydrated ECM, embeds signaling molecules, single cell migration, electrome-

chanical signaling?

Shigei 2001, Shimeld 2000,

Karvinen 2003, Camenisch 2002, Schroeder 2003,

Mummert 2003, Termeer 2003, Roessler 2003,

Toole 2001, Knudson 2003

The ‘Interstitial Connective Tissue’ Hypothesis

Electromechanical signaling?

Langevin 2002

The ‘Electrophysiology of growth control’ Hypothesis

Shang 2001

Transepithelial Potentials and Galvanotaxis

Endogenous eletrical fields as directional signals in development and repair?

Robinson 2003, Altizer 2001, Zhao 2002, Song 2002, Hall 2000

Mapping the GRN on the Jing-Mai System?

Are the Xue (acupuncture points) Organizing Centers,

ie. Morphogen Sources

Bastiani

Establishment/Stabilization of Morphogen Gradients?

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22human FGFs

6

8

10

12

isoe

lect

rical

Poi

nt -

iP [p

H]

Fibroblast Growth Factors are differently charged at physiological pH

The Biochemistry of Yin and Yang

...

Yin-tonic herbs : antioxidant activity

Yang-tonic herbs : mitochondrial ATP production?

...

Ko 2004, Ou 2003

Fractal Rythms in Physiology and the Pulse Diagnosis

the Qi circulates through the Jing-Mai in circadian rythms

Noble 2002, Goldberger 2002

TCM : a translation problem

Jing-Mai: developmental paths and connections?

Yin/Yang: ATP production and REDOX management?

Qi: ‘life energy’ ? ‘natural air’

⇒ metabolism, mitochondrial oxidation?

Jing: the genes and the gene regulatory network?

Kaptchuck 2000, Li-Ling 2001 and 2003, Langevin 2002, Ko 2004, Ou 2003

References:

Altizer AM, Moriarty LJ, Bell SM, Schreiner CM, Scott WJ, Borgens RB. Endogenous elec-

tric current is associated with normal development of the vertebrate limb. Dev Dyn. 2001

Aug ; 221(4): 391-401

Barrett, TW. Hyaluronic acid salt–a mechanoelectrical transducer. Biochim Biophys Acta.

1975 Mar 14; 385(1): 157-61

Barrett, TW. Mechanoelectrical transduction in hyaluronic acid salt solution is an entropy-

driven process. Physiol Chem Phys. 1976 ; 8(2): 125-30

Bastiani M., Lecture on Developmental Biology, Online Material to Lecture 13 Limb Develop-

ment: http://courses.biology.utah.edu/bastiani/3230/DB%20Lecture/Lectures/Lec13Limb.html

Beck, M. et.al. Graph Grammars as Models for the Evolution of Developmental Pathways.

Proc. GWAL-6 (2004)

Bhalla, US. and Ram, PT. and Iyengar, R. MAP kinase phosphatase as a locus of flexibility

in a mitogen-activated protein kinase signaling network. 2002. Science, 297(5583):1018-

1023.

Bhalla, US. and Iyengar, R. Emergent properties of networks of biological signaling path-

ways. 1999. Science, 283(5400):381-387.

Blagosklonny, MV. and Pardee, AB. Conceptual biology: unearthing the gems. 2002. Na-

ture, 416(6879):373-373.

Bronner-Fraser, M. Development. Making sense of the sensory lineage. 2004. Science,

303(5660):966-968.

Camenisch, TD. and Schroeder, JA. and Bradley, J. and Klewer, SE. and McDonald, JA.

Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of

ErbB2-ErbB3 receptors. 2002. Nat Med, 8(8):850-855.

Chao, PH. and Roy, R. and Mauck, RL. and Liu, W. and Valhmu, WB. and Hung, CT.

Chondrocyte translocation response to direct current electric fields. 2000. J Biomech Eng,

122(3):261-267.

Davidson, EH. et.al. A genomic regulatory network for development. 2002. Science,

295(5560):1669-1678.

Gammill, LS. and Bronner-Fraser, M. Neural crest specification: migrating into genomics.

2003. Nat Rev Neurosci, 4(10):795-805.

Glycoforum, Section ’Hyaluronan Today’: http://www.glycoforum.gr.jp/

Goldberger, AL. and Amaral, LA. and Hausdorff, JM. and Ivanov, PCh. and Peng, CK. and

Stanley, HE. Fractal dynamics in physiology: alterations with disease and aging. 2002. Proc

Natl Acad Sci U S A, 99 Suppl 1(”):2466-2472.

Hanahan, D. and Weinberg, RA. The hallmarks of cancer. 2000. Cell, 100(1):57-70.

Hall, BK. and Miyake, T. All for one and one for all: condensations and the initiation of

skeletal development. 2000. Bioessays, 22(2):138-147.

Kaptchuk, TJ. The Web That Has No Weaver : Understanding Chinese Medicine, 2nd edi-

tion (April 11, 2000), McGraw-Hill/Contemporary Books.

Karvinen, S. and Pasonen-Seppanen, S. and Hyttinen, JM. and Pienimaki, JP. and Torronen,

K. and Jokela, TA. and Tammi, MI. and Tammi, R. Keratinocyte growth factor stimulates

migration and hyaluronan synthesis in the epidermis by activation of keratinocyte hyaluronan

synthases 2 and 3. 2003. J Biol Chem, 278(49):49495-49504.

Kitano H. The Standard Graphical Notation for Biological Networks. The Sixth Workshop on

Software Platforms for Systems Biology. (http://www.sbml.org/workshops/sixth/sbmlsbwstockholm.htm)

Knecht, AK. and Bronner-Fraser, M. Induction of the neural crest: a multigene process.

2002. Nat Rev Genet, 3(6):453-461.

Knudson, CB. Hyaluronan and CD44: strategic players for cell-matrix interactions during

chondrogenesis and matrix assembly. Birth Defects Res Part C Embryo Today. 2003 May ;

69(2): 174-96

Ko, KM. and Mak, DH. and Chiu, PY. and Poon, MK. Pharmacological basis of ’Yang-

invigoration’ in Chinese medicine. 2004. Trends Pharmacol Sci, 25(1):3-6.

Kohn, KW. Molecular interaction map of the mammalian cell cycle control and DNA repair

systems. 1999. Mol Biol Cell, 10(8):2703-2734.

Krieger CJ, Zhang P, Mueller LA, Wang A, Paley S, Arnaud M, Pick J, Rhee SY, Karp PD.

MetaCyc: a multiorganism database of metabolic pathways and enzymes. Nucleic Acids

Res. 2004 Jan 1; 32 Database issue(): D438-42.

Langevin, HM. and Yandow, JA. Relationship of acupuncture points and meridians to con-

nective tissue planes. 2002. Anat Rec, 269(6):257-265

Lee, JY. and Spicer, AP. Hyaluronan: a multifunctional, megaDalton, stealth molecule.

2000. Curr Opin Cell Biol, 12(5):581-586.

Li, X. and Kolega, J. Effects of direct current electric fields on cell migration and actin

filament distribution in bovine vascular endothelial cells. 2002. J Vasc Res, 39(5):391-404.

Li-Ling, J. Connections between traditional Chinese medicine and congenital syndromes.

2001. Am J Med Genet, 103(3):257-262.

Li-Ling, J. The Jing-Mai connections of the heart. 2003. Int J Cardiol, 89(1):1-11.

Maimon, R. and S. Browning. Diagramatic Notation and Computational Structure of Gene

Networks. in The Second International Conference on Systems Biology. 2001. Pasadena.

Mummert, DI. and Takashima, A. and Ellinger, L. and Mummert, ME. Involvement of

hyaluronan in epidermal Langerhans cell maturation and mig ration in vivo. 2003. J Der-

matol Sci, 33(2):91-97.

Noble, D. Modeling the heart-from genes to cells to the whole organ. 2002. Science,

295(5560):1678-1682.

Ou, B. and Huang, D. and Hampsch-Woodill, M. and Flanagan, JA. When east meets west:

the relationship between yin-yang and antioxidation-oxidation. 2003. FASEB J, 17(2):127-

129.

Pollack, GH. The role of aqueous interfaces in the cell. 2003. Adv Colloid Interface Sci,

103(2):173-196.

Robinson, KR. and Messerli, MA. Left/right, up/down: the role of endogenous electrical

fields as directional signals in development, repair and invasion. 2003. Bioessays, 25(8):759-

766.

Roessler A, Hinghofer-Szalkay H. Hyaluronan fragments: an information-carrying system?

Horm Metab Res. 2003 Feb ; 35(2): 67-8

Schroeder, JA. and Jackson, LF. and Lee, DC. and Camenisch, TD. Form and function of

developing heart valves: coordination by extracellular matrix and growth factor signaling.

2003. J Mol Med, 81(7):392-403.

Shang, C. Electrophysiology of growth control and acupuncture. 2001. Life Sci, 68(12):1333-

1342.

Shigei T, Tsuru H, Ishikawa N, Yoshioka K. Absence of endothelium in invertebrate blood

vessels: significance of endothelium and sympathetic nerve/medial smooth muscle in the

vertebrate vascular system. Jpn J Pharmacol. 2001 Dec ; 87(4): 253-60

Song B, Zhao M, Forrester JV, McCaig CD. Electrical cues regulate the orientation and

frequency of cell division and the rate of wound healing in vivo. Proc Natl Acad Sci U S A.

2002 Oct 15; 99(21): 13577-82

Spicer, AP. and McDonald, JA. Characterization and molecular evolution of a vertebrate

hyaluronan synth ase gene family. 1998. J Biol Chem, 273(4):1923-1932.

Termeer, C. and Sleeman, JP. and Simon, JC. Hyaluronan-magic glue for the regulation of

the immune response. 2003. Trends Immunol, 24(3):112-114.

Toole, BP. Hyaluronan in morphogenesis. Semin Cell Dev Biol. 2001 Apr ; 12(2): 79-87

Zhao, M. and Pu, J. and Forrester, JV. and McCaig, CD. Membrane lipids, EGF receptors,

and intracellular signals colocalize and are polarized in epithelial cells moving directionally in

a physiological electric field. 2002. FASEB J, 16(8):857-859.