A Systems Biology View to Diabetes

Jia-Rui Wu吴 家 睿

Shanghai Institutes for Biological Sciences, CASDepartment of Systems Biology, USTC

New Trends in Life Science in 21th Century:

Systems Biology

Part I

Scientific Revolution in Life Science in 21th

Normal Sciences

1950 1990

Central Dogma

Molecular Biology

Time

Scien

tific

Revolu

tion

Normal Sciences

Scien

tific

Revolu

tion

Human Genome ProjectSc

ient

ific

Kno

wle

dge

Systems Biology

First Scientific Revolution

Change the View of Life

Philosophy for Biologists in 20th Century: Reductionism

Gene

Protein

FunctionC

entr

al D

ogm

a

2005，7，1167

Research limited in individual gene or protein

One proteinOne gene One function

Classic View of Life: Simple System

Classic View of Life: Simple System

Research based on linear interaction

Real Picture of Life

Genes of Human

~ 300 00

Proteins of Human

Millions

Real Picture of Life

Signaling Network

Protein Interaction Network

Human Genome Project

23 Chromosome

( 3.3X109 bp )

Genes： ~ 30, 000

~1.5% for coding protein

DNA Books

Fish Arabidopsis

Thermophile

Rice

Post-Genome Era

-Omics

Genomics

Transcriptomics

Proteomics

Metabolomics

Novel View of Life in 21th Century: Holism

p53 network

Novel View of Life : Complex System

ErbBsignaling

Traditional Biology

Classical Biology

Systems Biology

Systems Biology View of Life

Input OutputBlack Box

A (gene/protein)

B (gene/protein)

Input OutputSimple System

OutputInput

Complex System

Second Scientific Revolution

Change the View of Life Science

Process of Biological Knowledge Discovery

Wet Lab. Data Personal-based Knowledge

Wet Lab. Researcher

20th Century

Dry Lab.Information-based

Knowledge

Wet Lab. Researcher

Wet Lab. Data

21th Century

Huge amount of Experimental Date

Complexity of Experimental Date

Cell signaling

Protein interaction network

Computing capability decide understanding biological complexity

Life is information：Digital

DNA

RNA

Protein

Protein interactive network

Cell

Tissue

Organism

Information Flow in Biological System

Central Dogma

Computing in Biological System

Traditional Biology Era

Life is vitalism

Molecular Biology Era

Life is machine

Post-Genome Era

Life is information

Novel View of Life Science in 21th Century

Systems Biology

Integration Science

Integration of All Kinds of Molecules

GenomeTranscriptome

Proteome

Citric acid cycle

Metabolome

Integration of Different Levels

Gene / Protein

Cell

Gene / Protein Network

Organism

Integration of Small Science and Big Science

Systems Biology

1， 2， 3， n “Omics”

（Discovery Science）

Gene（Protein）

Gene clone

Gene expression

Gene mutation

Protein structure

Protein interaction

Experimental Biology

（Hypothesis-driven Science）

Molecular BiologyCell Biology

GenomicsProteomicsMetabolomics

Wet Laboratory

ComputingInformaticsModelingMathematics

Dry Laboratory

Integration of Wet Lab. and Dry Lab.

Systems

Biology

New Way against Diabetes:

Systems Biology

Part II

Diabetes in the World

2006-12-20, UN decided Nov. 14th of every year “World Diabetes Day” to be

“United Nations Day”

150 millions diabetes patients / 2000

Nature Reviews Drug Discovery, 2005, 4:367

19701970 19751975 19801980 19851985 19901990 19951995 20002000 20052005

248724872487 251725172517349834983498

456645664566610161016101

695569556955

931593159315

167951679516795

Answer Question or Solve Question ?

Challenge OneHow to study molecular network

Tradition Way for Analyzing Diabetes

Signaling (13)PTP1B Meg1/Grb10IR Aging galectin-3Insulin2 PAI-1Socs7 SOCS1IGF-I CDIRS1 IRS2Gas6

Endocrinology (14)COX-2 NOSNPY ACC2apo E p75(NTR)p27(Kip1) HSLUSF1 USF2Ifng OrexinSHIP2 HO-1

Beta cell (9)Wfs1 TCF2Pdx1 OGG-1ARNT Stat4cyclin D1 cyclin D2P58(IPK)

Insulin resistance (10)MC4R ARGK L-PGDSGLUT4 PTENAlms1 ORPIkbkb Acc2

Insulin secretion (8)HNF-4alpha SGK1P35 HNF-4alphaFem1b PKClambdaIA-2 MafA

2005

Knockout-mice used for diabetes research

Annu. Rev. Physiol. 2003. 65:313

Tissue-specific knockout insulin receptor

Nature Rev. Mol. Cell Biol. 2006, 7:85

Diabetes: a disease involving complex networkInsulin signaling network

IRS Family

Challenge TwoHow to study complexity of systems

Linear deduction

Tradition Way for Studying Diseases

Gene

Gene

Gene

Gene

Metabolism is system work

Cell 1998, 92:593

Diabetes: dynamic development of systems

“when it comes to the control of intermediary metabolism and plasma glucose levels, there may sometimes be important differences between mice and humans.”

Science，2005， 307：370

“when it comes to the control of intermediary metabolism and plasma glucose levels, there may sometimes be important differences between mice and humans.”

Science，2005， 307：370

MouseMouse HumanHuman

MODY gene mutationMODY gene mutation

HyperglycemiaHyperglycemia

MODY gene knockoutMODY gene knockout

NormalNormalPPAR γ -Pro467Leu mutPPAR γ -Pro467Leu mutPPARγ-Pro467Leu mutPPARγ-Pro467Leu mut

Insulin resistanceInsulin resistanceNormalNormal

Animal System is different from Human System

Nature 2003, 423,599

Environ. factorsEnviron. factors

Genetic factorsGenetic factors

Diabetes: Personalized disease

Genetic factors Environment factors

19801980 20022002

4X!4X! 2.6%2.6%

0.67%0.67%3.74%3.74%

1.83%1.83%

6.07%6.07%

RuralRural Small citySmall city Big cityBig city

Factors involved in Chinese diabetes population

Solution against diabetes

Systems Biology

http://www.bair.org.uk/bair_organisation.html

Biological Atlas of Insulin Resistance - BAIR

Type 2 diabetes of Chinese

clinic / population

Systems for analysis Methodology

Mol. biology

Cell biology

Genetics

GenomicsProteomics

MetobolomicsBioinformation

Genetic factors

Environment factors

Clinic/population

Strategy of diabetes project in China

Animal model Cell model

Scientific questions

Study

What is life?

Systems Biologist

Components (Nodes) Interactions (Links)

Life is a statistical complex system rather than a determined simple system

Thank You!