Systems Biology Lecture 1history, introduction and definitions

Pawan Dhar

Historical context

1900 1950 2000

Dominantapproach

Focus ofstudy

Paradigmaticdiscovery

Limitationsof approach

Physiology

Functioning oforgans andmetabolism

Homeostasis

Inability to identify /modify cellularcomponents

Molecular biology

Identification andfunctioning of cellularcomponents

DNA discovery, Wholegenome Sequencing

Inability to explain howcomponents interact toproduce phenotype

N.Chomsky. Systems Biology Meeting, MIT, Boston Jan 8-9, 2004

2000 10-15 years ? Another 10-15years or more

We know geneproducts of majorpathways

Identify all theinteractions amongproteins in the pathway

Quantitativeunderstandingof biology. Major“how and why”questions resolved

Future timeline

N.Chomsky. Systems Biology Meeting, MIT, Boston Jan 8-9, 2004

The genesis of systems biology

1940s: Nobert Wiener - Father of Cybernetics

1960s, 70s: Biochemical system theory, Metabolic control theory

Mid 1990s: Systems Biology - Leroy Hood

Defintion and complexity• Systems Biology is defined by assays, data types, global assays and

the types of data integrations

• Hypothesis drivenGlobalQuantitativeIntegrativeIterativeDynamicMultiscaleCross-disciplinary

Leroy Hood. Systems Biology Meeting, MIT, Boston Jan 8-9, 2004

Bottomline: System is really where you draw the box !

Levels of biological complexity

- DNA- RNA- Proteins- Protein-protein & protein DNA Interactions- Pathways- Networks- Cells & tissue- Organs & Systems- Organisms- Population- Ecology

Fundamental ConceptsWhat is :

system

model

modeling

Simulation

Validation

What is a:

steppathpathwayNetwork?

Step: 1 reaction eventPath: 1 entry, 1 exitPathway: 1 entry, 1-many exitsNetwork: many entries, many exits

Measure-ment

Experi-mentation

Comput-ationalmodeling

My initiation into Systems BiologyThe E-Cell System

E4P

PGI PFK

GLCtr

ATP

GLC

ADP G6P

GLC

ATP ADP

F6P ALD

DHAP

TPI

GAPDHGA3P

DPGM

2,3DPG

1,3DPG PGK

DPGase

Pi

NAD NADHPi

3PG PGM 2PG

ATPADP ADP ATP

PEPEN PK

ATP

ADP

ATPaseLDH

PYRtr

LACtr

Glycolysis

NADNADH

PYR

LAC

PYR

LAC

G6PDH

HKFDP

GL6P

6PGLase

NADPGSH

GO6P

GSSGR

6PGODH

Ru5PCO2

NADPH GSSG

GSHox

X5PX5PI

TK1

TK2

TA

S7P

R5PI

Pentose phosphate pathway

AMP

ATPR5P

PRPP

ADE

PRPPsyn

PiPi

PiPi

ADPRT AMP

AMPDA

PRM

APK AK

AMPase

PiIMP

Pi

ADO

ADA

INO

PNPase

HGPRT

R1PPi

HX

IMPase

HXtr

HX

Nucleotide metabolism

CAH

HCO3

H+

H+

CO2

HCO3

Na/K Pump

K+K+

Na+Na+

ATP

ADP

K+

K+Na+

Na+

ADE

ADE

ADEtr

Membranetransport

mOsm VOL

mOsm VOL

Donnan ratio

H+

Where arewe now ?

Grid version released in

Why is it difficult to model cellular transactions?• Qualitative biology

• Inaccuracy of data

• Incompleteness of data

• Memory

• Sensing

• Feedback

• Communication

• Toggle switches (feedback loops +/-),amplifiers, resistors and oscillators,bistable states, unstable states, attractors,hysteresis?

• Where do cells derive their robustnessfrom?

Sci.Am. Jan2004 issue

Problem What we understand…

Biological chemistry,Transmission of genetic information

What we don’t understand ?

Biological complexity

The best non-living equivalent of life(for in-silico modeling)

Emergent phenomena

Heavy usage of mathematics !Mathematics: Usually approach driven, not problem driven

From fusion to confusioncomputational & Intellectual

Assuming 5 parameters / protein30,000 genes = 150,000 parameters space (PS)Cell physiology = 1 point in this PS

Dynamics of regulation

Change 1 point in PS

5000 genes respondEquivalent to 25000 parameters change

Q1: How do cells find safe paths betweencontinuously changing physiological states ?

Q2: Hidden Laws of Biological Complexity ?

Unanswered questions

Q1. What are the initial and boundaryconditions in biological systems ?

Q2: Is there a broader set of primitivesone can use in biology?

Q3. Can a simple rule give rise tocomplex biological patterns ?

Q4. How are networks generated frommolecular interactions?

Q5. Rules that generate a combination ofscale-free / modular network ?

Q7: The big one: How do organismshandle information 6 orders ofmagnitude apart ?

The why files ?

Q1.Why model pathways,networks, cells and tissues ?

Q2: Has Systems Biologygone far beyond its intendedmeaning ?

Q3: Experimental SystemsBiology vs. ComputationalSystems Biology

Challenges Requirements

• Number ofcomponents -enormous

• Rules of howthey fit together ?

• Principles of complexand robust behavior

• Biology

• Math

• Comp Science

• Physics

• Engineering

Training new breed ofbiologists whounderstand non-biological concepts !!

3 billion years of metabolism and1 billion year of Cell biology

1986-2003: 3500 fold HTS

2003 - 2013: 3500 more !

Leroy Hood. Systems Biology Meeting, MIT, Boston Jan 8-9, 2004

Systems Biology is NOT a subculture of Mathematical Biosciences !

Biological knowledge

Validated model

Conceptual Model

Makepredictions

Explain non-intuitivephenomenon

Use model fordiagnosticpurposes

Analytical Model

Computer simulation

Rate EquationsConstraintsGuess missing parametersAdd lots of assumptions !

Match in-silico & in-vivo

Revise

OurModelingstrategy

Data

Model

Classic Wish listState-of-the-art

Reading materialLeroy Hood GroupDrug Discov Today. 2003 May 15;8(10):436-8.

Mech Ageing Dev. 2003 Jan;124(1):9-16.

Nature. 2003 Jan 23;421(6921):444-8. Review

Annu Rev Genomics Hum Genet. 2001;2:343-72. Review.

Tomita Group - JapanE-Cell publication: Bioinformatics (1999) 15(1): 72-84.

BIIArtificial Life and Robotics (2002) 6: 99-107.

Complex Systems Science in Biomedicine (Kluver, in press)

Encyclopedia of Molecular cell biology and Molecular Medicine (Wiley-Verlag)

The Ecell Book. Kluver-Landes

Bioessays. 2004 Jan;26(1):68-72.

OthersDe Jong. J Comput Biol. 2002;9(1):67-103.

Hoefstadt et al. In Silico Biol. 1998;1(1):39-53.

Caltech group: Bioinformatics. 2003 Mar 1;19(4):524-31.