What happened to computing 1930-80 is now happening to biology Friden mechanical calculator: 1930-1966 Friden electronic calculator: 1965 Intel 4004

What happened to computing 1930-80 is now happening to biology

Friden mechanical calculator: 1930-1966

Friden electronic calculator: 1965Intel 4004

proc:1971

Sharp single chip calculator: 1977

What happened to computing 1930-80 is now happening to biology- Example: electroporation

Pro

port

ion

of

cells

tra

nsf

ect

ed

Pre-2000

Today

Tomorrow

The complete protocol

% c

ells

dam

ag

ed

by t

ran

sfect

ion

Another example: automated parallel mini-preps

Pathway/ interaction

DBs / literature

data analysis

model construction

model analysis

hypothesis formulation

experimentalplanning

experiments to test hypothesesBiology

Technology

Computation

The geek shall inherit (systems) biology

cell-specific, comprehensive,

kinetic and quantitative data

Top-down, global, systematic

• Discovery science via high throughput ‘omic technologies

• Screening- multi-target/multi-component drugs- multi-parameter disease signatures

• Observation & data-driven

• Focus on nonlinear interactions

• Study irreducible systems

• Analyzing emergent (difficult-to-predict, nonlinear) properties

• Hypothesis and model-driven

Bottom-up, local dynamics

2 complementary approaches in systems biology:

global climate local weather

The yeast galactose utilization pathway – bottom up viewd

e A

tau

ri e

t a

l B

ioc

he

m J

. 2

00

5

Galactose

Galactose 1-phosphate

Glucose 1-phosphate

Glucose 6-phosphate

UDP-galactose

PGM1PGM2

UDP- glucose

UGP1

1,3-â-Glucan

Glycogen synthesis

Threhalose synthesis

GPH1

GSY1GSY2

GSC2FKS1FKS3TPS1

TSL1TPS3

Galactose

Gal10p(epimerase)

Gal7p(transferase)

Gal1p(kinase)

Gal2p(transporter)

Gal80

Gal3

Gal2

Gal 1,7,10

Gal3p

Gal3p*

Gal80p

+ feedback

+ feedback

- feedback

Gal4p

Gal4p

Gal4p

Gal4p

The yeast galactose utilization pathway – top down view

How do we make sense of this?

A network graph viewed in Cytoscape; what does it do?

. • • ••••

•

••

•

in1

in2

out = XOR

Vdd

Gnd

T1

T2

T3

T4

T5

T6

T7

T8

T9

T10

T11

T12

T13

T14

1

0

2

3

4

5

6

7

8

NOR (1) NAND (2) NOT (3) NOR (4)

in1in2

out

• • 1

2 3

4

in1 in2 NOR 1 NAND 2

NOT 3 NOR 4

0 0 1 1 0 0

0 1 0 1 0 1

1 0 0 1 0 1

1 1 0 0 1 0

out = XOR

An Exclusive OR gate

p38pathway

Phagocytosis

Cell adhesion

Translation

Fas

mRNA stability

Actin polymerization

Transfac documentedP-DNA interaction

Transfac/HPRD/in-house documented P-P interaction

Red nodes: down-regulated

Green nodes: up-regulated

“Guilt by association” network analysis

Uri Alon & colleagues Rick Young & colleagues

Ecoli

yeast

Community effect

Nonlinear switchRegulated &/or rapid response

sea urchin functional building blocks

Bolouri & DavidsonBioEssays 2002

Unidirectional switch

Network motifs & functional building blocks

. • • ••••

•

••

•

in1

in2

T1

T2

T3

T4

T5

T6

T8

T9

T10

T11

T12

T13

T14

1

0

2

5

7

•

•T1

1

T1

2

T1

3

7

B A if (select1=on & select2=on) •

select1select2

A

Cannot guess function from topology alone

Network topology:

equivalent network motifs/modules

Possible (mis)interpretation:

Network motifs have many additional inputs and interactions

Alon & colleagues, Nature Genetics, 2002. 31(1): p. 64-8

see also:

The feed forward motif:

A topological motif may implement different functions

A coherent feedforward motif acting as a gradient sensor

Need a functional abstraction hierarchy

(B)

(A)

(C)

(D)

(E)

(g)

Potential genetic regulatory functional building blocks

(F)

BioTapestry.org

PSS = (ks/kdp).mRNA

mRNASS= (kt/kdm).Y

At steady state:

GataE

Otx

GCM

P

mRNA

mRNAss

Pss1st o

rder

2 cooperative site

s

kt.ks/2.kdm.kdp

Kd

iss

(B)

(A)

(C)

(D)

(E)

(g)


(F)

positive intercellular feedback

positive driver

cell type specific gene battery

(1) (2) (3)

-catenin/Wnt8 ‘Community Effect’ filters out expression variability

Cells in a reinforcing loop

- all cells in group adopt same fate

- sharp boundary between cell types

- insensitive to level of “driver”

Simulated time

blue

gen

e ac

tivi

ty le

vel

_ cell 1_ cell 2_ cell 3

cell 1 driver gene

NTCF

frizzledGSK-3

Wnt8

c

Krox

c

Intercellular positive feedback: The community effect

Gurdon ‘88, Nature, 336, 772-4

Data from Davidson lab

(B)

(A)

(C)

(D)

(E)

(g)


(F)

Intracellular negative feedback

(A) tuned for regulated level

(C) tuned for rapid response

(B) single transcriptional pulseSee also Ashburner et al 1973-1981 (see Cell, 1990. 61(1):1-3)

x

(D) tuned for long lasting oscillation

FoxA

(B)

(A)

(C)

(D)

(E)

(g)


(F)

NkdTCF

EnTCF

Wnt pathway

Wnt

Ptc

Cell 1 (posterior)Cell 2 (anterior)

SlpCiHh

Dlp

Ptc: :H

hS

mo

_I

Cos2::GSK3

Sm

oCiA CiR

Sm

o::C

os2Su(Fu) Fu

Ci::Su(Fu)

u

Hh pathway

0

1000

2000

3000

4000

5000

6000

1 9 17 25 33 41 49 57 65 73 81 89 97 105 113 121 129 137 145 153 161 169 177 185 193 201

DshA

DshA2

En

En2

Mutual exclusion in a mammalian adult cell specification process

ratedecayK

rateproduction

Diss _*

_

ratedecayK

rateproduction

Diss _*

_

gene 1

gene 2

Mutual exclusion operator

after Cherry & Adler, JTB 2000

cooperativity factor = 2



Multi-cellular mutual exclusion

(B)

(A)

(C)

(D)

(E)

(g)


(F)

Alon & colleagues, Nature Genetics, 2002. 31(1): p. 64-8

see also:

The feed forward motif:

100 molecules

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

6000 7000 8000 9000

protein_A

protein_AA

protein_B

0

2000

4000

6000

8000

10000

0 2001.334

protein_A

protein_AA

protein_B

yeast

M

~ 2 days

(B)

(A)

(C)

(D)

(E)

(g)


(F)

activator levelstead

y s

tate

gen

e 2

activator levelstead

y s

tate

gen

e 2

Direct activation Repression cascade

gene2gene1

gene2gene1

gene2, cell2

gene2, cell1

timetimetime

gene2gene1

activator

gene2gene1

activator gene3

cell type 1 cell type 2

U

U

Regulatory circuit elements: boundary detection switches

(B)

(A)

(C)

(D)

(E)

(g)


(F)

(B)

(A)

(C)

(D)

(E)

(g)


(F)

ATF3NFB

IL6, IL12b…

TLR4

A feedforward motif functioning as a reset (homeostasis) mechanism

NFkB

ATF3

ATF3

TLR4 genes

Gilchrist et al, Nature, 2006

NFkB

quantitative measure of behavior

P1

P2

Convex:

• Large stability margins

• Parameter independence

Robust behavior in parameter space

P1

P2

Concave:

• Poor stability margins

• Parameter interdependence

Note also rate of change of ‘desired’ behavior away from operating point

The same genes take part in different processes and functional blocksDifferent genes implement the same functional building blocks

Data from Davidson lab

Heart specification functional module:conserved from flies to humans?

vertebrate

fly

maveric, multi-talented enthusiastsearly adopters standardize,

develop “Killer Apps”

performance, reliability, usability and manufacturability

diverse, specialized suppliers ofmodular, standardized parts

http://magnet.systemsbiology.net/software/Pointillist/

http://www.septicshock.org/

http://sugp.caltech.edu/endomes/

Gilchrist et al, Nature 2006 Davidson et al, Science 2002Hwang et al, PNAS 2005a, bOrrell et al, Physica D, 2006Ramsey et al, Nat. Gen. 2006

Steve Ramsey Daehee Hwang

Alistair Rust

Christophe Battail

Mark Robinson

Bin Li

Jennifer Smith, Deena Leslie, Andrea Weston, Marcello Marelli, Tim Petersen

Andy Siegel, John Aitchison, Lee Hood

Ben Buelow, Mark Gilchrist, Katy Kennedy, Adrian Ozinsky,

Jared Roach, Carrie Baldwin, Natalya Yudkovsly

Alan Aderem

Bill Longabaugh

Davidson Lab & Eric Davidson

Vesteinn ThorssonMartin Korb

David Orrell Pedro de Atauri

Department of Cellular & Physiological Sciences University of British ColumbiaLife Sciences Centre2350 Health Sciences MallVancouver, BC Canada V6T 1Z3

Recruiting:

- Graduate students- Post docs- Technicians- Professional staff

Subjects:

- molecular & cell biology- transcriptional regulation- single cell assays- math, stats- physics, engineering- computer science- software engineering

What happened to computing 1930-80 is now happening to biology Friden mechanical calculator: 1930-1966 Friden electronic calculator: 1965 Intel 4004

Documents

network graph

pp interaction red nodes

topological motif

biology example

sharp single chip calculator

topology alonenetwork

feed forward motif

friden electronic calculator