How Do Cells Compute? John J. Tyson Department of Biological Sciences Virginia Bioinformatics...

How Do Cells Compute?

John J. TysonDepartment of Biological Sciences

Virginia Bioinformatics Institute

Do Cells Compute?

Computer

bit string bit string

N N2

x x

01

00

10

11

1

0

1

0

either A or Bbut not both

computations

decisions

Is the cell anInformation Processing System?

IPSinput output

Cellnutrients

repellants

damage

hormones

heat shock

growth & division

movement

geneexpression

death

BacteriaGlucose

Lactose

1

0

glucosemetabolizing

enzymes

1

lactosemetabolizing

enzymes

0

BacteriaGlucose

Lactose

lactosemetabolizing

enzymes

1

1 0

glucosemetabolizing

enzymes

1

BacteriaGlucose

Lactose

lactosemetabolizing

enzymes

0

1 1

glucosemetabolizing

enzymes

1

BacteriaGlucose

Lactose

lactosemetabolizing

enzymes

0

0 0

glucosemetabolizing

enzymes

1

Fission Yeast

14 m

7 m

Wild type Mutant (wee1)

“size control” different “set point”

Fibroblast

Ionizing radiationdamages DNA

cell cycle arrest

repair

Fibroblast

ProgrammedCell Death

Is a cell like a computer?

Laptop Cell

Solid state Watery

Programmable Hard-wired

Precise Sloppy

Digital Analog

Sequential Parallel

Manufactured Self-reproducing

Designed Evolved

Silicon CarbonSilicon Carbon

DGaD LoDD

…in the last 5 years

“Molecular Systems Biology”

CellCarbon

Watery

Hard-wired

Sloppy

Analog

Parallel

Self-reproducing

Evolved

Carbon

20 years ago…

Winfree & Kauffman

Oster & Perelson

Goldbeter & Segel

Glass & Mackey

Rinzel & Keizer

Goodwin, Meinhardt, Odell, Tyson, …

CellCarbon

Watery

Hard-wired

Sloppy

Analog

Parallel

Self-reproducing

Evolved

Carbon

How do cells make decisions?

WT

cdc

wee

Paul Nurse, Nature (1975)

Fission Yeast

P Wee1

Wee1P

Cdc25

CycB

CycB

Cdc25

MPFMitosis Promoting Factor

++P

WT

cdc

wee

cdc25ts

wee1ts

wee1OP

cdc25OP

Fission Yeast

P Wee1

Wee1P

Cdc25

CycB

CycB

Cdc25

mass/ DNA

0 1 2

Cdc2/Cdc13

10-3

10-2

10-1

100

S/G2

M

size

MP

F

size

SN14m

wee1OPwee1

P++

DNA synthesis

Mitosis & Cell Division

0.01 0.1 1 10 100 1000 10000

1

10

100

1000

0.4

3.0

WT

Cdc25 activity (%)

Wee

1 ac

tivity

(%

) cdc

cut

wee

quantized

Size at Division1.0 = WT size

wee1ts

wee1OP

cdc25OP

cdc25ts

P

Cdc25

Wee1

Wee1P

Cdc25

CycB

PCdc20

Cdc20

APC-PAPC

CycB

0

0.5

1

0 1 2

MP

F

total cyclin

ks

MPF

Joe Pomerening

Cell (2005)

MPF

total cyclin

How do cells compute?

Switches and Clocks

ks

MPF

mass/ DNA

0 1 2

Cdc2/Cdc13

10-3

10-2

10-1

100

S/G2

M

size

MP

F

The class of chemical switching networks will be promising

candidates for a possible new technology of chemical reaction

systems.

nutrients

repellants

damage

hormones

heat shock

growth & division

movement

geneexpression

death

The living cell is Rössler’s“flüssiges Automata”:

a miniature, self-reproducing, water-soluble biochemical

computer.

$$: DARPA, NIH, McDonnell Foundation