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