Transcript No Slide Title

Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Proteins
Catabolism
Precursors
Core metabolism
Nutrients
Ligand
Receptor
In
GDP
GTP

Nucleotides

Trans*
G
G
GDP
Carriers
Genes
GTP
P
DNA
replication
John Doyle
John G Braun Professor
Control and Dynamical Systems,
BioEng, and ElecEng
Caltech
www.cds.caltech.edu/~doyle
RGS
In
Out
Collaborators and contributors
(partial list)
Biology: Csete,Yi, Tanaka, Arkin, Savageau, Simon, AfCS, Kurata,
Khammash, El-Samad, Gross, Kitano, Hucka, Sauro, Finney,
Bolouri, Gillespie, Petzold, F Doyle, Stelling, …
Theory: Parrilo, Carlson, Paganini, Papachristodoulou, Prajna,
Goncalves, Fazel, Liu, Lall, D’Andrea, Jadbabaie, Dahleh, Martins,
Recht, many more current and former students, …
Web/Internet: Li, Alderson, Chen, Low, Willinger, Vinnicombe, Kelly,
Zhu,Yu, Wang, Chandy, …
Turbulence: Bamieh, Bobba, Gharib, Marsden, …
Physics: Mabuchi, Doherty, Barahona, Reynolds,
Disturbance ecology: Moritz, Carlson,…
Finance: Martinez, Primbs, Yamada, Giannelli,…
Engineering CAD: Ortiz, Murray, Schroder, Burdick, …
Current Caltech
Former Caltech
Longterm Visitor
Other
Multiscale
Physics
Network
Centric,
Pervasive,
Embedded,
Ubiquitous
Core
theory
challenges
Systems
Biology
Today’s
focus
Network
Centric,
Pervasive,
Embedded,
Ubiquitous
Core
theory
challenges
Systems
Biology
Status
Consistent,
coherent,
convergent
understanding.
Core theory
challenges
Pervasive,
Networked,
Embedded
Remarkably
common core
theoretical
Core theory
challenges.
challenges
Dramatic
recent
progress in
laying the
foundation.
Yet also striking
increase in
unnecessary
confusion???
Core theory
challenges
Systems
Biology
Feathers
and
flapping?
Or lift, drag, propulsion,
and control?
The danger of
biomemetics
Wilbur Wright on Control, 1901
• “We know how to construct airplanes.” (lift and drag)
• “Men also know how to build engines.” (propulsion)
• “Inability to balance and steer still confronts students
of the flying problem.” (control)
• “When this one feature has been worked out, the age
of flying will have arrived, for all other difficulties are of
minor importance.”
Core theory challenges
• Hard constraints
• Simple models
• Short proofs
• Architecture
A look back and forward
• The Internet architecture was designed
without a theory.
• Many academic theorists told the engineers
it would never work.
• We now have a nascent theory that confirms
that the engineers were right.
• For systems biology, future networks, and
other new technologies, let’s hope we can
avoid a repeat of this history.
Architecture?
• “The bacterial cell and the Internet have
– architectures
– that are robust and evolvable”
• What does “architecture” mean?
• What does it mean for an “architecture” to
be robust and evolvable?
• Robust yet fragile?
• Rigorous and coherent theory?
Hard constraints
On systems and their components
• Thermodynamics (Carnot)
• Communications (Shannon)
• Control (Bode)
• Computation (Turing/Gödel)
• Fragmented and incompatible
• We need a more integrated view
and have the beginnings
Assume
different
architectures
a priori.
Hard constraints (progress)
• Thermodynamics (Carnot)
• Communications (Shannon)
• Control (Bode)
• Computation (Turing/Gödel)
• We need a more integrated view and have
the beginnings
Work in progress
• Thermodynamics (Carnot)
• Communications (Shannon)
• Control (Bode)
• Computation (Turing/Gödel)
• We need a more integrated view and have
the beginnings
Short proofs (progress)
• Robust yet fragile systems
• Proof complexity implies problem fragility (!?!)
• Designing for robustness and verifiability are
compatible objectives
• Hope for a unifying framework?
– SOS, Psatz (Prajna, P*)
– Temporal specifications (Pnueli)
– SAT (Selman)
• Integrating simple models and short proofs?
Simple models (challenges)
• Rigorous connections between
– Multiple scales
– Experiment, data, and models
• Essential starting point for short proofs
• Microscopic state: discrete, finite, enormous
– Packet level
– Software, digital hardware
– Molecular-level interactions
• Macroscopic behavior: robust yet fragile
Proteins
Core metabolism
Catabolism
Precursors
Nutrients
Taxis and
transport
Polymerization
and complex
Autocatalytic feedback
assembly
Nucleotides
Regulation
Trans*
& control
Carriers
Genes
Regulation & control
DNA
replication
The architecture of the cell.
Bowtie: Flow of energy and materials
Universal organizational
structures/architectures
Hourglass
Organization
of control
Proteins
Core metabolism
Catabolism
Precursors
Nutrients
Taxis and
transport
Polymerization
and complex
Autocatalytic feedback
assembly
Nucleotides
Regulation
Trans*
& control
Carriers
Genes
Regulation & control
DNA
replication
The architecture of the cell.
Proteins
Taxis and
transport
Carriers
Catabolism
Nucleotides
Carriers
Regulation & control
Proteins
Proteins
Catabolism
Precursors
Regulation
Trans* & control
Carriers
Nucleotides
Regulation & control
DNA
replication
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Proteins
Regulation
Trans* & control
Catabolism
Nucleotides
Regulation
Trans* & control
Carriers
Genes
Regulation & control
DNA
replication
Core metabolism
Carriers
Genes
Regulation & control
Genes
DNA
replication
Core metabolism
Nutrients
Precursors
Nutrients
Nucleotides
Regulation
Trans* & control
Carriers
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Core metabolism
Catabolism
Nucleotides
Genes
DNA
replication
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Catabolism
Precursors
Genes
Regulation & control
Regulation
Trans* & control
Nutrients
Regulation
Trans* & control
Proteins
Core metabolism
Nutrients
Nucleotides
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Core metabolism
Nutrients
Catabolism
Precursors
Nutrients
Core metabolism
Proteins
Precursors
Taxis and
transport
Polymerization
and complex
Autocatalytic feedback
assembly
Precursors
Polymerization
and complex
Autocatalytic feedback
assembly
DNA
replication
Regulation & control
Multicellularity
Genes
Regulation & control
DNA
replication
Robustness:
Efficient and flexible metabolism
Fragility: Obesity and diabetes
Cell
Cell
Glucose
and
Oxygen
Transport
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Autocatalytic and regulatory feedback
Robust
Yet Fragile
1. Efficient, flexible
metabolism
1. Obesity and diabetes
and
2. Complex development
and
2. Rich parasite
ecosystem
3. Immune systems
3. Auto-immune disease
4. Regeneration & renewal
4. Cancer
5. Complex societies
5. Epidemics, war,
genocide, …
Human robustness and fragility
Nightmare?
Biology: We might accumulate more complete
parts lists but never “understand” how it all works.
Technology: We might build increasingly complex
and incomprehensible systems which will
eventually fail completely yet cryptically.
Nothing in the orthodox views of complexity
says this won’t happen (apparently).
HOPE?
Interesting systems are robust yet fragile.
Identify the fragility, evaluate and protect it.
The rest (robust) is “easy”.
Nothing in the orthodox views of complexity
says this can’t happen (apparently).
Architecture?
• “The bacterial cell and the Internet have
– architectures
– that are robust and evolvable”
• What does “architecture” mean?
• What does it mean for an “architecture” to
be robust and evolvable?
• Robust yet fragile?
• Rigorous and coherent theory?
rpoH
Heat
 mRNA
Regulation
of
protein
levels
Regulation of
protein action



• Cartoons
and stories
• No math
+
Taxis and
RNAP

DnaK
ftsH
Lon
RNAP
DnaK
transport
DnaK
DnaK
FtsH
Autocatalytic feedback
Lon
+
Proteins
+
Gly
G1P
Catabolism
G6P
F6P
Precursors
Core+metabolism
Nucleotides
Trans*
F1-6BP
Carriers
Gly3p
ATP
13BPG
Genes
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
Regulation & control
motif
rpoH
Other
operons
DnaK
Lon
motif
Heat
rpoH
folded
unfolded
Other
operons
DnaK
Lon
degradation
DnaK
Lon
rpoH
Heat
 mRNA

Other
operons
DnaK
RNAP
Lon

RNAP
DnaK
FtsH
Lon
rpoH
Heat
 mRNA


Other
operons

RNAP
DnaK
DnaK
DnaK
ftsH
Lon

RNAP
DnaK
FtsH
Lon
rpoH
Heat
 mRNA


Other
operons

RNAP
DnaK
DnaK
DnaK
ftsH
Lon

RNAP
DnaK
FtsH
Lon
rpoH
Heat
 mRNA
Regulation
of
protein
levels
Regulation of
protein action



RNAP
DnaK
DnaK
DnaK
ftsH
Lon

RNAP
DnaK
FtsH
Lon
rpoH
Heat
 mRNA


Other
operons

RNAP
DnaK
DnaK
DnaK
ftsH
Lon

RNAP
DnaK
FtsH
Lon
motif
rpoH
Other
operons
DnaK
Lon
Variety of
Ligands &
Receptors
Transmitter
Receiver
•
•
•
•
•
•
Ubiquitous protocol
“Hourglass”
“Robust yet fragile”
Robust & evolvable
Fragile to “hijacking”
Manages extreme
heterogeneity with
selected homogeneity
• Accident or necessity?
Variety of
responses
Signal transduction
Variety of
Ligands &
Receptors
Gproteins
Primary
targets
Variety of
responses
Bio: Huge variety of environments, metabolisms
Universal
control
architecture
Allosteric
regulation
Regulation of
enzyme levels
Huge variety of genomes
Huge variety of components
The Internet hourglass
Applications
Web
FTP
Mail
Ethernet 802.11
News
Video
Power lines ATM
Audio
Optical
Link technologies
ping
napster
Satellite Bluetooth
The Internet hourglass
Applications
Web
FTP
Mail
News
Video
Audio
ping
napster
TCP
IP
Ethernet 802.11
Power lines ATM
Optical
Link technologies
Satellite Bluetooth
The Internet hourglass
Applications
Web
FTP
Mail
News
Video Audio
IP under
everything
ping
napster
TCP
IP
Ethernet 802.11
IP on
Power lines ATM Optical
everything
Link technologies
Satellite Bluetooth
Bio: Huge variety of environments, metabolisms
Internet: Huge variety of applications
Huge variety of components
Bio: Huge variety of environments, metabolisms
Internet: Huge variety of applications
Both components
and applications are
highly uncertain.
Huge variety of components
Bio: Huge variety of environments, metabolisms
Internet: Huge variety of applications
Huge variety of genomes
Huge variety of physical networks
Huge variety of components
Hourglass architectures
Bio: Huge variety of environments, metabolisms
Internet: Huge variety of applications
Feedback
control
Identical
control
architecture
Huge variety of genomes
Huge variety of physical networks
Huge variety of components
Bio: Huge variety of environments, metabolisms
Universal
control
architecture
Allosteric
regulation
Regulation of
enzyme levels
Huge variety of genomes
Huge variety of components
rpoH
Heat
 mRNA
Regulation
of
protein
levels
Gly
Regulation of
protein action



RNAP
DnaK
DnaK
DnaK
ftsH
G1P
Lon
G6P

RNAP
F6P
DnaK
FtsH
Lon
F1-6BP
Gly3p
ATP
13BPG
3PG
2PG
Allosteric
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
Trans*
TCP/IP
Metabolism/biochem
5:Application/function: variable supply/demand
4:TCP
3:IP
Feedback
Control
4:Allosteric
3:Transcriptional
2:Potential physical network
1:Hardware components
TCP/IP robustness/evolvability on many timescales
• Shortest: File transfers from different users
– Application-specific navigation (application)
– Congestion control to share the net (TCP)
– Ack-based retransmission (TCP)
• Short: Fail-off of routers and servers
– Rerouting around failures (IP)
– Hot-swaps and rebooting of hardware
• Long: Rearrangements of existing components
– Applications/clients/servers can come and go
– Hardware of all types can come and go
• Longer: New applications and hardware
– Plug and play if they obey the protocols
TCP/IP fragility on many timescales
• Shortest: File transfers from different users
– End systems w/o congestion control won’t
fairly share
• Short: Fail-on of components
– Distributed denial of service
– Black-holing and other fail-on cascading
failures
• Long: Spam, viruses, worms
• Longer: No economic model for ISPs?
Robustness/evolvability on many timescales
• Shortest to short: Fluctuations in supply/demand
– Allosteric regulation of enzymes (4)
– Expression of enzyme level (3)
• Short: Failure/loss of individual enzyme
molecules (3)
– Chaperones attempt repair, proteases degrade
– Transcription makes more
• Long: Incorporating new components
– Acquire new enzymes by lateral gene transfer
• Longer: Creating new applications and hardware
– Duplication and divergent evolution of new
enzymes that still obey basic protocols
Biochem fragility on many timescales
• Shortest: Fluctuations in demand/supply
that exceeds regulatory capability (e.g.
glycolytic oscillations)
• Short: Fail-on of components
– Indiscriminate kinases, loss of repression, …
– Loss of tumor suppressors
• Long: Infectious hijacking
• Longer: Diabetes, obesity
Robust yet fragile (RYF)
• The same mechanisms responsible for
robustness to most perturbations
• Allows possible extreme fragilities to others
• Usually involving hijacking the robustness
mechanism in some way
• High variability (and thus power laws)
Experimental (and network) biology
• Laws: Conservation of energy and matter
• Modules: Pipettes, Petri dishes, PCR
machines, microscopes,…
• Protocols: Rules and recipes by which
modules interact to create function
• All 3 must be understood.
• Laws are immutable
• Protocols are more important than modules
Taxis and
transport
Polymerization
and complex
Autocatalytic feedback
assembly
Proteins
• Laws: Conservation of energy, matter, and
robustness/fragility
Regulation
Catabolism
Nucleotides
Trans* & control
• Modules: Enzymes and metabolites
• Protocols: Control, bowties and hourglasses
Carriers
• Principles???
Precursors
Nutrients
Core metabolism
Genes
Regulation & control
DNA
replication
Bowtie: Flow of energy and materials
Universal organizational
structures/architectures
Hourglass
Organization
of control
Proteins
Core metabolism
Catabolism
Precursors
Nutrients
Taxis and
transport
Polymerization
and complex
Autocatalytic feedback
assembly
Nucleotides
Regulation
Trans*
& control
Carriers
Genes
Regulation & control
DNA
replication
The architecture of the cell.
Bacterial cell
Environment
Huge
Variety
Environment
Huge
Variety
Catabolism
Precursors
Nutrients
Taxis and
transport
20
same
in all
cells
Core metabolism
Nucleotides
Carriers
Huge
Variety
100
same
in all
organisms
Catabolism
Precursors
Core metabolism
Nucleotides
Carriers
Nested bowties
Precursors
Catabolism
Carriers
Nucleotides
Precursors
Catabolism
Carriers
Gly
G1P
G6P
Catabolism
F6P
F1-6BP
Gly3p
ATP
13BPG
3PG
2PG
NADH
Oxa
PEP
Pyr
ACA
TCA
Cit
Gly
Precursors
G1P
G6P
F6P
F1-6BP
Gly3p
13BPG
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
Cit
Gly
Precursors
G1P
G6P
F6P
Autocatalytic
F1-6BP
Gly3p
Carriers
ATP
13BPG
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
Gly
G1P
G6P
F6P
Precursors
20 same
in all cells
F1-6BP
Gly3p
Carriers
ATP
13BPG
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
Gly
G1P
G6P
Regulatory
F6P
F1-6BP
Gly3p
ATP
13BPG
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
Gly
This is still a cartoon.
(Cartoons are useful.)
G1P
G6P
F6P
F1-6BP
Gly3p
ATP
13BPG
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
13BPG
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
Cit
If we drew the feedback loops the
diagram would be unreadable.
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
ATP
13BPG
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
Gly
Gly
G1P
G1P
This
cannot.
G6P
G6P
F6P
F6P
F1-6BP
F1-6BP
This can be
modeled to some
13BPG
extent as a graph.
Gly3p
3PG
2PG
PEP
Pyr
ACA
Gly3p
ATP
13BPG
3PG
2PG
PEP
NADH
Unfortunate and unnecessary confusion
results from not “getting” this.
Pyr
ACA
Biology is not a graph.
Stoichiometry plus
regulation
dx
 Sv( x)
dt
 Mass & 
 Reaction 
d


 Mass&Energy    Energy  

flux 
dt

 Balance 
dx
 S
Sv( x)
dt
 Mass & 
 Reaction 


  Energy  

flux

 Balance  
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
ATP
Stoichiometry
matrix
13BPG
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
dx
 Sv( x)
dt
 Mass & 
 Reaction 


  Energy  

flux

 Balance  
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
Regulation of enzyme levels by
transcription/translation/degradation
13BPG
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
Cit
dx
 Sv( x)
dt
 Mass & 
 Reaction 


  Energy  

flux

 Balance  
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
ATP
13BPG
Allosteric regulation
of enzymes
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
 Mass & 
 Reaction 
dx


 Sv( x)   Energy  

flux
dt

 Balance  
Gly
G1P
G6P
Allosteric regulation
of enzymes
F6P
F1-6BP
Regulation of
enzyme levels
Gly3p
ATP
13BPG
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
Regulation of
protein action
Allosteric regulation
of enzymes
Regulation of
protein levels
Regulation of
enzyme levels
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Proteins
Catabolism
Precursors
Nutrients
Core metabolism
Nucleotides
Regulation
Trans* & control
Carriers
Genes
Regulation & control
DNA
replication
Gene networks?
essential:
nonessential:
unknown:
total:
230
2373
1804
4407
http://www.shigen.nig.ac.jp/ecoli/pec
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Proteins
Catabolism
Precursors
Nutrients
Core metabolism
Nucleotides
Trans*
Carriers
Genes
DNA
replication
Regulation
& control
E. coli
genome
Precursors
Fragility example: Viruses
Carriers
Viruses exploit the universal
bowtie/hourglass structure
to hijack the cell machinery.
Trans*
Fragility example: Viruses
Catabolism
Precursors
Nutrients
Core metabolism
Nucleotides
Proteins
Viral
proteins
Trans*
Carriers
Genes
Viral
genes DNA
Viruses exploit the universal
bowtie/hourglass structure
to hijack the cell machinery.
replication
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Proteins
Catabolism
Precursors
Nutrients
Core metabolism
Nucleotides
Regulation
Trans* & control
Carriers
Genes
Regulation & control
DNA
replication
Proteins
Taxis and
transport
Carriers
Catabolism
Nucleotides
Carriers
Regulation & control
Proteins
Proteins
Catabolism
Precursors
Regulation
Trans* & control
Carriers
Nucleotides
Regulation & control
DNA
replication
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Proteins
Regulation
Trans* & control
Catabolism
Nucleotides
Regulation
Trans* & control
Carriers
Genes
Regulation & control
DNA
replication
Core metabolism
Carriers
Genes
Regulation & control
Genes
DNA
replication
Core metabolism
Nutrients
Precursors
Nutrients
Nucleotides
Regulation
Trans* & control
Carriers
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Core metabolism
Catabolism
Nucleotides
Genes
DNA
replication
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Catabolism
Precursors
Genes
Regulation & control
Regulation
Trans* & control
Nutrients
Regulation
Trans* & control
Proteins
Core metabolism
Nutrients
Nucleotides
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Core metabolism
Nutrients
Catabolism
Precursors
Nutrients
Core metabolism
Proteins
Precursors
Taxis and
transport
Polymerization
and complex
Autocatalytic feedback
assembly
Precursors
Polymerization
and complex
Autocatalytic feedback
assembly
DNA
replication
Regulation & control
Multicellularity
Genes
Regulation & control
DNA
replication
Robustness:
Efficient and flexible metabolism
Fragility: Obesity and diabetes
Cell
Cell
Glucose
and
Oxygen
Transport
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Autocatalytic and regulatory feedback
Robust
Yet Fragile
1. Efficient, flexible
metabolism
1. Obesity and diabetes
and
2. Complex development
and
2. Rich parasite
ecosystem
3. Immune systems
3. Auto-immune disease
4. Regeneration & renewal
4. Cancer
5. Complex societies
5. Epidemics, war,
genocide, …
Human robustness and fragility
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Proteins
Catabolism
Precursors
Nutrients
Core metabolism
Nucleotides
Trans*
Carriers
Genes
DNA
replication
Regulation
& control
E. coli
genome
motif
rpoH
Other
operons
DnaK
Lon
motif
Heat
rpoH
folded
unfolded
Other
operons
DnaK
Lon
degradation
DnaK
Lon
rpoH
Heat
 mRNA

Other
operons
DnaK
RNAP
Lon

RNAP
DnaK
FtsH
Lon
rpoH
Heat
 mRNA


Other
operons

RNAP
DnaK
DnaK
DnaK
ftsH
Lon

RNAP
DnaK
FtsH
Lon
rpoH
Heat
 mRNA


Other
operons

RNAP
DnaK
DnaK
DnaK
ftsH
Lon

RNAP
DnaK
FtsH
Lon
rpoH
Heat
 mRNA
Regulation
of
protein
levels
Regulation of
protein action



RNAP
DnaK
DnaK
DnaK
ftsH
Lon

RNAP
DnaK
FtsH
Lon
Polymerization
and complex
Autocatalytic feedback
assembly
Taxis and
transport
Proteins
Catabolism
Precursors
Nutrients
Core metabolism
Nucleotides
Trans*
Carriers
Genes
DNA
replication
Regulation
& control
Bowtie: Flow of energy and materials
Universal organizational structures/architectures
Hourglass
Organization
of control
Hourglass
Organization
of control
The Internet hourglass
Applications
Web
FTP
Mail
Ethernet 802.11
News
Video
Power lines ATM
Audio
Optical
Link technologies
ping
napster
Satellite Bluetooth
The Internet hourglass
Applications
Web
FTP
Mail
News
Video
Audio
ping
napster
TCP
IP
Ethernet 802.11
Power lines ATM
Optical
Link technologies
Satellite Bluetooth
The Internet hourglass
Applications
Web
FTP
Mail
News
Video Audio
IP under
everything
ping
napster
TCP
IP
Ethernet 802.11
IP on
Power lines ATM Optical
everything
Link technologies
Satellite Bluetooth
Bio: Huge variety of environments, metabolisms
Internet: Huge variety of applications
Huge variety of components
Bio: Huge variety of environments, metabolisms
Internet: Huge variety of applications
Both components
and applications are
highly uncertain.
Huge variety of components
Bio: Huge variety of environments, metabolisms
Internet: Huge variety of applications
Huge variety of genomes
Huge variety of physical networks
Huge variety of components
Hourglass architectures
Bio: Huge variety of environments, metabolisms
Internet: Huge variety of applications
Feedback
control
Identical
control
architecture
Huge variety of genomes
Huge variety of physical networks
Huge variety of components
Bio: Huge variety of environments, metabolisms
Universal
control
architecture
Allosteric
regulation
Regulation of
enzyme levels
Huge variety of genomes
Huge variety of components
rpoH
Heat
 mRNA
Regulation
of
protein
levels
Regulation of
protein action



RNAP
DnaK
DnaK
DnaK
ftsH
Gly
Lon
G1P

RNAP
G6P
DnaK
FtsH
Lon
F6P
F1-6BP
Gly3p
ATP
13BPG
3PG
2PG
Allosteric
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
Trans*
TCP/IP
Metabolism/biochem
5:Apps: Supply and
demand of packet flux
5:Apps:supply and demand
of nutrients and products
4:TCP: robustness to
changing supply/demand,
and packet losses
4:Allosteric regulation of
enzymes: robust to changing
supply/demand
3:IP: routes on physical
network, rerouting for
router losses
3:Transcriptional regulation
of enzyme levels
2:Physical: Raw
physical network
2:Genome: Raw potential
stoichiometry network
1:Hardware catalog: routers,
links, servers, hosts,…
1:Hardware catalog: DNA,
genes, enzymes, carriers,…
TCP/IP
Metabolism/biochem
5:Application/function: variable supply/demand
4:TCP
3:IP
Feedback
Control
4:Allosteric
3:Transcriptional
2:Potential physical network
1:Hardware components
Protocols and modules
• Protocols are the rules by which
modules are interconnected
• Protocols are more fundamental to
“modularity” than modules
TCP
IP
Vertical decomposition
Protocol Stack
Application
IP
Application
Application
Each layer can evolve
TCP
TCP
independently provided:
1. Follow the rules
2. Everyone else does
IP
IP with IP
“good enough”
their layer
Routing
Provisioning
Application
Application
TCP
TCP
IP
Application
IP
IP
TCP
IP
IP
Horizontal decomposition
Each level is decentralized and asynchronous
Routing
Provisioning
Bowtie: Flow of energy and materials
Universal organizational
structures/architectures
Hourglass
Organization
of control
Robust yet fragile (RYF)
• The same mechanisms responsible for
robustness to most perturbations
• Allows possible extreme fragilities to others
• Usually involving hijacking the robustness
mechanism in some way
• High variability (and thus power laws)
Facilitate regulation on multiple time scales:
1. Fast: allostery
2. Slower: transcriptional regulation (by regulated
recruitment) and degradation
3. Even slower: transfer of genes
4. Even slower: copying and evolution of genes
TCP/IP robustness/evolvability on many timescales
• Shortest: File transfers from different users
– Application-specific navigation (application)
– Congestion control to share the net (TCP)
– Ack-based retransmission (TCP)
• Short: Fail-off of routers and servers
– Rerouting around failures (IP)
– Hot-swaps and rebooting of hardware
• Long: Rearrangements of existing components
– Applications/clients/servers can come and go
– Hardware of all types can come and go
• Longer: New applications and hardware
– Plug and play if they obey the protocols
TCP/IP fragility on many timescales
• Shortest: File transfers from different users
– End systems w/o congestion control won’t
fairly share
• Short: Fail-on of components
– Distributed denial of service
– Black-holing and other fail-on cascading
failures
• Long: Spam, viruses, worms
• Longer: No economic model for ISPs?
Robustness/evolvability on many timescales
• Shortest to short: Fluctuations in supply/demand
– Allosteric regulation of enzymes (4)
– Expression of enzyme level (3)
• Short: Failure/loss of individual enzyme
molecules (3)
– Chaperones attempt repair, proteases degrade
– Transcription makes more
• Long: Incorporating new components
– Acquire new enzymes by lateral gene transfer
• Longer: Creating new applications and hardware
– Duplication and divergent evolution of new enzymes
that still obey basic protocols
Allosteric regulation
Polymerization
and complex
assembly
Nutrient
Precursors
Proteins
Nucleotides
Trans*
Carriers
Genes
DNA
replication
Polymerization
and complex
Autocatalytic feedback
assembly
Nutrient
Precursors
Proteins
Nucleotides
Regulation
Trans* & control
Carriers
Genes
Regulation & control
DNA
replication
Robustness/evolvability on many timescales
• Shortest to short: Fluctuations in supply/demand
– Allosteric regulation of enzymes (4)
– Expression of enzyme level (3)
• Short: Failure/loss of individual enzyme
molecules (3)
– Chaperones attempt repair, proteases degrade
– Transcription makes more
• Long: Incorporating new components
– Acquire new enzymes by lateral gene transfer
• Longer: Creating new applications and hardware
– Duplication and divergent evolution of new enzymes
that still obey basic protocols
Robustness/evolvability on many timescales
• Shortest to short: Fluctuations in supply/demand
– Allosteric regulation of enzymes (4)
– Expression of enzyme level (3)
• Short: Failure/loss of individual enzyme
molecules (3)
– Chaperones attempt repair, proteases degrade
– Transcription makes more
• Long: Incorporating new components
– Acquire new enzymes by lateral gene transfer
• Longer: Creating new applications and hardware
– Duplication and divergent evolution of new enzymes
that still obey basic protocols
What if a pathway is needed?
But isn’t there?
Slower time scales (  hoursdays), genes are transferred
between organisms.
This is only possible with
shared protocols.
Robustness/evolvability on many timescales
• Shortest to short: Fluctuations in supply/demand
– Allosteric regulation of enzymes (4)
– Expression of enzyme level (3)
• Short: Failure/loss of individual enzyme
molecules (3)
– Chaperones attempt repair, proteases degrade
– Transcription makes more
• Long: Incorporating new components
– Acquire new enzymes by lateral gene transfer
• Longer: Creating new applications and hardware
– Duplication and divergent evolution of new
enzymes that still obey basic protocols
Slowest time scales (  forever), genes are
copied and mutate to create new enzymes.
Evolving evolvability?
Variation
Selection
?
Evolving evolvability?
Variation
“facilitated”
“structured”
“organized”
Selection
transport
metabolism
assembly
Robust?: Fragile to fluctuations
Evolvable?: Hard to change
Variety of
producers
Energy
carriers
Variety of
consumers
Biochem fragility on many timescales
• Shortest: Fluctuations in demand/supply
that exceeds regulatory capability (e.g.
glycolytic oscillations)
• Short: Fail-on of components
– Indiscriminate kinases, loss of repression, …
– Loss of tumor suppressors
• Long: Infectious hijacking
• Longer: Diabetes, obesity
Robust yet fragile (RYF)
• The same mechanisms responsible for
robustness to most perturbations
• Allows possible extreme fragilities to others
• Usually involving hijacking the robustness
mechanism in some way
• High variability (and thus power laws)
Bowtie: Flow of energy and materials
Universal organizational structures/architectures
Hourglass
Organization
of control
Variety of
Ligands &
Receptors
Transmitter
Receiver
•
•
•
•
•
•
Ubiquitous protocol
“Hourglass”
“Robust yet fragile”
Robust & evolvable
Fragile to “hijacking”
Manages extreme
heterogeneity with
selected homogeneity
• Accident or necessity?
Variety of
responses
Signal transduction
Variety of
Ligands &
Receptors
Gproteins
Primary
targets
Variety of
responses
Random walk
Ligand
Motion
Motor
Bacterial chemotaxis
Biased random walk
gradient
Ligand
Motion
Signal
Transduction
Motor
CheY
Common
energy carrier
++
Variety of
receptors/
ligands
Common
signal
carrier
+
+
Common
cytoplasmic
domains
From Taylor, Zhulin, Johnson
Motor
Transmitter
Receiver
Variety of Ligands
& Receptors
Variety of Ligands
& Receptors
Transmitter
Receiver
Motor
Variety of
Ligands &
Receptors
Transmitter
Receiver
Variety of
responses
• 50 such “two component”
systems in E. Coli
• All use the same protocol
- Histidine autokinase
transmitter
- Aspartyl phosphoacceptor receiver
• Huge variety of receptors
and responses
Signal
transduction
Applications
TCP
Variety of
Ligands &
Receptors
Transmitter
Receiver
IP
Link
Variety of
responses
Variety of Ligands
& Receptors
Transmitter
Receiver
Motor
• 50 such “two component”
Variety of Ligands
systems in E. Coli
& Receptors Other
Other
Receptors
Other&
• All use the same protocol
Receptors
Other&
Ligands
Receptors
Other&
- Histidine autokinase
Ligands
Receptors
Other&
Ligands
Receptors
Other&
transmitter
Ligands
Receptors
Other&
Ligands
Receptors
Other&
Ligands
Receptors
Other&
- Aspartyl phosphoLigands
Receptors
Other
&
Transmitter
Ligands
Receptors
Other&
acceptor receiver
Ligands
Receptors
&
Transmitter
ReceiverTransmitter Ligands
Receptors & • Huge variety of receptors
Ligands
Receiver
Transmitter
Ligands
Receiver
Transmitter
and responses
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Motor Other
Receiver
Transmitter
Receiver
Other
Receiver
Responses
Other
Responses
Other
Responses
Other
Responses
Other
Responses
Other
Responses
Other
Responses
Other
Responses
Other
Responses
Other
Responses
Other
Responses
Responses
Molecular
phylogenies
show
evolvability of
the bowtie
architecture.
conserved residues of
interaction surface with
phosphotransferase
domains
invariant
active-site
residues
highly variable amino acids
of the interaction surface
that are responsible for
specificity of the
interaction
conserved functional
domains
invariant
active-site
residues
• Automobiles: Keys
provide specificity but no
other function. Other
function conserved,
driver/vehicle interface
protocol is “universal.”
• Ethernet cables:
Specificity via MAC
MAC
addresses, function via
standardized protocols.
highly
variability for
specificity of the
interaction
Variety of
Ligands &
Receptors
Transmitter
Receiver
• 50 such “two component”
systems in E. Coli
• Ubiquitous eukaryote
protocol
• Huge variety of
– receptors/ligands
– downstream responses
Variety of
responses
• Large number of Gproteins grouped into
similar classes
• Handful of primary
targets
Variety of
Ligands &
Receptors
Gproteins
Primary
targets
Variety of
responses
Ligand
GEF
In
In
Receptor
GDP
GTP
GDP
GTP

GDI

G
GDI
G
GDP
GTP
Out
Rho
Rho
GDP
P
P
RGS
In
In
GAP
GTP
Out
Receptors
In
GDP
GTP
G-proteins
Out
GDP
GTP
Primary
targets
P
In
Responses
Speed, adaptation,
integration, evolvability
In
GDP
GTP
Robustness
GDP
GTP
Out
Impedance
matching:
Independent of
G of inputs and
outputs
P
In
Signal integration:
High “fan in” and
“fan out”
Uncertain
Variety of Ligands
& Receptors
Robust and
highly
evolvable
Intermediates
Variety of
responses
Uncertain
Fragile
and hard
to change
Fragility?
• A huge variety of pathogens attack
and hijack GTPases.
• A huge variety of cancers are
associated with altered (hijacked)
GTPase pathways.
• The GTPases may be the least
evolvable elements in signaling
pathways, in part because they
facilitate evolvability elsewhere
GEF
In
GDP
GTP
GDI
GDI
Rho
Rho
GDP
GTP
P
In
GAP
Out
Hijacking
Ligand
In
Receptor
GDP
GTP


G
GDP
G C-AMP
GTP
P
Cholera toxin
Cholera toxins hijack
the signal transduction
by blocking a GTPase
activity.
Bacterial virulence factors targeting Rho
GTPases: parasitism or symbiosis?
Patrice Boquet and Emmanuel Lemichez
TRENDS in Cell Biology May 2003
Variety of
Ligands &
Receptors
Transmitter
Receiver
Variety of
responses
But you already knew all this.
•
•
•
•
•
Ubiquitous protocol
“Hourglass”
Robust & evolvable
Fragile to “hijacking”
Manages extreme
heterogeneity with
selected homogeneity
• Accident or necessity?
Variety of
Ligands &
Receptors
Gproteins
Primary
targets
Variety of
responses
Theoretical foundations for networks
• The most rigorous, sophisticated, and
applicable of existing theories
– Computation
– Control
– Communications
•
•
•
•
Have become fragmented and isolated
Failed attempts at unified “new sciences”
Need new mathematics
Recent progress has been spectacular, both
in rigor and relevance
A look back and forward
• The Internet architecture was designed
without a theory.
• Many academic theorists told the engineers
it would never work.
• We now have a nascent theory that confirms
that the engineers were right.
• For MANETs and other new technologies,
let’s hope we can avoid a repeat of this
history.
Multiscale
Physics
Network
Centric,
Pervasive,
Embedded,
Ubiquitous
Core
theory
challenges
Systems
Biology