Co-factors

1
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
Complexity and Robustness
DNA replication
John Doyle John G Braun Professor Control and
Dynamical Systems, BioEng, and ElecEng Caltech
www.cds.caltech.edu/doyle
2
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, DAndrea, 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
Other
Longterm Visitor
3
Multiscale Physics
Core theory challenges
Network Centric, Pervasive, Embedded, Ubiquitous
Systems Biology
4
Todays focus
Core theory challenges
Network Centric, Pervasive, Embedded, Ubiquitous
Systems Biology
5
Status
Yet also striking increase in unnecessary
confusion???
Consistent, coherent, convergent understanding.
Remarkably common core theoretical challenges.
Core theory challenges
Core theory challenges
Dramatic recent progress in laying the foundation.
Core theory challenges
Systems Biology
Pervasive, Networked, Embedded
6
Feathers and flapping?
Or lift, drag, propulsion, and control?
The danger of biomemetics
7
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.

8
Core theory challenges

• Hard constraints
• Simple models
• Short proofs
• Architecture

9
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, lets hope we can avoid a
  repeat of this history.

10
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?

11
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.
12
Hard constraints (progress)

• Thermodynamics (Carnot)
• Communications (Shannon)
• Control (Bode)
• Computation (Turing/Gödel)
• We need a more integrated view and have the
  beginnings

13
Work in progress

• Thermodynamics (Carnot)
• Communications (Shannon)
• Control (Bode)
• Computation (Turing/Gödel)
• We need a more integrated view and have the
  beginnings

14
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?

15
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

16
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Precursors
Nucleotides
Regulation control
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
The architecture of the cell.
17
Bowtie Flow of energy and materials
Universal organizational structures/architectures
Organization of control
Hourglass
18
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Precursors
Nucleotides
Regulation control
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
The architecture of the cell.
19
Regulation control
Multicellularity
20
Robustness Efficient and flexible metabolism
Fragility Obesity and diabetes
Glucose and Oxygen
Cell
Transport
Cell
Autocatalytic and regulatory feedback
21
Robust
Yet Fragile

1. Efficient, flexible metabolism
2. Complex development and
3. Immune systems
4. Regeneration renewal
5. Complex societies

1. Obesity and diabetes and
2. Rich parasite ecosystem
3. Auto-immune disease
4. Cancer
5. Epidemics, war, genocide,

Human robustness and fragility
22
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 wont happen (apparently).
23
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 cant happen (apparently).
24
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?

25

• Cartoons and stories
• No math

Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Precursors
Nucleotides
Trans
Fatty acids
Genes
Co-factors
Carriers
Regulation control
From Taylor, Zhulin, Johnson
26
(No Transcript)
27
(No Transcript)
28
motif
rpoH
Other operons
DnaK
Lon
29
motif
Heat
rpoH
folded
unfolded
Other operons
DnaK
Lon
DnaK
Lon
30
Heat
rpoH
? mRNA
?
Other operons
DnaK
RNAP
Lon
RNAP
?
DnaK
FtsH
Lon
31
Heat
rpoH
? mRNA
?
?
DnaK
Other operons
?
DnaK
DnaK
RNAP
ftsH
Lon
RNAP
?
DnaK
FtsH
Lon
32
Heat
rpoH
? mRNA
?
?
DnaK
Other operons
?
DnaK
DnaK
ftsH
RNAP
Lon
?
RNAP
DnaK
FtsH
Lon
33
Heat
rpoH
? mRNA
Regulation of protein action
Regulation of protein levels
?
?
DnaK
?
DnaK
DnaK
ftsH
RNAP
Lon
?
RNAP
DnaK
FtsH
Lon
34
Heat
rpoH
? mRNA
?
?
DnaK
Other operons
?
DnaK
DnaK
ftsH
RNAP
Lon
?
RNAP
DnaK
FtsH
Lon
35
motif
rpoH
Other operons
DnaK
Lon
36
(No Transcript)
37
Variety of Ligands Receptors

• Ubiquitous protocol
• Hourglass
• Robust yet fragile
• Robust evolvable
• Fragile to hijacking
• Manages extreme heterogeneity with selected
  homogeneity
• Accident or necessity?

Transmitter
Receiver
Variety of responses
Signal transduction
38
Bio Huge variety of environments, metabolisms
Allosteric regulation
Universal control architecture
Regulation of enzyme levels
Huge variety of genomes
Huge variety of components
39
The Internet hourglass
Applications
Web
FTP
Mail
News
Video
Audio
ping
napster
Ethernet
802.11
Satellite
Optical
Power lines
Bluetooth
ATM
Link technologies
40
The Internet hourglass
Applications
Web
FTP
Mail
News
Video
Audio
ping
napster
TCP
IP
Ethernet
802.11
Satellite
Optical
Power lines
Bluetooth
ATM
Link technologies
41
The Internet hourglass
Applications
IP under everything
Web
FTP
Mail
News
Video
Audio
ping
napster
TCP
IP
Ethernet
802.11
Satellite
Optical
Power lines
Bluetooth
ATM
Link technologies
42
Bio Huge variety of environments,
metabolisms Internet Huge variety of applications
Huge variety of components
43
Bio Huge variety of environments,
metabolisms Internet Huge variety of applications
Both components and applications are highly
uncertain.
Huge variety of components
44
Bio Huge variety of environments,
metabolisms Internet Huge variety of applications
Huge variety of genomes Huge variety of physical
networks
Huge variety of components
45
Hourglass architectures
Bio Huge variety of environments,
metabolisms Internet Huge variety of applications
Identical control architecture
Feedback control
Huge variety of genomes Huge variety of physical
networks
Huge variety of components
46
Bio Huge variety of environments, metabolisms
Allosteric regulation
Universal control architecture
Regulation of enzyme levels
Huge variety of genomes
Huge variety of components
47
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
ATP
13BPG
Allosteric
TCA
3PG
Oxa
Trans
ACA
PEP
Pyr
2PG
NADH
Cit
48
TCP/IP
Metabolism/biochem
5Application/function variable supply/demand
Feedback Control
4TCP
4Allosteric
3Transcriptional
3IP
2Potential physical network
1Hardware components
49
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

50
TCP/IP fragility on many timescales

• Shortest File transfers from different users
• End systems w/o congestion control wont 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?

51
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

52
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

53
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)

54
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

55
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars

• Laws Conservation of energy, matter, and
  robustness/fragility
• Modules Enzymes and metabolites
• Protocols Control, bowties and hourglasses
• Principles???

Catabolism
Amino Acids
Nucleotides
Precursors
Regulation control
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
56
Bowtie Flow of energy and materials
Universal organizational structures/architectures
Organization of control
Hourglass
57
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Precursors
Nucleotides
Regulation control
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
The architecture of the cell.
58
Bacterial cell
Environment
Environment
Huge Variety
Huge Variety
59
?20 same in all cells
Taxis and transport
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Fatty acids
Co-factors
Carriers

• ?100
• same
• in all
• organisms

Huge Variety
60
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Fatty acids
Co-factors
Carriers
Nested bowties
61
Sugars
Amino Acids
Nucleotides
Fatty acids
Co-factors
62
(No Transcript)
63
Catabolism
64
Precursors
65
Gly
G1P
G6P
Precursors
F6P
Autocatalytic
F1-6BP
Gly3p
Carriers
ATP
13BPG
TCA
3PG
Oxa
ACA
Pyr
PEP
2PG
NADH
Cit
66
Gly
?20 same in all cells
G1P
G6P
Precursors
F6P
F1-6BP
Gly3p
Carriers
ATP
13BPG
TCA
3PG
Oxa
ACA
Pyr
PEP
2PG
NADH
Cit
67
Gly
G1P
G6P
Regulatory
F6P
F1-6BP
Gly3p
ATP
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
68
Gly
This is still a cartoon. (Cartoons are useful.)
G1P
G6P
F6P
F1-6BP
Gly3p
ATP
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
69
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
13BPG
TCA
3PG
Oxa
ACA
Pyr
PEP
2PG
Cit
70
If we drew the feedback loops the diagram would
be unreadable.
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
ATP
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
71
Gly
Gly
G1P
G1P
This cannot.
G6P
G6P
F6P
F6P
F1-6BP
F1-6BP
This can be modeled to some extent as a graph.
Gly3p
Gly3p
ATP
13BPG
13BPG
3PG
3PG
PEP
Pyr
2PG
ACA
PEP
Pyr
2PG
ACA
NADH
Unfortunate and unnecessary confusion results
from not getting this.
72
Stoichiometry plus regulation
Biology is not a graph.
73
S
Stoichiometry matrix
74
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
Regulation of enzyme levels by transcription/trans
lation/degradation
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
Cit
75
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
Allosteric regulation of enzymes
ATP
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
76
Gly
G1P
G6P
Allosteric regulation of enzymes
F6P
F1-6BP
Regulation of enzyme levels
Gly3p
ATP
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
77
Allosteric regulation of enzymes
Regulation of protein action
Regulation of enzyme levels
Regulation of protein levels
78
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Not to scale
Nucleotides
Precursors
Regulation control
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
79
Gene networks?
essential 230   nonessential 2373  
unknown 1804   total 4407
http//www.shigen.nig.ac.jp/ecoli/pec
80
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
E. coli genome
81
Fragility example Viruses
Precursors
Trans
Carriers
Viruses exploit the universal bowtie/hourglass
structure to hijack the cell machinery.
82
Fragility example Viruses
Viral proteins
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Precursors
Nucleotides
Nutrients
Trans
Fatty acids
Genes
Viral genes
Co-factors
Carriers
DNA replication
Viruses exploit the universal bowtie/hourglass
structure to hijack the cell machinery.
83
(No Transcript)
84
Regulation control
Multicellularity
85
Robustness Efficient and flexible metabolism
Fragility Obesity and diabetes
Glucose and Oxygen
Cell
Transport
Cell
Autocatalytic and regulatory feedback
86
Robust
Yet Fragile

1. Efficient, flexible metabolism
2. Complex development and
3. Immune systems
4. Regeneration renewal
5. Complex societies

1. Obesity and diabetes and
2. Rich parasite ecosystem
3. Auto-immune disease
4. Cancer
5. Epidemics, war, genocide,

Human robustness and fragility
87
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
E. coli genome
88
(No Transcript)
89
(No Transcript)
90
motif
rpoH
Other operons
DnaK
Lon
91
motif
Heat
rpoH
folded
unfolded
Other operons
DnaK
Lon
DnaK
Lon
92
Heat
rpoH
? mRNA
?
Other operons
DnaK
RNAP
Lon
RNAP
?
DnaK
FtsH
Lon
93
Heat
rpoH
? mRNA
?
?
DnaK
Other operons
?
DnaK
DnaK
RNAP
ftsH
Lon
RNAP
?
DnaK
FtsH
Lon
94
Heat
rpoH
? mRNA
?
?
DnaK
Other operons
?
DnaK
DnaK
ftsH
RNAP
Lon
?
RNAP
DnaK
FtsH
Lon
95
Heat
rpoH
? mRNA
Regulation of protein action
Regulation of protein levels
?
?
DnaK
?
DnaK
DnaK
ftsH
RNAP
Lon
?
RNAP
DnaK
FtsH
Lon
96
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
97
Bowtie Flow of energy and materials
Universal organizational structures/architectures
Organization of control

Hourglass
98
Organization of control

Hourglass
99
The Internet hourglass
Applications
Web
FTP
Mail
News
Video
Audio
ping
napster
Ethernet
802.11
Satellite
Optical
Power lines
Bluetooth
ATM
Link technologies
100
The Internet hourglass
Applications
Web
FTP
Mail
News
Video
Audio
ping
napster
TCP
IP
Ethernet
802.11
Satellite
Optical
Power lines
Bluetooth
ATM
Link technologies
101
The Internet hourglass
Applications
IP under everything
Web
FTP
Mail
News
Video
Audio
ping
napster
TCP
IP
Ethernet
802.11
Satellite
Optical
Power lines
Bluetooth
ATM
Link technologies
102
Bio Huge variety of environments,
metabolisms Internet Huge variety of applications
Huge variety of components
103
Bio Huge variety of environments,
metabolisms Internet Huge variety of applications
Both components and applications are highly
uncertain.
Huge variety of components
104
Bio Huge variety of environments,
metabolisms Internet Huge variety of applications
Huge variety of genomes Huge variety of physical
networks
Huge variety of components
105
Hourglass architectures
Bio Huge variety of environments,
metabolisms Internet Huge variety of applications
Identical control architecture
Feedback control
Huge variety of genomes Huge variety of physical
networks
Huge variety of components
106
Bio Huge variety of environments, metabolisms
Allosteric regulation
Universal control architecture
Regulation of enzyme levels
Huge variety of genomes
Huge variety of components
107
Heat
rpoH
? mRNA
Regulation of protein action
Regulation of protein levels
?
?
DnaK
?
DnaK
DnaK
ftsH
RNAP
Gly
Lon
G1P
?
RNAP
G6P
DnaK
FtsH
Lon
F6P
F1-6BP
Gly3p
ATP
13BPG
Allosteric
TCA
3PG
Oxa
Trans
ACA
PEP
Pyr
2PG
NADH
Cit
108
TCP/IP
Metabolism/biochem
5Appssupply and demand of nutrients and products
5Apps Supply and demand of packet flux
4Allosteric regulation of enzymes robust to
changing supply/demand
4TCP robustness to changing supply/demand, and
packet losses
3IP routes on physical network, rerouting for
router losses
3Transcriptional regulation of enzyme levels
2Physical Raw physical network
2Genome Raw potential stoichiometry network
1Hardware catalog routers, links, servers,
hosts,
1Hardware catalog DNA, genes, enzymes,
carriers,
109
TCP/IP
Metabolism/biochem
5Application/function variable supply/demand
Feedback Control
4TCP
4Allosteric
3Transcriptional
3IP
2Potential physical network
1Hardware components
110
Protocols and modules

• Protocols are the rules by which modules are
  interconnected
• Protocols are more fundamental to modularity
  than modules

111

• Each layer can evolve independently provided
• Follow the rules
• Everyone else does good enough with their layer

Vertical decomposition Protocol Stack
112
Application
Application
Application
TCP
TCP
TCP
Horizontal decomposition Each level is
decentralized and asynchronous
IP
IP
IP
IP
IP
Routing Provisioning
113
Bowtie Flow of energy and materials
Universal organizational structures/architectures

Organization of control
Hourglass
114
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)

115

• Facilitate regulation on multiple time scales
• Fast allostery
• Slower transcriptional regulation (by regulated
  recruitment) and degradation
• Even slower transfer of genes
• Even slower copying and evolution of genes

116
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

117
TCP/IP fragility on many timescales

• Shortest File transfers from different users
• End systems w/o congestion control wont 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?

118
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

119
Polymerization and complex assembly
Allosteric regulation
Proteins
Sugars
Nutrient

Amino Acids
Nucleotides
Precursors
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
120
Polymerization and complex assembly
Autocatalytic feedback
Proteins
Sugars

Amino Acids
Nucleotides
Precursors
Regulation control
Trans
Fatty acids
Genes
Nutrient
Co-factors
Carriers
DNA replication
Regulation control
121
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

122
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

123
What if a pathway is needed?
But isnt there?
124
Slower time scales ( ? hours-days), genes are
transferred between organisms.
125
This is only possible with shared protocols.
126
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

127
Slowest time scales ( ? forever), genes are
copied and mutate to create new enzymes.
128
Evolving evolvability?
Variation
Selection
?
129
Evolving evolvability?
Selection
Variation
facilitated structured organized
130
assembly
metabolism
transport
Robust? Fragile to fluctuations Evolvable?
Hard to change
Variety of consumers
Variety of producers
Energy carriers
131
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

132
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)

133
Bowtie Flow of energy and materials
Universal organizational structures/architectures

Organization of control
Hourglass
134
Variety of Ligands Receptors

• Ubiquitous protocol
• Hourglass
• Robust yet fragile
• Robust evolvable
• Fragile to hijacking
• Manages extreme heterogeneity with selected
  homogeneity
• Accident or necessity?

Transmitter
Receiver
Variety of responses
Signal transduction
135
Random walk
Ligand
Motion
Motor
Bacterial chemotaxis
136
Biased random walk
gradient
Ligand
Motion
Motor
CheY
Signal Transduction
137
Common energy carrier
Common signal carrier
Variety of receptors/ ligands
Common cytoplasmic domains
From Taylor, Zhulin, Johnson
138
(No Transcript)
139
Variety of Ligands Receptors
Transmitter
Receiver
Motor
140
Variety of Ligands Receptors

• ?50 such two component systems in E. Coli
• All use the same protocol
• - Histidine autokinase transmitter
• - Aspartyl phospho-acceptor receiver
• Huge variety of receptors and responses

Transmitter
Receiver
Variety of responses
Signal transduction
141
Applications
Variety of Ligands Receptors
TCP
Transmitter
Receiver
Variety of responses
IP
142
Variety of Ligands Receptors
Transmitter
Receiver
Motor
143

• ?50 such two component systems in E. Coli
• All use the same protocol
• - Histidine autokinase transmitter
• - Aspartyl phospho-acceptor receiver
• Huge variety of receptors and responses

144
Molecular phylogenies show evolvability of the
bowtie architecture.
145
conserved residues of interaction surface with
phosphotransferase domains
highly variable amino acids of the interaction
surface that are responsible for specificity of
the interaction
invariant active-site residues
146
conserved functional domains
highly variability for specificity of the
interaction
invariant active-site residues
147

• ?50 such two component systems in E. Coli

Variety of Ligands Receptors
Transmitter

• Ubiquitous eukaryote protocol
• Huge variety of
• receptors/ligands
• downstream responses
• Large number of G-proteins grouped into similar
  classes
• Handful of primary targets

Receiver
Variety of responses
148
Ligand
In
In
GEF
Receptor
GDP
GTP
GDP
GTP
GDI
??
Out
GDI
Out
??
Rho
Rho
G?
G?
GDP
GTP
GDP
GTP
P
P
In
In
RGS
GAP
149
In
GDP
GTP
Out
GDP
GTP
P
In
150
In
Speed, adaptation, integration, evolvability
GDP
GTP
Impedance matching Independent of ?G of inputs
and outputs
Out
Robustness
GDP
GTP
P
In
Signal integration High fan in and fan out
151
Uncertain
Variety of Ligands Receptors
Robust and highly evolvable
Fragile and hard to change
Intermediates
Variety of responses
Uncertain
152
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

153
Hijacking
Ligand
In
Receptor
GDP
GTP
Cholera toxins hijack the signal transduction by
blocking a GTPase activity.
??
C-AMP
??
G?
G?
GDP
GTP
P
154
Bacterial virulence factors targeting Rho
GTPases parasitism or symbiosis?
Patrice Boquet and Emmanuel Lemichez
TRENDS in Cell Biology May 2003
155
(No Transcript)
156
(No Transcript)
157
Variety of Ligands Receptors
But you already knew all this.
Transmitter

• Ubiquitous protocol
• Hourglass
• Robust evolvable
• Fragile to hijacking
• Manages extreme heterogeneity with selected
  homogeneity
• Accident or necessity?

Receiver
Variety of responses
158
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

159
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, lets hope
  we can avoid a repeat of this history.

160
Multiscale Physics
Core theory challenges
Network Centric, Pervasive, Embedded, Ubiquitous
Systems Biology