Genes

1

• Carriers
• Precursors
• Trans
• 2CST

Bacterial bowties
Sugars

Fatty acids
Precursors
Co-factors
Catabolism
Amino Acids
Nucleotides
Genes
Proteins
Carriers
Trans
DNA replication
2

• Carriers
• Precursors
• Trans
• 2CST

Modules are less important than protocols the
rules by which modules interact.
Precursors
Carriers
Trans
3
Constraints
Precursors
Carriers
Trans
4


Variety of Ligands Receptors
Variety of responses
Transmitter
Receiver
Constraints That Deconstrain
(Gerhart and Kirschner)
Sugars

Fatty acids
Precursors
Catabolism
Co-factors
Amino Acids
Nucleotides
Genes
Proteins
Carriers
Trans
DNA replication
5
No variety
Huge Variety
Huge variety

• Virtually unlimited variability and
  heterogeneity (within and between organisms)
• E.g Time constants, rates, molecular counts and
  sizes, fluxes, variety of molecules,
• Very limited but critical points of homogeneity
  (within and between organisms)

6
No variety
Why?
Huge Variety
Huge variety

• Provides plug and play modularity between huge
  variety of input and output components
• Facilitates robust regulation and evolvability
  on every timescale (constraints that
  deconstrain)
• But has extreme fragilities to parasitism and
  predation (knots are easily hijacked or consumed)

7
Why bowties?

• Metabolism, biosynthesis, assembly
• Carriers Charging carriers in central metabolism
  
• Precursors Biosynthesis of precursors and
  building blocks
• Trans DNA replication, transcription, and
  translation
• Signal transduction
• 2CST Two-component signal transduction

8
Stoichiometry plus regulation
? Matrix of integers ? Simple, can be known
exactly ? Amenable to high throughput assays and
manipulation ? Bowtie architecture
? Vector of (complex?) functions ? Difficult to
determine and manipulate ? Effected by
stochastics and spatial/mechanical structure ?
Hourglass architecture ? Can be modeled by
optimal controller (?!?)
9
Metabolism, biosynthesis, assembly
Taxis and transport
Autocatalytic feedback
Polymerization and complex assembly
Core metabolism
Sugars

Fatty acids
Precursors
Co-factors
Catabolism
Nutrients
Amino Acids
Genes
Proteins
Nucleotides
Carriers
Trans
DNA replication
Regulation control
10
Metabolism, biosynthesis, assembly
Taxis and transport
Autocatalytic feedback
Polymerization and complex assembly
Core metabolism
Sugars

Fatty acids
Precursors
Co-factors
Catabolism
Nutrients
Amino Acids
Genes
Proteins
Nucleotides
Carriers
Trans
DNA replication
The architecture of stoichiometry.
11
Autocatalytic feedback
Core metabolism
Sugars

Fatty acids
Precursors
Co-factors
Catabolism
Nutrients
Amino Acids
Genes
Proteins
Nucleotides
Carriers
Trans
DNA replication
12
Bacterial cell
Environment
Environment
Huge Variety
Huge Variety
13
Same 12 in all cells
Taxis and transport
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Fatty acids

• ?100
• same
• in all
• organisms

Co-factors
Carriers
Same 8 in all cells
Huge Variety
14
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.
15
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Fatty acids
Co-factors
Carriers
Nested bowties
16
Sugars
Amino Acids
Nucleotides
Fatty acids
Co-factors
17
(No Transcript)
18
Catabolism
19
Precursors
20
Gly
G1P
G6P
Precursors
F6P
Autocatalytic
F1-6BP
Gly3p
Carriers
ATP
13BPG
TCA
3PG
Oxa
ACA
Pyr
PEP
2PG
NADH
Cit
21
Gly
G1P
G6P
Regulatory
F6P
F1-6BP
Gly3p
ATP
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
22
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
13BPG
TCA
3PG
Oxa
ACA
Pyr
PEP
2PG
Cit
23
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
24
S
Stoichiometry matrix
25
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
26
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
Allosteric regulation of enzymes
ATP
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
27
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
28
Gly
Fast
G1P
G6P
Allosteric regulation of enzymes
F6P
F1-6BP
Regulation of enzyme levels
Gly3p
ATP
13BPG
Slow
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
29
Taxis and transport
12
Autocatalytic feedback
Polymerization and complex assembly
Core metabolism
Sugars

Fatty acids
Precursors
Co-factors
Catabolism
Nutrients
Amino Acids
Genes
Proteins
Nucleotides
Carriers
Trans
8
?100
Huge Variety
DNA replication
?104 to ? 8 in one organisms
30
Autocatalytic feedback
Few polymerases Highly conserved
Polymerization and complex assembly
Genes
Proteins
Trans
DNA replication
?104 to ? 8 in one organisms
Huge Variety
31
Why bowties?

• Metabolism, biosynthesis, assembly
• Carriers Charging carriers in central metabolism
  
• Precursors Biosynthesis of precursors and
  building blocks
• Trans DNA replication, transcription, and
  translation
• Signal transduction
• 2CST Two-component signal transduction

32

• ?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
• Also multistage (phosphorelay) versions

Signal transduction
33
Two components Highly conserved
Huge variety
Huge variety
34


Variety of Ligands Receptors
Variety of responses
Transmitter
Receiver
Signal transduction
35
Flow of signal
Shared protocols


Ligands Receptors
Transmitter
Receiver
Responses
Recognition, specificity
36
Flow of signal
Shared protocols


Ligands Receptors
Transmitter
Receiver
Responses
Recognition, specificity
Flow of packets
Note The wireless system in this room and the
Internet to which it is connected work the same
way.
Laptop
Router
Recognition, specificity
37
Fragility example Viruses
Autocatalytic feedback
Core metabolism
Viruses exploit the universal bowtie/hourglass
structure to hijack the cell machinery.
Sugars

Fatty acids
Precursors
Co-factors
Catabolism
Nutrients
Amino Acids
Genes
Proteins
Nucleotides
Carriers
Trans
DNA replication
Regulation control
38
Fragility example Viruses
Viruses exploit the universal bowtie/hourglass
structure to hijack the cell machinery.
Precursors
Carriers
Trans
39
Fragility example Viruses
Autocatalytic feedback
Core metabolism
Sugars

Fatty acids
Precursors
Precursors
Co-factors
Catabolism
Nutrients
Viral genes
Amino Acids
Viral proteins
Genes
Proteins
Nucleotides
Carriers
Carriers
Trans
Trans
DNA replication
Regulation control
40
Polymerization and complex assembly
Energy materials
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
41
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
42
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
43
Gene networks?
essential 230   nonessential 2373  
unknown 1804   total 4407
http//www.shigen.nig.ac.jp/ecoli/pec
44
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
45
Steering
Brakes
Mirrors
Wipers
Anti-skid
Cruise control
GPS
Radio
Traction control
Headlights
Shifting
Electronic ignition
Temperature control
Seats
Electronic fuel injection
Seatbelts
Fenders
Bumpers
Airbags
Suspension (control)
46
Knockouts often lethal
Steering
Brakes
Mirrors
Wipers
Anti-skid
Knockouts often lose robustness, not minimal
functionality
Cruise control
GPS
Radio
Traction control
Headlights
Shifting
Electronic ignition
Temperature control
Seats
Electronic fuel injection
Seatbelts
Fenders
Bumpers
Airbags
Suspension (control)
47
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Trans
Knockouts often lethal
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Knockouts often lose robustness, not minimal
functionality
Regulation control
48
Polymerization and complex assembly
Autocatalytic feedback
Proteins
Regulation control
Trans
Genes
DNA replication
49
(No Transcript)
50
(No Transcript)
51
motif
rpoH
Other operons
See El-Samad, Kurata, et al PNAS, PLOS CompBio
DnaK
Lon
52
motif
Heat
rpoH
folded
unfolded
Other operons
DnaK
Lon
DnaK
Lon
53
Heat
rpoH
? mRNA
?
Other operons
DnaK
RNAP
Lon
RNAP
?
DnaK
FtsH
Lon
54
Heat
rpoH
? mRNA
?
?
DnaK
Other operons
?
DnaK
DnaK
RNAP
ftsH
Lon
RNAP
?
DnaK
FtsH
Lon
55
Heat
rpoH
? mRNA
?
?
DnaK
Other operons
?
DnaK
DnaK
ftsH
RNAP
Lon
?
RNAP
DnaK
FtsH
Lon
56
Heat
rpoH
? mRNA
Regulation of protein action
Regulation of protein levels
?
?
DnaK
?
DnaK
DnaK
ftsH
RNAP
Lon
?
RNAP
DnaK
FtsH
Lon
57
Layered control architectures
Allosteric
Trans
58
Heat
rpoH
? mRNA
?
?
DnaK
Other operons
?
DnaK
DnaK
ftsH
RNAP
Lon
?
RNAP
DnaK
FtsH
Lon
59
motif
rpoH
Other operons
DnaK
Lon
60
(No Transcript)
61
Bacterial hourglass
Regulation of protein action
Regulation of protein levels
Core metabolism
Sugars

Fatty acids
Co-factors
Precursors
Catabolism
Amino Acids
Genes
Nucleotides
Proteins
Carriers
Trans
DNA replication
62
Regulatory hourglass
Huge variety of environments, metabolisms,
functions
Regulation of protein action
Regulation of protein levels
Huge variety of components
63
Huge variety
Environments, metabolisms, functions
Standardized mechanisms Highly conserved
Regulation of protein action
Regulation of protein levels
Huge variety
Components (genes)
Variety is within a specie (across time and
space) and of course between species.
64
Evolving evolvability?
Random Variation
Structured Selection
?
65
Random variation is harmful, yet
Variation
Structured Selection
Random, Small, Harmful
66
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
Architecture
E. coli genome
67
Structured variation can be good
Structured Selection
Variation
Structured, Large, Beneficial
Architecture
68
Structured variation can be good
Not random
Structured Selection
Variation
Structured, Large, Beneficial
Architecture
69
Structured variation can be good

• Robust architectures facilitate change
• Small genotype ? ? large, functional phenotype ?
  
• (Wolves ? Dogs) ? regulatory regions
• Large (but functional) genotype ? are
  facilitated
• (Antibiotic resistance) Horizontal gene transfer

Structured Selection
Variation
Structured, Large, Beneficial
Architecture
70
This happened very fast (years)

• Robust architectures facilitate change
• Small genotype ? ? large, functional phenotype ?
  
• (Wolves ? Dogs) ? regulatory regions
• Large (but functional) genotype ? are
  facilitated
• (Antibiotic resistance) Horizontal gene transfer

71
Evolving evolvability?
Structured Selection
Structured Variation
facilitated structured organized
Architecture
72
Lego hourglass
Diverse function
Universal Control
control
Diverse components
assembly
73
Lego hourglass
Huge variety
Standardized mechanisms Highly conserved
control
assembly
Huge variety
74
Lego
Huge variety
Limited environmental uncertainty needs minimal
control
Standard assembly
Huge variety
75
Question what is the difference between
hourglass and bowtie here?
Diverse function
Standard assembly
Diverse components
This seems like a minimal place to address this
issue.
Variety of systems
Variety of bricks
Snap
76
The snap is a static interface specification.
Variety of systems
Variety of bricks
Snap
77
Diverse function
Assembly is a control process that evolves in
time, and respects the snap, but adds to it. It
inputs instructions and components and outputs
assembled systems.
Standard assembly
Diverse components
Instructions
Instructions
Instructions
78
With the snap and assembly, complex toys can be
created, and require additional layers of control.
Variety of systems
Variety of bricks
Snap
79
Random
Not random
Variety of systems
Variety of bricks
Snap
80
Lego hourglass
Uncertain environments
Require additional layers
control
assembly
Huge variety
81
NXT controller
Variety of actuators
Variety of sensors
Real- time control
82
fan-out of diverse outputs
universal carriers
fan-in of diverse inputs
Diverse function
Bowties andHourglasses
Universal Control
Diverse components
83
Variety of actuators
Variety of sensors
Control
Lego Bowties
Variety of systems
Variety of bricks
Snap
84
Random
Qualitatively unchanged by random rewiring
SOC Lego?
85
Not random
Almost certainly destroyed by random rewiring,
yet
Large structured rewirings are functional.
The essence of architecture.
86
Not random
Most of the complexity is in digital hardware and
software.
87
Variety
control
Lego hourglass
assembly
Variety
88
(No Transcript)
89
(No Transcript)
90
Figure 7. How market-centered social
organization contributes to mortality from
hypervigilance and hyposatisfaction.
91
Universal reward systems
work family community nature
Prefrontal cortex Accumbens
dopamine
VTA
sex toolmaking sports music dance crafts art
Robust and adaptive, yet
92
work family community nature
Prefrontal cortex Accumbens
dopamine
VTA
sex toolmaking sports music dance crafts art
93
work family community nature
market/ consumer culture
money
salt sugar/fat nicotine alcohol
Prefrontal cortex Accumbens
dopamine
VTA
Vicarious
sex toolmaking sports music dance crafts art
industrial agriculture
94
work family community nature
money
salt sugar/fat nicotine alcohol
Prefrontal cortex Accumbens
dopamine
VTA
Vicarious
sex toolmaking sports music dance crafts art
cocaine amphetamine
95
high sodium
money
obesity
salt sugar/fat nicotine alcohol
overwork
smoking
Vicarious
alcoholism
drug abuse
96
Molecular levels