Key systems biology themes

1
Key systems biology themes

• Software infrastructure (SBML, Hucka)
• Multiscale, stochastic simulation (Petzold)
• Analysis beyond simulation (SOSTOOLS)
• Fundamental principles

2
Feathers and flapping?
Or lift, drag, propulsion, and control?
3
We know how to construct airplanes. Men also know
how to build engines. Inability to balance and
steer still confronts students of the flying
problem. When this one feature has been worked
out, the age of flying will have arrived, for all
other difficulties are of minor importance.

Wilbur Wright 1901
4
The most important stories are already told to
children.
Feedback is a central feature of life. The
process of feedback governs how we grow, respond
to stress and challenge, and regulate factors
such as body temperature, blood pressure, and
cholesterol level. The mechanisms operate at
every level, from the interaction of proteins in
cells to the interaction of organisms in complex
ecologies. Mahlon B Hoagland and B Dodson The
Way Life Works Times Books 1995
5
It is not the strongest of the species that
survive, nor the most intelligent, it is the one
that is most adaptable to change. Charles Darwin
6
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Regulation control
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
Global architecture of cell physiology
7
Experimental 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
• Laws are immutable
• Protocols are more important than modules

8
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
9
Outline

• Review basic biochemistry
• Aim for a shared background for understanding
  basic organizational principles of large complex
  networks
• Implications for cellular function, particularly
  robustness and evolvability
• Implications for medicine
• Quantitative recap of the above qualitative
  story, compare with alternatives

10
Review of basic biochemistry
11
Standard cartoon of metabolism.
Enzyme
Metabolite
12
Precursors
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
13BPG
TCA
3PG
Oxa
ACA
Pyr
PEP
2PG
Cit
13
Precursors
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
13BPG
TCA
3PG
Oxa
ACA
Pyr
PEP
2PG
Cit
14
Gly
G1P
Whats left out of these cartoons?
G6P
F6P
F1-6BP
Gly3p
13BPG
TCA
3PG
Oxa
ACA
Pyr
PEP
2PG
Cit
15
Gly
G1P
Autocatalytic
G6P
F6P
F1-6BP
Gly3p
ATP
13BPG
TCA
3PG
Oxa
ACA
Pyr
PEP
2PG
NADH
Cit
16
Gly
G1P
G6P
Regulatory
F6P
F1-6BP
Gly3p
ATP
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
17
Gly
This is a cartoon. (Cartoons are useful.)
G1P
G6P
F6P
Reducing it to a graph is a joke. (Jokes are
funny.)
F1-6BP
Gly3p
ATP
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
18
Stoichiometry or mass and energy balance
Biology is not a graph.
19
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
ATP
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
20
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
21
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
Allosteric regulation of enzymes
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
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Fatty acids
Co-factors
A more aggregated view.
25
Catabolism
Gly
G1P
Precursors
G6P
Catabolism
F6P
Carriers
F1-6BP
Gly3p
ATP
13BPG
TCA
3PG
Oxa
ACA
Pyr
PEP
2PG
NADH
Cit
26
Catabolism
Gly
G1P
Precursors
G6P
Catabolism
F6P
Carriers
F1-6BP
Gly3p
ATP
13BPG
TCA
3PG
Oxa
ACA
Pyr
PEP
2PG
NADH
Cit
27
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Fatty acids
Co-factors
Carriers

• Even without explicitly including regulation, it
  drives the protocols organizing flow of energy
  and materials, including autocatalysis
• Start with flows of energy and materials
• Add in regulation later

28
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Fatty acids
Co-factors
Carriers
Bowtie architecture
29
Polymerization and complex assembly
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Nested bowties
30
Polymerization and complex assembly
Autocatalytic
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
31
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Regulation control
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
32
Gene networks?
essential 230   nonessential 2373  
unknown 1804   total 4407
http//www.shigen.nig.ac.jp/ecoli/pec
33
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
34
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
35
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)
36
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)
37
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
38
Polymerization and complex assembly
Supplies Materials Energy
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Robustness ? Complexity
Supplies Robustness
Regulation control
39
Gly
Gly
G1P
G1P
G6P
G6P
F6P
F6P
F1-6BP
F1-6BP
Gly3p
Gly3p
Robustness and complexity issues must ultimately
be addressed here.
ATP
13BPG
13BPG
TCA
3PG
TCA
3PG
Oxa
Oxa
ACA
ACA
PEP
Pyr
2PG
PEP
Pyr
2PG
NADH
Cit
Cit
40
Gly
G1P
G6P
F6P
F1-6BP
Gly3p
But this is what we know best.
ATP
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
41
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Top-down and global approach.
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
What can we say about robustness and complexity
using only what we know for certain and at the
undergrad biochemistry level?
42
Stoichiometry or mass and energy balance
Biology is not a graph.
43
Vertical decomposition
Reaction
44
H. Pylori Amino Acid Biosynthesis
45
DHS
SME
S5P
ADP
NADP
ATP
NADPH
46
DHS
SME
S5P
ADP
NADP
ATP
NADPH
47
H. Pylori Amino Acid Biosynthesis
48
Stoichiometry matrix
49

• Regulation
• Trans/degradation
• Allosteric

Substrates
S1
S2
Enzyme
ADP ATP
Carriers
50
S1
S2
1
Substrates
2
S3
S4
Carriers
ADP ATP
51
Stoichiometry
S1
S2
1
2
S3
S4
ADP ATP
52
H. Pylori Amino Acid Biosynthesis
53
Without carriers
GLC
G6P
PGL
PRPP
PGC
RL5P
R5P
AN
NAN
CD5
IGP
TRP
F6P
DAH
DQT
DHS
SME
S5P
PSM
CHO
X5P
E4P
PPN
HPP
TYR
6PG
T3P
CYS
PEP
ASE
DPG
3PG
PHP
PPS
SER
PYR
GLY
ASP
MAL
OA
BAP
ASN
ASS
CIT
HSE
PHS
THR
DHD
PIP
SAK
SDP
DPI
MDP
LYS
SUC
FUM
SUCOA
GLN
ICIT
AKG
GLU
54
Without carriers
GLC
G6P
PGL
PRPP
PGC
RL5P
R5P
AN
NAN
CD5
IGP
TRP
F6P
DAH
DQT
DHS
SME
S5P
PSM
CHO
X5P
E4P
PPN
HPP
TYR
6PG
T3P
CYS
PEP
ASE
DPG
3PG
PHP
PPS
SER
PYR
GLY
ASP
MAL
OA
BAP
ASN
ASS
CIT
HSE
PHS
THR
DHD
PIP
SAK
SDP
DPI
MDP
LYS
SUC
FUM
SUCOA
GLN
ICIT
AKG
GLU
precursors
amino acids
55
Carriers
AKG
GLU
NAD
ADP
NADP
COA
AMP
THF
PI
CO2
PPI
NH3
AC
H2S
NADH
ATP
NADPH
ACCOA
ATP
MTH
56
GLC
G6P
PGL
PRPP
TRP
PGC
RL5P
R5P
AN
NAN
CD5
IGP
F6P
DAH
DQT
DHS
SME
S5P
PSM
CHO
X5P
E4P
PPN
HPP
TYR
6PG
T3P
CYS
PEP
ASE
DPG
3PG
PHP
PPS
SER
PYR
GLY
ASP
MAL
OA
BAP
ASN
ASS
CIT
HSE
PHS
THR
DHD
PIP
SAK
SDP
DPI
MDP
LYS
SUC
FUM
SUCOA
GLN
precursors
ICIT
AKG
GLU
amino acids

• WT is highly organized, structured
• Simple reactions
• Long assembly lines
• Universal common carriers
• Universal precursors
• Universal regulatory mechanisms

57
Biosynthetic pathways
Amino acids
Precursors
Carriers
58
(No Transcript)
59
precursors
other metabolites
amino acids
carriers
Glycolysis
Amino Acid Biosyn
60
Vertical decomposition
61
metabolites
carriers
Vertical decomposition
reactions
62
metabolites
carriers
Vertical decomposition
reactions
63
precursors
other metabolites
amino acids
carriers
Horizontal decomposition
Glycolysis
Amino Acid Biosyn
64
precursors
other metabolites
amino acids
carriers
Glycolysis
Amino Acid Biosyn
Horizontal decomposition
65
32
86
106
138
158
190
205
267
276
289
58
133
190
240
66
Amino acids
Nucleotides
Lipids fatty acids
Cofactors
Precursors
Carriers
Amino acid
Catabolism
Lipids fatty acid
Cofactor
Nucleotide
67
32
Other metabolites
86
Nucleotides
Vitamins
106
Other metabolites
Catabolism
Sugars
Lipids
138
Amino Acids
158
Precursors
190
205
Enzymes
Carriers
267
Precursors
276
289
Carriers
Vertical decomposition
58
133
190
240
Reactions
68
32
86
106
138
Amino acid
158
Nucleotide
Lipid fatty acid
190
205
Cofactor
267
276
289
58
133
190
240
Catabolism
Biosynthesis
Nucleotides
Vitamins
Catabolism
Sugars
Lipids
Horizontal decomposition
Amino Acids
Precursors
69
catabolism
12
Amino acid biosynthesis
precursors
23
amino acids biosyn
50
61
carriers
21
70
E. Coli all metabolism
Stoichiometry matrix
External
metabolites
Other inputs
98
105
111
Reduced carriers
Activated carriers
174
180
Precursor
192
metabolites
500 metabolites
275
Amino acids
295
membrane lipid
Vitamin and cofactor
Nucleotides
351
359

• Highly structured
• Scale-rich (not scale-free)
• Self-dissimilar (not self-similar)

Lipid and LPS
397
408
Fatty acids and
CO2, Pi, H etc CC
506
514
700 reactions
Other outputs
537
140
282
440
553
608
739
Membrane
Amino acids
Nucleotides
Catabolism
transport
71
Catabolism intermediates
Activated carriers
Precursor metabolites
Amino acid biosynthesis intermediates
Amino acids
Catabolism
Amino acid biosynthesis
reactions
72
E. Coli all metabolism
External
metabolites
Other inputs
98
105
111
Reduced carriers
Activated carriers
174
180
Precursor
192
metabolites
275
Amino acids
295
membrane lipid
Vitamin and cofactor
Nucleotides
351
359
Lipid and LPS
397
408
Fatty acids and
CO2, Pi, H etc CC
506
514
Other outputs
537
140
282
440
553
608
739
Membrane
Amino acids
Nucleotides
Catabolism
transport
73
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
Why all this structure and heterogeneity?
Why this architecture?
74
No variety
Huge Variety
Huge variety
75
Environment
Taxis and transport
Nutrients
Huge Variety
76
?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
77

• ?104-106
• in one
• organisms

Polymerization and complex assembly
?20
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers

• ?100

Huge Variety
DNA replication
78
No variety
Huge Variety
Huge variety

• Virtually unlimited variability and
  heterogeneity Time constants, rates, molecular
  counts and sizes, fluxes, variety of molecules,
• Very limited but critical points of homogeneity
• Every cell is similar, so what to compare with?

79
Nested bowties advanced technologies
Everything is made this way cars, planes,
buildings, laptops,
80
Manufacturing and metabolism
Collect and import raw materials
Common currencies and building blocks
Complex assembly
Collect and import raw materials
Common currencies and building blocks
Complex assembly
Polymerization and assembly
Taxis and transport
Core metabolism
Autocatalytic and regulatory feedback
81
Electric power
Variety of producers
Variety of consumers
82
Standard interface
Variety of consumers
Variety of producers
Energy carriers

• Carrier 60 Hz AC

83
Variety of consumers
Variety of producers
Energy carriers

• 110 V, 60 Hz AC
• (230V, 50 Hz AC)
• Gasoline
• ATP, glucose, etc
• Proton motive force

84
Raw materials
Timber, Iron ore, Gypsum, Sand,
Raw materials
Complex assembly
Building blocks
85
Caves
Raw materials
86
Simple assembly
Timber, Stone, Mud,
Huts, cabins,
Raw materials
Simple assembly
87
Raw materials
Evolving evolvability
Complex assembly
Building blocks
Raw materials
Simple assembly
Protocol evolution
Raw materials
88
Raw materials
Complex assembly
Hidden from the user
Building blocks

• In advanced technologies, the complexities of
• assembly
• operation
• repair
• are hidden from the user behind the deliberate
  illusion of a simple interface.

89
As modern cars, planes, computers, etc have
exploding internal complexity, they are simpler
to use and more robust. They tend to work
perfectly or not at all.
90
As modern cars, planes, computers, etc have
exploding internal complexity, they are simpler
to use and more robust. They tend to work
perfectly or not at all.
91
No variety
Huge Variety
Huge variety
92
(No Transcript)
93
Towards the core Highly efficient, special
purpose enzymes, controlled by competitive
inhibition and allostery, small metabolites
Uncertain product demand
Uncertain nutrient supply
Towards the edges Robustness and
flexibility, general purpose polymerases,
control by regulated recruitment
94

• Universally shared bowtie protocol suites
  facilitate regulation on multiple time scales
• Fast metabolite fluxes and concentrations via
  enzyme rates using allostery
• Slower concentrations of enzymes using
  transcriptional regulation (by regulated
  recruitment)
• Even slower transfer of genes
• Even slower copying and evolution of genes by
  accumulation of point mutations

95
Gly
Fast Regulation
G1P
G6P
Precursors
F6P
F1-6BP
Gly3p
ATP
Carriers
13BPG
TCA
3PG
Oxa
ACA
PEP
Pyr
2PG
NADH
Cit
96
Polymerization and complex assembly
Allosteric regulation
Proteins
Sugars
Nutrient

Amino Acids
Nucleotides
Precursors
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
97
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
98
assembly
metabolism
transport
Evolvability robustness of lineages to large
changes on long timescales
Variety of consumers
Variety of producers
Energy carriers
99
Slower time scales ( ? hours-days), genes are
transferred between organisms.
100
Slowest time scales ( ? forever), genes are
copied and mutate to create new enzymes.
101

• Universally shared bowtie protocol suites
  facilitate regulation on multiple time scales
• Fast metabolite fluxes and concentrations via
  enzyme rates using allostery
• Slower concentrations of enzymes using
  transcriptional regulation (by regulated
  recruitment)
• Even slower transfer of genes
• Even slower copying, evolution of genes

102
assembly
metabolism
transport
Robust? Fragile to fluctuations Evolvable?
Hard to change
Variety of consumers
Variety of producers
Energy carriers
103
Robust and evolvable yet fragile. HOT Highly
Optimized/Organized Tradeoffs
104
assembly
metabolism
transport

• Preserved by selection on three levels
• Fragile to change (short term)
• Facilitates robustness elsewhere (short term)
• Facilitates evolution (long term)

Variety of consumers
Variety of producers
Energy carriers
105
Fragility example Viruses
Viral proteins
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Precursors
Nucleotides
Nutrients
Trans
Fatty acids
Genes
Viral genes
Co-factors
Carriers
Viruses exploit the universal bowtie/hourglass
structure to hijack the cell machinery.
DNA replication
106
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Regulation control
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
107
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Regulation control
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
108
(No Transcript)
109
Multiple knots
Precursors
Trans
Carriers
110
Proteins
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Trans
Fatty acids
Genes
Co-factors
Carriers
111
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins
Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Regulation control
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers
DNA replication
Regulation control
112
Regulation control
113
Robustness Efficient and flexible metabolism
Fragility Obesity and diabetes
114
Robustness and fragility

• Efficient, flexible metabolism
• Complex development
• Immune systems
• Regeneration renewal
• Complex societies

• Obesity and diabetes
• Rich parasite ecosystem
• Auto-immune disease
• Cancer
• Epidemics

115

• Universally shared bowtie protocol suites
  facilitates control and evolution on many time
  scales
• Manages massive heterogeneity with minimal
  homogeneity
• Robust yet fragile
• Power laws everywhere