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fragile
slow
fast
efficient
waste
robust
flexible
inflexible
body
slow
Combo
brain
fast
efficient
waste
flexible
inflexible
HMT
Contextual
Prefrontal
Slow
Adaptive
Motor Fast Sense
Reactive
Combo
Fast
Flexible
Reflex
Inflexible
Soma
vision
Prefrontal
Slow
Fast
Motor Fast Sense
HGT
DNA repair
VOR
Mutation
DNA replication
Apps
Transcription
Reflex
OS
OS
Translation
HW
HW
Metabolism
Dig.
Dig.
Digital
Signal
Lump. Lump. Lump. Lumped
Distrib. Distrib. Distrib. Distrib. Distrib.
Inflexible
Flexible
Special
General
Layered
Architecture
DNA
New Gene
gene
RNA
Transcription
Other
Control
RNAp
mRNA Amino
Acids
Ribosomes
Translation
Other
Control
Proteins
Metabolism
Products
Signal transduction
control feedback
Slow HGT
DNA repair
Cheap
Mutation
Fast
Costly
ATP
DNA replication
Transcription
Translation
Today
Metabolism
Signal…
Flexible
Inflexible
Efficiency/instability/layers/feedback
• All create new efficiencies but also instabilities
• Needs new distributed/layered/complex/active control
•
•
•
•
•
•
•
•
•
•
•
•
Sustainable infrastructure? (e.g. smartgrids)
Money/finance/lobbyists/etc
Industrialization
Society/agriculture/weapons/etc
Bipedalism
Maternal care
Major transitions
Warm blood
Flight
Mitochondria
Oxygen
Translation (ribosomes)
Glycolysis (2011 Science)
1
fragile
robust
10
Universal
laws?
fragile
Ideal
efficient
0
wasteful
10 -1
10
k
0
10
1
10
expensive
100
exp
10
2
.1
  ln T   exp  p  z  p
T
.2
.5
Length, m
1


z p
Robust=maintain energy charge
w/fluctuating cell demand
Efficient=minimize metabolic
waste and overhead
Gly
G1P
G6P
Autocatalysis
F6P
Control
F1-6BP
Gly3p
Feedbacks
ATP
13BPG
3PG
2PG
Oxa
PEP
Pyr
ACA
TCA
NADH
Cit
enzymes catalyze
reactions, another
source of autocatalysis
Reaction
1 (“PFK”)
energy Rest
Protein
biosyn
Reaction
2 (“PK”)
enzymes
Efficient =
low metabolic overhead
 low enzyme amount
enzymes
ATP
of cell
enzymes catalyze
reactions, another
source of autocatalysis
ATP
Ribosomes must make
ribosomal proteins
Ribosomal protein content:
Mitochondria >> Bacteria
of cell
Protein
biosyn
enzymes
Autocatalysis
energy Rest
A pathway view
1.
2.
3.
4.
5.
6.
7.
8.
DNA repair
Mutation
DNA replication
Transcription
Translation
Metabolism
Signal transduction
…
DNA
RNA
Protein
A pathway view
Substrate
Reaction
Product
Enzyme
(Protein)
DNA
RNA
Protein
A pathway view
Substrate
Reaction
Control
Product
Enzyme
(Protein)
DNA
Gene
RNA
RNAp
Transcription
Other
Control
mRNA
Polymerization
RNA
RNA
Gene
DNA
RNAp
Transcription
Other
Control
RNA
mRNA
Amino
Acids
Protein
Ribosomes
Translation
Other
Control
Proteins
RNA
Gene
RNAp
Transcription
Other
Control
Autocatalytic
feedback
mRNA
Amino
Acids
Ribosomes
Translation
Other
Control
Proteins
Proteins
Substrates
Metabolism
Products
Core
Protocols
Gene
Transcription
mRNA
Translation
Proteins
Metabolism
Products
Gene
Autocatalytic
feedback
RNA
RNAp
Transcription
Other
mRNA
Control
Amino
Acids
Ribosomes
Translation
Other
Control
Proteins
Metabolism
Products
Autocatalytic
feedback
RNA
Gene
RNAp
Transcription
Other
Control
mRNA
Amino
Acids
Ribosomes
Translation
Other
Control
Proteins
Metabolism
control
feedback
Signal transduction
Products
Autocatalytic
feedback
RNA
Gene
RNAp
Transcription
Other
Control
mRNA
Amino
Acids
Ribosomes
Translation
Other
Control
Proteins
Metabolism
control
feedback
Signal transduction
Products
1.
2.
3.
4.
5.
6.
7.
8.
DNA repair
Mutation
DNA replication
Transcription
Translation
Metabolism
Signal transduction
…
Red blood cells
Proteins
Metabolism
control
feedback
Signal transduction
Products
Autocatalytic
feedback
RNA
Gene
RNAp
Transcription
Other
Control
mRNA
Amino
Acids
Ribosomes
Translation
Other
Control
Proteins
Metabolism
control
feedback
Signal transduction
Products
Gene
RNAp
Transcription
Other
Control
Autocatalytic
feedback
RNA
mRNA
Translation
Other
Control
Amino
Acids
Ribosomes
Proteins
Metabolism
control
feedback
Products
autocatalytic
Signal transduction
control
Core metabolism
PFK
x
PK
a
H
ATP
g
Rest
Control 1.0
1.
2.
3.
4.
5.
6.
7.
8.
DNA repair
Mutation
DNA replication
Transcription
Translation
Metabolism
Signal transduction
…
Highly
controlled
Think of this as a “protocol stack”
RNA
Gene
RNAp
Transcription
Other
Control
mRNA
Amino
Acids
Ribosomes
Translation
Other
Control
Proteins
Metabolism
control
feedback
Signal transduction
Products
Gene
Transcription
Other
Control
RNA
RNAp
mRNA
Gene
RNA
DNA
RNAp
Transcription
Other
Control
RNA
mRNA
Protein
Replication
DNA
DNAp
Gene
Gene
RNA
DNA
RNAp
Transcription
Other
Control
RNA
mRNA
Protein
Mutation and repair
Replication
DNA
Gene
DNAp
Gene’
DNA
RNA
Protein
Control 1.0
1.
2.
3.
4.
5.
6.
7.
8.
DNA repair
Mutation
DNA replication
Transcription
Translation
Metabolism
Signal transduction
…
Highly
controlled
Think of this as a “protocol stack”
Horizontal gene transfer (HGT)
Replication
DNAp
DNA
Gene
Gene’
New
gene
New
gen
New
gene
DNA
Gene
RNA
Transcription
Other
Control
0.
1.
2.
3.
4.
5.
6.
7.
8.
RNAp
mRNA Amino
Acids
Ribosomes
Translation
Other
Control
Proteins
Metabolism
Products
Signal transduction
control feedback
ATP
HGT
DNA repair
Mutation
DNA replication
Transcription
Translation
Metabolism
Signal transduction
…
Control 1.0
0.
1.
2.
3.
4.
5.
6.
7.
8.
HGT
DNA repair
Mutation
DNA replication
Transcription
Translation
Metabolism
Signal transduction
…
Highly
controlled
Think of this as a “protocol stack”
Control 2.0
0.
1.
2.
3.
4.
5.
6.
7.
8.
Evolution  Adaptation  Control
HGT
DNA repair
Mutation
DNA replication
Transcription
Translation
Metabolism
Signal transduction
…
Highly
controlled
(slow)
Highly
controlled
(fast)
Think of this as a “protocol stack”
Horizontal
Gene
Transfer
Sequence ~100 E Coli (not chosen randomly)
• ~ 4K genes per cell
• ~20K different genes in total (pangenome)
• ~ 1K universally shared genes
• ~ 300 essential (minimal) genes
Exploiting
layered
architecture
Virus
Horizontal
Bad Gene
Transfer
Meme
Horizontal
Bad App
Transfer
Virus
Horizontal
Bad Meme
Transfer
Fragility?
Parasites
&
Hijacking
Layered
Architecture
DNA
New Gene
gene
RNA
Transcription
Other
Control
RNAp
mRNA Amino
Acids
Ribosomes
Translation
Other
Control
Proteins
Metabolism
Products
Signal transduction
control feedback
Slow HGT
DNA repair
Cheap
Mutation
ATP
DNA replication
Transcription
Translation
Metabolism
Signal…
Fast
Costly
Flexible
Inflexible
Transmitter
Transmitter
Transmitter
Transmitter
Receiver
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Receiver
Receiver
Receiver
Variety of
Variety of
Variety &
of
Ligands
Ligands
Variety
& of
Ligands
Variety
& of
Receptors
Receptors
Ligands
Variety
& of
Transmitter
• 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
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands &
Receptors
Ligands &
Receptors
Receptors
Signal
transduction
Variety of
Variety of
Variety of
responses
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
responses
Receiver
Ligands &
Receptors
Transmitter
Flow of “signal”
Shared
protocols
Responses
Recognition,
specificity
• “Name resolution” within signal transduction
• Transmitter must locate “cognate” receiver
and avoid non-cognate receivers
• Global search by rapid, local diffusion
• Limited to very small volumes
“Name” recognition
= molecular recognition
= localized functionally
= global spatially
Receiver
Transmitter
Ligands &
Receptors
Responses
Transcription factors
do “name” to “address”
translation
Receiver
Transmitter
Ligands &
Receptors
Responses
“Name” recognition
= molecular recognition
= localized functionally
Transcription factors
do “name” to “address”
translation
DNA
Transmitter
Ligands &
Receptors
“Name” recognition
= molecular recognition
= localized functionally
Responses
Both are
• Almost digital
• Highly
programmable
Receiver
DNA
Transcription factors
do “name” to “address”
translation
“Addressing”
= molecular recognition
= localized spatially
Receiver
Transmitter
Ligands &
Receptors
There are simpler
transcription
factors for sensing
internal states
Responses
Feedback control
Receiver
Responses
2CST systems provide
speed, flexibility,
external sensing,
computation, impedance
match, more feedback,
but
greater complexity and
overhead
DNA
There are simpler
transcription
factors for sensing
internal states
DNA
Sensor domains
Domains can
be evolved
independently
or coordinated.
DNA and RNAp
binding domains
Highly
evolvable
architecture.
RNAp
DNA
There are simpler
transcription
factors for sensing
internal states
Application
layer cannot
access DNA
directly.
This is like a
“name to
address”
translation.
Sensing the
demand of the
application
layer
Sensor domains
DNA and RNAp
binding domains
Initiating
the change
in supply
RNAp
DNA
Any
input
DNA and RNAp
binding domains
Sensor
domains
Any
other
input
Sensing the
demand of the
application
layer
DNA and RNAp
binding domains
• Sensor sides attach to metabolites or other proteins
• This causes an allosteric (shape) change
• (Sensing is largely analog (# of bound proteins))
• Effecting the DNA/RNAp binding domains
• Protein and DNA/RNAp recognition is more digital
• Extensively discussed in both Ptashne and Alon
“Cross talk” can be
finely controlled
Any
input
Sensor
domains
Any
other
input
• Application layer signals can be integrated or not
• Huge combinatorial space of (mis)matching shapes
• A functionally meaningful “name space”
• Highly adaptable architecture
• Interactions are fast (but expensive)
• Return to this issue in “signal transduction”
“Name” recognition
= molecular recognition
= localized functionally
= global spatially
Transcription factors
do “name” to “address”
translation
Both are
• Almost digital
• Highly
programmable
“Addressing”
= molecular recognition
= localized spatially
DNA
Can activate
or repress
And work in
complex logical
combinations
RNAp
Promoter
Gene1
Gene2
…
• Both protein and DNA sides have sequence/shape
• Huge combinatorial space of “addresses”
• Modest amount of “logic” can be done at promoter
• Transcription is very noise (but efficient)
• Extremely adaptable architecture
(almost analog)
rate determined
by relative copy
number
Binding
recognition
nearly digital
Promoter
Gene5 Gene6
…
Recall: can work by
pulse code
modulation so for
small copy number
does digital to
analog conversion
rate (almost analog)
determined by copy number
Promoter
Gene5 Gene6
…
Any
input
Promoter
No crossing layers
• Highly structured interactions
• Transcription factor proteins
control all cross-layer interactions
• DNA layer details hidden from
application layer
• Robust and evolvable
• Functional (and global) demand
mapped logically to local supply
chain processes
Gene1
Gene2
…
Receiver
Transmitter
Ligands &
Receptors
Responses
control
Protein
Inside
Outside
control
Reactions
Assembly
control
DNA/RNA
Receiver
Cross-layer control
Responses
DNA
• Highly organized
• Naming and addressing
• Prices? Duality?
• Minimal case study?
Transmitter
Transmitter
Transmitter
Transmitter
Receiver
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Transmitter
Receiver
Receiver
Receiver
Receiver
Variety of
Variety of
Variety &
of
Ligands
Ligands
Variety
& of
Ligands
Variety
& of
Receptors
Receptors
Ligands
Variety
& of
Transmitter
• 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
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands
Variety
& of
Receptors
Ligands &
Receptors
Ligands &
Receptors
Receptors
Signal
transduction
Variety of
Variety of
Variety of
responses
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
Variety of
responses
responses
Next layered architectures (SDN)
Deconstrained
(Applications)
Few global variables
Don’t cross layers
Constrained
Optimize
& control, share,
?
virtualize, manage resources
Deconstrained
(Hardware)
Comms
Memory, storage
Latency
Processing
Cyber-physical
TCP/IP architecture?
Deconstrained
(Applications)
Few global variables
Don’t cross layers
TCP/IP
Deconstrained
(Hardware)
Comms
Memory, storage
Latency
Processing
Cyber-physical
IPC
App
caltech.edu?
App
DNS
IP addresses
interfaces
(not nodes)
Global
and direct
access to
physical
address!
131.215.9.49
IPC
App
App
DNS
Robust?
• Secure
• Scalable
• Verifiable
• Evolvable
• Maintainable
• Designable
•…
IP addresses
interfaces
(not nodes)
Global
and direct
access to
physical
address!
“Issues” (hacks)
• VPNs
• NATS
• Firewalls
• Multihoming
• Mobility
• Routing table size
• Overlays
•…
Application
TCP
IP
Physical
Aside:
Graph topology is not architecture,
but deconstrained by layered architectures.
Application
TCP
Internet
graph
topologies?
IP
Physical
Original design challenge?
Deconstrained
(Applications)
Constrained TCP/
IP
Deconstrained
(Hardware)
Networked OS
• Expensive mainframes
• Trusted end systems
• Homogeneous
• Sender centric
• Unreliable comms
Facilitated wild evolution
Created
• whole new ecosystem
• completely opposite
Unfortunately, not
intelligent design
Ouch.
Why?
left
recurrent
laryngeal
nerve
Why? Building humans from fish parts.
Fish
parts
It could be worse.
Next layered architectures (SDN)
Deconstrained
(Applications)
Few global variables
Don’t cross layers
Constrained
Optimize
& control, share,
?
virtualize, manage resources
Deconstrained
(Hardware)
Comms
Memory, storage
Latency
Processing
Cyber-physical
Human physiology
Endless
details
Ouch.
Human physiology
Robust




Fragile
Metabolism
Regeneration & repair
Healing wound /infect
Efficient cardiovascular





Obesity, diabetes
Cancer
AutoImmune/Inflame
C-V diseases
Infectious diseases
Lots of triage
Benefits
Robust




Metabolism
Regeneration & repair
Healing wound /infect
Efficient cardiovascular




Efficient
Mobility
Survive uncertain food supply
Recover from moderate trauma
and infection
Mechanism?
Robust
Fragile
 Metabolism
 Regeneration & repair
 Healing wound /infect
 Obesity, diabetes
 Cancer
 AutoImmune/Inflame
 Fat accumulation
 Insulin resistance
 Proliferation
 Inflammation
Mechanism?
Robust
Fragile
 Metabolism
 Regeneration & repair
 Healing wound /infect
 Fat accumulation
 Insulin resistance
 Proliferation
 Inflammation
 Obesity, diabetes
 Cancer
 AutoImmune/Inflame
 Fat accumulation
 Insulin resistance
 Proliferation
 Inflammation
What’s the difference?
Robust
Fragile
 Metabolism
 Regeneration & repair
 Healing wound /infect




 Obesity, diabetes
 Cancer
 AutoImmune/Inflame
Fat accumulation
Insulin resistance
Proliferation
Inflammation
Controlled
Acute/responsive
Uncontrolled
Chronic




Fat accumulation
Insulin resistance
Proliferation
Inflammation
Controlled
Acute/responsive
Low mean
High variability
Death
Controlled
Acute
Low mean
High variability




Fat accumulation
Insulin resistance
Proliferation
Inflammation
Uncontrolled
Chronic
High mean
Low variability
140
120
100
Endless
details
on HRV
High mean
Low variability
80
60
Low mean
High variability
40
Heart rate variability (HRV)
Healthy =
Not =
Low mean
High variability
time(sec)
High mean
Low variability
Restoring robustness?
Robust
Fragile
 Metabolism
 Regeneration & repair
 Healing wound /infect




 Obesity, diabetes
 Cancer
 AutoImmune/Inflame




Fat accumulation
Insulin resistance
Proliferation
Inflammation
Controlled
Acute
Heal
Fat accumulation
Insulin resistance
Proliferation
Inflammation
Uncontrolled
Chronic
Human complexity
Robust








Metabolism
Regeneration & repair
Immune/inflammation
Microbe symbionts
Neuro-endocrine
Complex societies
Advanced technologies
Risk “management”
Yet Fragile
 Obesity, diabetes
 Cancer
 AutoImmune/Inflame
 Parasites, infection
 Addiction, psychosis,…
 Epidemics, war,…
 Disasters, global &!%$#
 Obfuscate, amplify,…
Accident or necessity?
Robust
Fragile
 Metabolism
 Obesity, diabetes
 Regeneration &repair
 Cancer
Fat accumulation
 Healing wound
/infect
 AutoImmune/Inflame
Insulin resistance
 Proliferation
 Inflammation
•
•
•
•
Fragility  Hijacking, side effects, unintended…
Of mechanisms evolved for robustness
Complexity  control, robust/fragile tradeoffs
Math: robust/fragile constraints (“conservation laws”)
Both
Accident or necessity?
Unfortunately, not
intelligent design
Ouch.
The dangers of
naïve biomemetics
Feathers
and
flapping?
Or lift, drag, propulsion,
and control?
Getting it (W)right, 1901
• “We know how to construct airplanes...(lift and drag)
• … how to build engines.” (propulsion)
• “When... balance and steer[ing]... has been worked
out, the age of flying will have arrived, for all other
difficulties are of minor importance.” (control)
Wilbur Wright on Control, 1901
(First powered flight, 1903)
Universals?
Feathers
and
flapping?
Or lift, drag, propulsion,
and control?
rpoH
Heat
 mRNA


Other
operons

RNAP
DnaK
DnaK
DnaK
ftsH
Lon

RNAP
DnaK
FtsH
Lon
Recycle
proteins
that
can’t
refold