Cofactors

1
Polymerization and complex assembly
Autocatalytic feedback
Taxis and transport
Proteins

• Complexity and

Core metabolism
Sugars
Catabolism
Amino Acids
Nucleotides
Precursors
Nutrients
Trans
Fatty acids
Genes
Co-factors
Carriers

• Architecture

DNA replication
John Doyle John G Braun Professor Control and
Dynamical Systems, BioEng, and ElecEng Caltech
www.cds.caltech.edu/doyle
2
My interests
Multiscale Physics
Core theory challenges
Network Centric, Pervasive, Embedded, Ubiquitous
Systems Biology
3
Collaborators and contributors(partial list)

• Biology Csete,Yi, El-Samad, Khammash, Tanaka,
  Arkin, Savageau, Simon, AfCS, Kurata, Smolke,
  Gross, Kitano, Hucka, Sauro, Finney, Bolouri,
  Gillespie, Petzold, F Doyle, Stelling, Caporale,
• Theory Parrilo, Carlson, Murray, Vinnicombe,
  Paganini, Mitra Papachristodoulou, Prajna,
  Goncalves, Fazel, Liu, Lall, DAndrea, Jadbabaie,
  Dahleh, Martins, Recht, many more current and
  former students,
• Web/Internet Li, Alderson, Chen, Low, Willinger,
  Kelly, Zhu,Yu, Wang, Chandy,
• Turbulence Bamieh, Bobba, McKeown, Gharib,
  Marsden,
• Physics Sandberg, Mabuchi, Doherty, Barahona,
  Reynolds,
• Disturbance ecology Moritz, Carlson,
• Finance Martinez, Primbs, Yamada, Giannelli,

Current Caltech
Former Caltech
Other
Longterm Visitor
4
Thanks to

• NSF
• ARO/ICB
• AFOSR
• NIH/NIGMS
• Boeing
• DARPA
• Lee Center for Advanced Networking (Caltech)
• Hiroaki Kitano (ERATO)
• Braun family

5
Q-bio highlights?

• Biology with function, organization, physiology,
  evolution
• Selection is on organism action, not genes,
  signals, protein levels, etc
• Applications of engineering approaches, ideas,
  tools, and theory to biological systems
• Stochastic dynamics but not random networks
• Primarily at the small circuit level
• Overall, surprising convergence

6
Surprising convergence

• gt90 sequence identity
• Yet highly divergent phenotype
• Surprisingly convergent message
• Organisms have function and organization at
  every level

7
Major difference

• Deliberately and successfully provocative, e.g.

Deliberately (successfully?) not provocative or
controversial
8
Conference in Santa Fe on biology?

• Edge of chaos?
• Self-organized criticality?
• Scale-free networks?
• New age medicine?
• Shamanism?
• Homeopathy?
• Creationism?
• Intelligent design?

9
Conference in Santa Fe on biology!

• Optimization
• Dynamics
• Feedback
• Delay
• Nonlinearity
• Stochastic dynamics
• Information
• Coding
• Computation

Control and Dynamical Systems
Information theory
CS
10
Q-bio issues?

• Has this effort been successful so far?
• Do these methods scale to large networks and
  whole organisms?
• Good news and bad news

11
Successful?

• Wow

12
Scalable?

• Bad news No, not in any obvious sense
• Engineering theories mostly 50 years old
• Great for simple circuits
• Dont even scale to network technologies
• Good news
• New theories are promising, already driven by
  network technology needs
• But much needs to be done to address a scalable
  systems biology
• Where are things going?

13
Background progress

• Spectacular progress, both depth and breadth
• Biological networks
• Technological networks
• Mathematical foundations
• Remarkably consistent, convergent, coherent
• Role of protocols, architecture, feedback, and
  dynamics
• Yet seemingly persistent errors and confusion
  both within science between science and public
  policy

14
Unifying concepts

• Robustness
• Constraints

Ruthless oversimplification Terribly boring
15
Robust
Human complexity
Yet Fragile

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

• Obesity and diabetes
• Rich microbe ecosystem
• Inflammation, Auto-Im.
• Cancer
• Epidemics, war,
• Catastrophic failures

• Evolved mechanisms for robustness allow for, even
  facilitate, novel, severe fragilities elsewhere
• often involving hijacking/exploiting the same
  mechanism
• There are hard constraints (i.e. theorems with
  proofs)

16
Architecture is a central challenge

• The bacterial cell and the Internet have
• architectures
• that are robust and evolvable (yet fragile?)
• What does architecture mean here?
• What does it mean for an architecture to be
  robust and evolvable?
• Robust yet fragile?

17
Architecture in organized complexity

• Architecture involves or facilitates
• System-level function (beyond components)
• Organization and structure
• Protocols and modules
• Design or evolution
• Robustness, evolvability, scalability
• Various -ilities (many of them)
• Perhaps aesthetics
• but is more than the sum of these

18
Constraints as unifying concept

• Robust yet fragile is a hard constraint
• Complexity of systems due to constraints on
  robustness/evolvability rather than minimal
  functionality
• Architecture Constraints that deconstrain
• Optimality special case of constraints

19
Hard limits and tradeoffs

• On systems and their components
• Thermodynamics (Carnot)
• Communications (Shannon)
• Control (Bode)
• Computation (Turing/Gödel)

No dynamics, feedback
No networks
20
Hard limits and tradeoffs

• On systems and their components
• Thermodynamics (Carnot)
• Communications (Shannon)
• Control (Bode)
• Computation (Turing/Gödel)
• Fragmented and incompatible
• Cannot be used as a basis for comparing
  architectures
• New unifications are encouraging

Assume different architectures a priori.
21
Defining Architecture

• The elements of structure and organization that
  are most universal, high-level, persistent
• Must facilitate system level functionality
• And robustness/evolvability to uncertainty and
  change in components, function, and environment
• Architectures can be designed or evolve, but when
  possible should be planned
• Usually involves specification of
• protocols (rules of interaction)
• more than modules (which obey protocols)

22
Architecture in organized complexity

• Design of architectures is replacing design of
  systems
• Architecture is central in biology and
  technology, but has been largely overlooked in
  other areas of complexity
• Emergent complexity can have order,
  structure and (ill-defined notions like)
  self-organization
• but architecture plays little role
• Architecture also has little to do with aspects
  of networks that can be modeled using graph
  theory (or power laws)

23
A few asides

• Robust yet fragile, architecture-based, bio and
  techno networks have high variability everywhere
• High variability is fundamental and important.
• High variability yields power laws because of
  their strong invariance Central Limit Theorem,
  marginalization, maximization, mixtures
• Power laws are more normal than Normal
• This strong statistical invariance also yields
  power laws due to analysis errors, which are
  amazingly widespread
• Architecture also has little to do with aspects
  of networks that can be modeled using graph
  theory (or power laws)

24
Architecture examples

• There are universal architectures that are
  ubiquitous in complex technological and
  biological networks
• Examples include
• Bowties for flows of materials, energy, redox,
  information, etc (stoichiometry)
• Hourglasses for layering and distribution of
  regulation and control (fluxes, kinetics,
  dynamics)
• Nascent theory confirms (reverse engineers)
  success stories but has (so far) limited forward
  engineering applications (e.g. FAST TCP/AQM)

25
fan-out of diverse outputs
universal carriers
fan-in of diverse inputs
Universal architectures
Diverse function

• Bowties for flows
• Hourglasses for control
• Robust and evolvable
• Architecture protocols constraints

Universal Control
Diverse components
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The Internet hourglass
Applications
Web
FTP
Mail
News
Video
Audio
ping
napster
Ethernet
802.11
Satellite
Optical
Power lines
Bluetooth
ATM
Link technologies
27
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
28
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
29
Applications
Top of waist provides robustness to variety
and uncertainty above
TCP/ AQM
Bottom of waist provides robustness to
variety and uncertainty below
IP
30
Main bowtie in Internet S


Variety of files
Variety of files
packets

• All sender files transported as packets
• All files are reconstructed from packets by
  receiver
• All advanced technologies have protocols
  specifying knot of carriers, building blocks,
  interfaces, etc
• This architecture facilitates control, enabling
  robustness and evolvability
• It also creates fragilities to hijacking and
  cascading failure

31
Many bowties in Internet


Variety of files
Variety of files
packets


Applications




TCP


IP


32
Examples of
knot
universal carriers

• Packets in the Internet
• 60 Hz AC in the power grid
• Lego snap
• Money in markets and economics
• Lots of biology examples (coming up)

33
Nested bowties advanced technologies
Everything is made this way cars, planes,
buildings, laptops,
34
Electric power
Variety of producers
Variety of consumers
35
Standard
interface
Variety of consumers
Variety of producers
Energy carriers

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