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Co-factors

Ligand. In. Receptor. GDP. GTP. . Out. . G . G . GDP. GTP. P. In. RGS. Polymerization and complex assembly. Autocatalytic feedback. Taxis and transport. Proteins. Core metabolism. Sugars. Catabolism. Amino Acids. Nucleotides. Precursors. Nutrients. Trans*.

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Co-factors

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  1. Ligand In Receptor GDP GTP  Out  G G GDP GTP P In RGS 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, D’Andrea, 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 Longterm Visitor Other

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

  4. Today’s focus Core theory challenges Network Centric, Pervasive, Embedded, Ubiquitous Systems Biology

  5. Today’s focus …is on stories you are unlikely to hear from anyone else. Core theory challenges Caution: maybe others are more sensible than I am. Core theory challenges Core theory challenges Systems Biology Pervasive, Networked, Embedded

  6. 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

  7. 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. • Parallel stories exist in “theoretical biology.” • For future networks and other new technologies, as well as systems biology of the cell, organism and brain, let’s hope we can avoid a repeat of this history.

  8. Robust yet fragile (RYF) • The same mechanisms responsible for robustness to most perturbations • Allows possible extreme fragilities to others

  9. Efficient, flexible metabolism Complex development and Immune systems Regeneration & renewal Complex societies Obesity and diabetes and Rich parasite ecosystem Auto-immune disease Cancer Epidemics, war, genocide, … Yet Fragile Robust Human robustness and fragility

  10. Efficient, flexible metabolism Complex development and Immune systems Regeneration & renewal Complex societies Advanced technologies Obesity and diabetes and Rich parasite ecosystem Auto-immune disease Cancer Epidemics, war, … ????? Yet Fragile Robust What about technology?

  11. Efficient, flexible metabolism Complex development and Immune systems Regeneration & renewal Complex societies Advanced technologies Obesity and diabetes and Rich parasite ecosystem Auto-immune disease Cancer Epidemics, war, … ????? Yet Fragile Robust What about technology?

  12. 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

  13. TCP/IP fragility on many timescales • Shortest: File transfers from different users • End systems w/o congestion control won’t 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?

  14. 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 • Ubiquitous in biology and advanced technology • High variability (and thus power laws)

  15. 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 won’t happen (apparently).

  16. 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 can’t happen (apparently).

  17. Working systems but no “proofs’

  18. Spectacular progress….

  19. Progress • Understanding mice and elephants • “Primal-dual” decompositions for layering • Global stability analysis with delays • New solutions to “classic” problems Many challenges • Rigorous multiscale models • Latency-based utilities • Wireless, MANETs • Interdomain routing

  20. “FAST” theory • Arbitrarily complex network • Topology • Number of routers and hosts • Nonlinear • Delays Routers • Short proof • Global stability • Equilibrium optimizes aggregate user utility Papachristodoulou, Li Hosts packets

  21. I2LSR, SC2004 Bandwidth Challenge OC48 Harvey Newman’s group, Caltech http://dnae.home.cern.ch/dnae/lsr4-nov04 OC192 November 8, 2004 Caltech and CERN transferred • 2,881 GBytes in one hour (6.86Gbps) • between Geneva - US - Geneva (25,280 km) • through LHCnet/DataTag, Abilene and CENIC backbones • using 18 FAST TCP streams

  22. Yet growing confusion… …sorry, but in the interest of scientific hygiene, we have to admit that all is not well…

  23. One of the most-read papers ever on the Internet!

  24. 2 10 1 10 0 10 0 1 2 3 10 10 10 10 “Scale-free” networks and the “Achilles’ heel” of the Internet High degree hub-like core power-law degrees

  25. High degree hub-like core Delete these “hubs” and the network disconnects! Delete “non-hubs” with little effect! Robust yet fragile!?!?!?

  26. Intermountain GigaPoP U. Memphis Indiana GigaPoP WiscREN Northern Lights OARNET Great Plains Front Range GigaPoP U. Louisville Merit NYSERNet OneNet StarLight Arizona St. NCSA Qwest Labs Iowa St. U. Arizona UNM Oregon GigaPoP WPI Pacific Wave Kansas City Indian- apolis Denver Pacific Northwest GigaPoP SINet Chicago Seattle SURFNet ESnet New York MANLAN U. Hawaii GEANT Rutgers U. Wash D.C. UniNet Sunnyvale MREN WIDE MAGPI CENIC Los Angeles Northern Crossroads TransPAC/APAN AMES NGIX Tulane U. Atlanta Houston LaNet SOX PSC North Texas GigaPoP U. Delaware Drexel U. DARPA BossNet Texas GigaPoP Mid-Atlantic Crossroads Texas Tech SFGP/ AMPATH Miss State GigaPoP UT Austin NCNI/MCNC U. Florida UMD NGIX UT-SW Med Ctr. U. So. Florida Florida A&M Abilene Backbone Physical Connectivity Internet router-level topology 0.1-0.5 Gbps 0.5-1.0 Gbps 1.0-5.0 Gbps 5.0-10.0 Gbps

  27. Internet router-level topology 0.1-0.5 Gbps 0.5-1.0 Gbps 1.0-5.0 Gbps 5.0-10.0 Gbps

  28. 0.1-0.5 Gbps 0.5-1.0 Gbps 1.0-5.0 Gbps 5.0-10.0 Gbps

  29. 2 10 1 10 0 10 0 1 2 3 10 10 10 10 High variability edge systems Low degree mesh-like core rank power-law degrees Completely different networks can have the same node degrees.

  30. 2 10 1 10 0 10 0 1 2 3 10 10 10 10 High degree hub-like core Low degree mesh-like core identical power-law degrees Completely different networks can have the same node degrees.

  31. Low degree core High performance and robustness High degree “hubs” Poor performance and robustness Nothing like the real Internet. See PNAS, Sigcomm, TransNet papers for details.

  32. Core theory challenges • Hard constraints • Simple models • Short proofs • Architecture

  33. 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?

  34. 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.

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

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

  37. 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? • Integrating simple models and short proofs?

  38. 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 (biology) • Macroscopic behavior: robust yet fragile

  39. 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?

  40. 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.

  41. Feathers and flapping? Or lift, drag, propulsion, and control? The danger of biomemetics

  42. 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.”

  43. Heat rpoH +  mRNA Regulation of protein action + Regulation of protein levels  PMF  DnaK + +  DnaK DnaK ftsH RNAP Gly Lon G1P  RNAP G6P DnaK FtsH Lon F6P F1-6BP Gly3p ATP 13BPG 3PG TCA Oxa ACA 2PG PEP Pyr NADH Cit Lessons from the cell and Internet 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

  44. 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.

  45. Bowtie: Flow of energy and materials Universal organizational structures/architectures Organization of control Hourglass

  46. The Internet hourglass Applications Web FTP Mail News Video Audio ping napster Ethernet 802.11 Power lines ATM Optical Satellite Bluetooth Linktechnologies

  47. The Internet hourglass Applications Web FTP Mail News Video Audio ping napster TCP IP Ethernet 802.11 Power lines ATM Optical Satellite Bluetooth Linktechnologies

  48. IP on everything The Internet hourglass Applications IP under everything Web FTP Mail News Video Audio ping napster TCP IP Ethernet 802.11 Power lines ATM Optical Satellite Bluetooth Linktechnologies

  49. Bio: Huge variety of environments, metabolisms Internet: Huge variety of applications Huge variety of components

  50. Bio: Huge variety of environments, metabolisms Internet: Huge variety of applications Both components and applications are highly uncertain. Huge variety of components

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