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cdsltech/~doyle/shortcourse.htm Systems Biology Shortcourse May 21-24

http://www.cds.caltech.edu/~doyle/shortcourse.htm Systems Biology Shortcourse May 21-24 Winnett Lounge, Caltech Speakers: Adam Arkin (UC Berkeley), Frank Doyle (UCSB), Drew Endy (MIT), Dan Gillespie (Caltech), Michael Savageau (UC Davis)

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cdsltech/~doyle/shortcourse.htm Systems Biology Shortcourse May 21-24

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  1. http://www.cds.caltech.edu/~doyle/shortcourse.htm Systems Biology Shortcourse May 21-24 Winnett Lounge, Caltech Speakers: Adam Arkin (UC Berkeley), Frank Doyle (UCSB), Drew Endy (MIT), Dan Gillespie (Caltech), Michael Savageau (UC Davis) Organized by John Doyle (Caltech). There is no registration or fees. Note: Friday 4pm talk by Adam Arkin in Beckman Institute Auditorium.

  2. Collaborators and contributors(partial list) Theory:Parrilo, Carlson,Paganini, Papachristodoulo, Prajna, Goncalves, Fazel, Lall, D’Andrea, Jadbabaie,many current and former students, … Web/Internet: Low, Willinger,Vinnicombe, Kelly, Zhu,Yu, Wang, Chandy, Effros, … Biology: Csete,Yi, Tanaka, Arkin, Savageau, Simon, AfCS, Kurata, Khammash, El-Samad, Gross, Bolouri, Kitano, Hucka, Sauro, Finney, … Turbulence: Bamieh, Dahleh, Bobba, Gharib, Marsden, … Physics:Mabuchi, Doherty, Barahona, Reynolds, Asimakapoulos,… Engineering CAD:Ortiz,Murray, Schroder, Burdick, … Disturbance ecology: Moritz, Carlson, Robert, … Finance:Martinez, Primbs, Yamada, Giannelli,… Caltech faculty Other Caltech Other

  3. Polymerization and assembly Transport Whole cell metabolism Core metabolism Autocatalytic and regulatory feedback

  4. +Regulation Autocatalysis Enzyme Metabolite

  5. +Regulation Autocatalysis Enzyme Metabolite

  6. + - + Enzyme Metabolite

  7. Stoichiometry or mass and energy balance Internal Products Nutrients

  8. Core metabolism

  9. Polymerization and assembly Transport Whole cell metabolism Core metabolism Autocatalytic and regulatory feedback

  10. Nested “bowties” Polymerization and assembly Core metabolism transport Autocatalytic and regulatory feedback

  11. Polymerization and assembly Core metabolism transport Nested “bowties” Our first universal architecture

  12. The core metabolism “bowtie” Nutrients Products

  13. Nucleotides Sugars Amino Acids Fatty acids Energy and reducing Biosynthesis Catabolism Carriers and Precursor Metabolites Cartoon metabolism

  14. Catabolism Nucleotides Synthesis Catabolism Nutrients Products Carriers and Precursor Metabolites Sugars Amino Acids Fatty acids Energy and reducing The metabolism “bowtie” protocol

  15. Core: special purpose enzymes controlled by competitive inhibition and allostery Edges: general purpose polymerases and machines controlled by regulated recruitment Uncertain Uncertain

  16. Core: Highly efficient Edges: Robustness and flexibility Uncertain Uncertain

  17. Almost everything complex is made this way: Cars, planes, buildings, power, fuel, laptops,… This “cartoon” is pure protocol.

  18. Collect and import raw materials Common currencies and building blocks Complex assembly Manufacturing and metabolism Collect and import raw materials Common currencies and building blocks Complex assembly Polymerization and assembly Taxis and transport Core metabolism Autocatalytic and regulatory feedback

  19. Electric power Variety of producers

  20. Electric power Variety of consumers

  21. 110 V, 60 Hz AC (230V, 50 Hz AC) Gasoline ATP, glucose, etc Proton motive force Variety of consumers Variety of producers Energy carriers

  22. Raw materials Complex assembly Raw materials Complex assembly Building blocks

  23. Collect and import raw materials Common currencies and building blocks Complex assembly Steel manufacturing

  24. metabolism assembly transport Core: special purpose machines controlled by allostery Variety of consumers Variety of producers Energy carriers

  25. metabolism assembly transport Edges: general purpose machines controlled by regulated recruitment Variety of consumers Variety of producers Energy carriers

  26. metabolism assembly transport Robust and evolvable Variety of consumers Variety of producers Energy carriers

  27. metabolism assembly transport Fragile and hard to change Variety of consumers Variety of producers Energy carriers

  28. metabolism assembly 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

  29. Modules and protocols • Much confusion surrounds these terms • Biologists already understand the important distinction • Most of basic sciences doesn’t

  30. Modules and protocols in experiments • Modules: components of experiments • Protocols: rules or recipes by which the modules interact • This generalizes to most important situations • Important distinction in experiments • Even more important in understanding the complexity of biological networks

  31. Modules and protocols example • Suppose some specific experimental protocol has a step that requires the use of a PCR machine module. • The PCR machine in turn implements a complex protocol with its own modules. • Thus protocols and modules are hierarchically nested. • A nested collection of protocols/modules is called an architecture or protocol suite.

  32. Modules and protocols example • Consider this laptop/projector combination. • The modules include software, hardware, and connectors. • The protocols are the rules by which these modules must interact. • Hardware modules change between talks • Within talks slides change, not hardware • Robust and “evolvable” yet fragile

  33. Modules and protocols example • Consider this laptop/projector combination. • The modules include software, hardware, and connectors. • The protocols are the rules by which these modules must interact. • Hardware modules change between talks • Within talks slides change, not hardware • Robust and “evolvable” yet fragile

  34. Varied systems Varied components The LEGO connector protocol Robust Mesoscale

  35. Early computing Software Hardware Various functionality Digital Analog substrate

  36. Applications Software Hardware Modern Computing Operating System Hardware

  37. Applications Software Hardware Modern Computing Operating System Hardware

  38. Modules and protocols • Protocols and modules are complementary (dual) notions • Primitive technologies = modules are more important than protocols • Advanced technologies = protocols are at least as important • Even bacteria are “advanced technology”

  39. Reductionism and protocols • Reductionism = modules are more important than protocols • Usually: “Huh? What’s a protocol?” • Systems approach: Protocols are as important as modules

  40. Necessity or “frozen accident”? • Laws are absolute necessity. • Conjecture: Protocols in biology are largely necessary. (More so than in engineering!) • Modules??? Appear to be more of a mix of necessity and accident.

  41. Necessity or “frozen accident”? • Conservation laws are necessary. • Bowtie protocols are essentially necessary if robustness and efficiency are required. • Conjecture: It is necessary that there is an energy carrier, it may not be necessary that it be ATP.

  42. Conjectures on laws and protocols • The important laws governing biological complexity have yet to be fully articulated • Biology has highly organized dynamics using protocol suites • Both are true for advanced technologies

  43. Nested bowtie and hourglass Polymerization and assembly Core metabolism Conservation of energy and moiety is a law. Taxis and transport Enzymes are modules. “Bowtie architectures” is a protocol. Autocatalytic and regulatory feedback

  44. essential: 230 nonessential: 2373 unknown: 1804 total: 4407 http://www.shigen.nig.ac.jp/ecoli/pec

  45. metabolism assembly transport Autocatalytic feedback Regulatory feedback

  46. metabolism assembly transport Knockouts often lethal Autocatalytic feedback Knockouts often lose robustness, not minimal functionality Regulatory feedback

  47. Steering Brakes Anti-skid Wipers Mirrors Cruise control GPS Radio Traction control Shifting Headlights Electronic ignition Temperature control Seats Electronic fuel injection Seatbelts Fenders Bumpers Airbags Suspension (control)

  48. Knockouts often lethal Steering Brakes Anti-skid Wipers Mirrors Knockouts often lose robustness, not minimal functionality Cruise control GPS Radio Traction control Shifting Headlights Electronic ignition Temperature control Seats Electronic fuel injection Seatbelts Fenders Bumpers Airbags Suspension (control)

  49. metabolism assembly transport Supplies Materials & Energy Autocatalytic feedback Robustness  Complexity Regulatory feedback Supplies Robustness

  50. metabolism assembly transport Autocatalytic feedback If feedback regulation is the dominant protocol, what are the laws constraining what’s possible? Regulatory feedback

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