1. slow flexible fast inflexible waste efficient fragile robust

2. slow flexible fast inflexible waste efficient body brain Combo

3. Sense Fast Slow Flexible Inflexible Motor Prefrontal Fast Learn Reflex Evolve HMT Soma Reactive Adaptive Contextual Cerebellum Combo

4. Slow Fast Flexible Inflexible General Special Apps OS HW Dig. Lump. Distrib. OS HW Dig. Lump. Distrib. Digital Lump. Distrib. Lumped Distrib. HGT DNA repair Mutation DNA replication Transcription Translation Metabolism Signal SenseMotor Prefrontal Fast Learn Reflex Evolve vision VOR

5. Fast Costly Slow Cheap Flexible Inflexible HGT DNA repair Mutation DNA replication Transcription Translation Metabolism Signal… Layered Architecture control feedback RNA mRNA RNAp Transcription Other Control Gene Amino Acids Proteins Ribosomes Other Control Translation Metabolism Products Signal transduction ATP DNA New gene Today

6. Efficiency/instability/layers/feedback Sustainable infrastructure? (e.g. smartgrids) Money/finance/lobbyists/etc Industrialization Society/agriculture/weapons/etc Bipedalism Maternal care Warm blood Flight Mitochondria Oxygen Translation (ribosomes) Glycolysis (2011 Science) All create new efficiencies but also instabilities Needs new distributed/layered/complex/active control Major transitions

7. Universal laws? 10 100 Length, m.11.5.2 2 10 10 0 1 0 1 expensive fragile wasteful fragile efficient robust Ideal

8. TCA Gly G1P G6P F6P F1-6BP PEPPyr Gly3p 13BPG 3PG 2PG ATP NADH Oxa Cit ACA Autocatalysis Control Feedbacks Robust=maintain energy charge w/fluctuating cell demand Efficient=minimize metabolic waste and overhead

9. ATP Rest of cell Reaction 2 (“PK”) Reaction 1 (“PFK”) Protein biosyn energy enzymes Efficient = low metabolic overhead  low enzyme amount enzymes catalyze reactions, another source of autocatalysis

10. ATP Rest of cell Protein biosyn energy enzymes enzymes catalyze reactions, another source of autocatalysis Ribosomes must make ribosomal proteins Ribosomal protein content: Mitochondria >> Bacteria Autocatalysis

11. 1.DNA repair 2.Mutation 3.DNA replication 4.Transcription 5.Translation 6.Metabolism 7.Signal transduction 8.… A pathway view DNA RNA Protein

12. A pathway view Substrate Product DNA RNA Protein Enzyme (Protein) Reaction

13. A pathway view Substrate Product Enzyme (Protein) Reaction Control

14. RNA mRNA RNAp Transcription Other Control DNA RNA Gene Polymerization

15. RNA mRNA RNAp Transcription Other Control DNA RNA Gene Protein Amino Acids Proteins Ribosomes Other Control Translation

16. RNA mRNA RNAp Transcription Other Control Gene Amino Acids Proteins Ribosomes Other Control Translation Autocatalytic feedback

17. Proteins Metabolism Substrates Products

18. mRNA Transcription Gene Proteins Translation Metabolism Products Core Protocols

19. RNA mRNA RNAp Transcription Other Control Gene Amino Acids Proteins Ribosomes Other Control Translation Metabolism Products Autocatalytic feedback

20. control feedback RNA mRNA RNAp Transcription Other Control Gene Amino Acids Proteins Ribosomes Other Control Translation Metabolism Products Autocatalytic feedback Signal transduction

21. control feedback RNA mRNA RNAp Transcription Other Control Gene Amino Acids Proteins Ribosomes Other Control Translation Metabolism Products Autocatalytic feedback Signal transduction

22. control feedback RNA mRNA RNAp Transcription Other Control Gene Amino Acids Proteins Ribosomes Other Control Translation Metabolism Products Autocatalytic feedback Signal transduction Prediction &Control

23. control feedback Proteins Metabolism Products Signal transduction Red blood cells 1.DNA repair 2.Mutation 3.DNA replication 4.Transcription 5.Translation 6.Metabolism 7.Signal transduction 8.…

24. control feedback RNA mRNA RNAp Transcription Other Control Gene Amino Acids Proteins Ribosomes Other Control Translation Metabolism Products Autocatalytic feedback Signal transduction

25. x ATP autocatalytic a H g control Rest PK PFK control feedback RNA mRNA RNAp Transcription Other Control Gene Amino Acids Proteins Ribosomes Other Control Products Autocatalytic feedback Signal transduction Metabolism Translation Core metabolism

26. Think of this as a “protocol stack” 1.DNA repair 2.Mutation 3.DNA replication 4.Transcription 5.Translation 6.Metabolism 7.Signal transduction 8.… Highly controlled Control 1.0

27. control feedback RNA mRNA RNAp Transcription Other Control Gene Amino Acids Proteins Ribosomes Other Control Translation Metabolism Products Signal transduction RNA mRNA RNAp Transcription Other Control Gene

28. RNA mRNA RNAp Transcription Other Control Gene

29. RNA mRNA RNAp Transcription Other Control DNA RNA Gene Protein

30. RNA mRNA RNAp Transcription Other Control DNA RNA Gene Protein DNAGene Replication DNAp

31. DNA RNA Gene Protein DNAGene’ Replication DNAp Mutation and repair

32. Think of this as a “protocol stack” 1.DNA repair 2.Mutation 3.DNA replication 4.Transcription 5.Translation 6.Metabolism 7.Signal transduction 8.… Highly controlled Control 1.0

33. Gene DNAGene’ Replication DNAp Horizontal gene transfer (HGT) New gene

34. control feedback RNA mRNA RNAp Transcription Other Control Gene Amino Acids Proteins Ribosomes Other Control Translation Metabolism Products Signal transduction ATP DNA New gene 0.HGT 1.DNA repair 2.Mutation 3.DNA replication 4.Transcription 5.Translation 6.Metabolism 7.Signal transduction 8.…

35. Think of this as a “protocol stack” 0.HGT 1.DNA repair 2.Mutation 3.DNA replication 4.Transcription 5.Translation 6.Metabolism 7.Signal transduction 8.… Highly controlled Control 1.0

36. Think of this as a “protocol stack” 0.HGT 1.DNA repair 2.Mutation 3.DNA replication 4.Transcription 5.Translation 6.Metabolism 7.Signal transduction 8.… Highly controlled (fast) Highly controlled (slow) Control 2.0 Evolution  Adaptation  Control

37. 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

38. Horizontal Bad Gene Transfer Horizontal Bad App Transfer Horizontal Bad Meme Transfer Parasites & Hijacking Fragility? Exploiting layered architecture Virus Meme

39. Fast Costly Slow Cheap Flexible Inflexible HGT DNA repair Mutation DNA replication Transcription Translation Metabolism Signal… Layered Architecture control feedback RNA mRNA RNAp Transcription Other Control Gene Amino Acids Proteins Ribosomes Other Control Translation Metabolism Products Signal transduction ATP DNA New gene Control across layers

40. TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses  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 Signal transduction

41. TransmitterReceiver Ligands & Receptors Responses Shared protocols Flow of “signal” 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

42. Transmitter Ligands & Receptors Receiver Responses “Name” recognition = molecular recognition = localized functionally = global spatially Transcription factors do “name” to “address” translation

43. DNA Transmitter Ligands & Receptors Receiver Responses “Name” recognition = molecular recognition = localized functionally Transcription factors do “name” to “address” translation

44. DNA Transmitter Ligands & Receptors Receiver Responses “Addressing” = molecular recognition = localized spatially Both are Almost digital Highly programmable “Name” recognition = molecular recognition = localized functionally Transcription factors do “name” to “address” translation

45. DNA 2CST systems provide speed, flexibility, external sensing, computation, impedance match, more feedback, but greater complexity and overhead Transmitter Ligands & Receptors Receiver Responses Receiver Responses Feedback control There are simpler transcription factors for sensing internal states

46. DNA There are simpler transcription factors for sensing internal states

47. DNA RNAp DNA and RNAp binding domains Sensor domains Domains can be evolved independently or coordinated. Application layer cannot access DNA directly. Highly evolvable architecture. There are simpler transcription factors for sensing internal states

48. DNA RNAp DNA and RNAp binding domains Sensor domains This is like a “name to address” translation. Sensing the demand of the application layer Initiating the change in supply

49. Sensor domains Sensing the demand of the application layer Any input Any other input 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 DNA and RNAp binding domains

50. Sensor domains “Cross talk” can be finely controlled Any input 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”

51. DNA “Addressing” = molecular recognition = localized spatially Both are Almost digital Highly programmable “Name” recognition = molecular recognition = localized functionally = global spatially Transcription factors do “name” to “address” translation

52. RNAp Can activate or repress And work in complex logical combinations PromoterGene1Gene2… 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

53. Promoter Gene5Gene6 … (almost analog) rate determined by relative copy number Binding recognition nearly digital

54. Promoter Gene5Gene6 … rate (almost analog) determined by copy number Recall: can work by pulse code modulation so for small copy number does digital to analog conversion

55. PromoterGene1Gene2… 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 Any input

56. Reactions Assembly DNA/RNA control DNA Outside Inside Transmitter Ligands & Receptors Receiver Responses control Receiver Responses Protein Cross-layer control Highly organized Naming and addressing Prices? Duality? Minimal case study?

57. TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses TransmitterReceiver Variety of Ligands & Receptors Variety of responses  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 Signal transduction

58. ? Deconstrained (Hardware) Deconstrained (Applications) Next layered architectures (SDN) Constrained Optimize & control, share, virtualize, manage resources Comms Memory, storage Latency Processing Cyber-physical Few global variables Don’t cross layers

59. TCP/IP Deconstrained (Hardware) Deconstrained (Applications) TCP/IP architecture? Comms Memory, storage Latency Processing Cyber-physical Few global variables Don’t cross layers

60. App IPC Global and direct access to physical address! DNS IP addresses interfaces (not nodes) caltech.edu? 131.215.9.49

61. App IPC Global and direct access to physical address! Robust? Secure Scalable Verifiable Evolvable Maintainable Designable … DNS IP addresses interfaces (not nodes)

62. “Issues” (hacks) VPNs NATS Firewalls Multihoming Mobility Routing table size Overlays …

63. Aside: Graph topology is not architecture, but deconstrained by layered architectures. Internet graph topologies?

64. Original design challenge? TCP/ IP Deconstrained (Hardware) Deconstrained (Applications) Constrained Expensive mainframes Trusted end systems Homogeneous Sender centric Unreliable comms Facilitated wild evolution Created whole new ecosystem completely opposite Networked OS

65. Ouch. Unfortunately, not intelligent design

66. Why? left recurrent laryngeal nerve

67. Why? Building humans from fish parts. Fish parts

68. It could be worse.

69. ? Deconstrained (Hardware) Deconstrained (Applications) Next layered architectures (SDN) Constrained Optimize & control, share, virtualize, manage resources Comms Memory, storage Latency Processing Cyber-physical Few global variables Don’t cross layers

70. Ouch. Human physiology Endless details

71. RobustFragile Human physiology Metabolism Regeneration & repair Healing wound /infect Efficient cardiovascular  Obesity, diabetes  Cancer  AutoImmune/Inflame  C-V diseases  Infectious diseases Lots of triage

72. Robust Benefits Metabolism Regeneration & repair Healing wound /infect Efficient cardiovascular Efficient Mobility Survive uncertain food supply Recover from moderate trauma and infection

73. RobustFragile Mechanism? Metabolism Regeneration & repair Healing wound /infect  Obesity, diabetes  Cancer  AutoImmune/Inflame  Fat accumulation  Insulin resistance  Proliferation  Inflammation

74. RobustFragile Mechanism? Metabolism Regeneration & repair Healing wound /infect Fat accumulation Insulin resistance Proliferation Inflammation  Obesity, diabetes  Cancer  AutoImmune/Inflame  Fat accumulation  Insulin resistance  Proliferation  Inflammation

75. RobustFragile What’s the difference? Metabolism Regeneration & repair Healing wound /infect  Obesity, diabetes  Cancer  AutoImmune/Inflame  Fat accumulation  Insulin resistance  Proliferation  Inflammation Controlled Acute/responsive Uncontrolled Chronic

76. Controlled Acute/responsive Low mean High variability  Fat accumulation  Insulin resistance  Proliferation  Inflammation

77. Controlled Acute Uncontrolled Chronic Low mean High variability High mean Low variability  Fat accumulation  Insulin resistance  Proliferation  Inflammation Death

78. 40 60 80 100 120 140 time(sec) Heart rate variability (HRV) Healthy = Not = Low mean High variability High mean Low variability High mean Low variability Low mean High variability Endless details on HRV

79. RobustFragile Restoring robustness? Metabolism Regeneration & repair Healing wound /infect  Obesity, diabetes  Cancer  AutoImmune/Inflame  Fat accumulation  Insulin resistance  Proliferation  Inflammation Controlled Acute Uncontrolled Chronic Heal Fat accumulation Insulin resistance Proliferation Inflammation

80. RobustYet Fragile Human complexity Metabolism Regeneration & repair Immune/inflammation Microbe symbionts Neuro-endocrine  Complex societies  Advanced technologies  Risk “management”  Obesity, diabetes  Cancer  AutoImmune/Inflame  Parasites, infection  Addiction, psychosis,…  Epidemics, war,…  Disasters, global &!%$#  Obfuscate, amplify,… Accident or necessity?

81. RobustFragile Metabolism Regeneration & repair Healing wound /infect  Obesity, diabetes  Cancer  AutoImmune/Inflame  Fat accumulation  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”) Accident or necessity? Both Fundamentals!

82. Ouch. Unfortunately, not intelligent design

83. Feathers and flapping? Or lift, drag, propulsion, and control? The dangers of naïve biomemetics

84. 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)

85. Feathers and flapping? Or lift, drag, propulsion, and control? Universals?

86. RNAP DnaK  RNAP  DnaK rpoH FtsHLon Heat   mRNA Other operons  DnaK ftsH Lon Recycle proteins that can’t refold