fragile slow robust fast efficient inflexible flexible waste

Transcription

1 slow fragile efficient fast robust flexible inflexible waste

2 slow body brain waste efficient fast Combo flexible inflexible

3 HMT Contextual Slow Prefrontal Adaptive Motor Fast Sense Reactive Fast Combo Flexible Inflexible Reflex Soma

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

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

6 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 Warm blood Major transitions Flight Mitochondria Oxygen Translation (ribosomes) Glycolysis (2011 Science)

7 fragile Universal laws? fragile 10 1 robust Ideal efficient wasteful expensive Length, m

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

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

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

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

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

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

14 Gene Transcription Other Control RNA mrna RNAp DNA RNA Polymerization

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

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

17 Proteins Substrates Metabolism Products

18 Gene Core Protocols Transcription mrna Translation Proteins Metabolism Products

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

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

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

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

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

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

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

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

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

28 Gene Transcription Other Control RNA mrna RNAp

29 Gene Transcription Other Control RNA mrna RNAp DNA RNA Protein

30 Replication DNAp DNA Gene Gene Transcription Other Control RNA mrna RNAp DNA RNA Protein

31 Mutation and repair Replication DNAp DNA Gene DNA Gene RNA Protein

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

33 Horizontal gene transfer (HGT) Gene Replication DNA DNAp Gene New gene New gene

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

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

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

37 Sequence ~100 E Coli (not chosen randomly) ~ 4K genes per cell ~20K different genes in total (pangenome) ~ 1K universally shared genes ~ 300 essenaal (minimal) genes Horizontal Gene Transfer

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

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

40 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 Variety of Variety of Variety Ligands & of Receptors transduction Transmitter Receiver Variety of 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 Variety & of Receptors Ligands Variety & of Receptors Ligands & Receptors Ligands & Receptors Receptors Transmitter Transmitter Transmitter Transmitter Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Receiver Receiver Receiver Receiver Variety of 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 Variety of responses Variety of responses responses

41 Ligands & Receptors Flow of signal Transmitter Receiver Recognition, specificity Responses Shared protocols 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 Ligands & Receptors Transmitter Receiver Responses Name recognition = molecular recognition = localized functionally = global spatially Transcription factors do name to address translation

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

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

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

46 DNA There are simpler transcription factors for sensing internal states

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

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

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

50 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

51 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

52 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

53 (almost analog) rate determined by relative copy number Binding recognition nearly digital Promoter Gene5 Gene6

54 rate (almost analog) determined by copy number Recall: can work by pulse code modulation so for small copy number does digital to analog conversion Promoter Gene5 Gene6

55 Any input 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 Promoter Gene1 Gene2

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

57 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 Variety of Variety of Variety Ligands & of Receptors transduction Transmitter Receiver Variety of 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 Variety & of Receptors Ligands Variety & of Receptors Ligands & Receptors Ligands & Receptors Receptors Transmitter Transmitter Transmitter Transmitter Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Receiver Receiver Receiver Receiver Variety of 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 Variety of responses Variety of responses responses

58 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

59 TCP/IP architecture? Deconstrained (Applications) Few global variables Don t cross layers TCP/IP Deconstrained (Hardware) Comms Memory, storage Latency Processing Cyber-physical

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

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

62 Issues (hacks) VPNs NATS Firewalls Multihoming Mobility Routing table size Overlays Application TCP IP Physical

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

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

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 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

70 Human physiology Ouch. Endless details

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

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

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

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

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

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

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

78 Endless details on HRV High mean Low variability Low mean High variability Heart rate variability (HRV) Healthy = Not = Low mean High variability time(sec) High mean Low variability

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

80 Robust Human complexity Yet Fragile 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 Robust Fragile Metabolism Obesity, diabetes Regeneration & repair Fat accumulation Cancer Healing wound /infect Insulin resistance AutoImmune/Inflame 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?

82 Ouch. Unfortunately, not intelligent design

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

84 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)

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

86 rpoh σ mrna Heat σ Other operons σ DnaK RNAP σ RNAP DnaK σ DnaK ftsh FtsH Lon DnaK Lon Recycle proteins that can t refold