slow

1. fragile slow robust fast efficient inflexible flexible waste

2. body slow Combo fast brain efficient inflexible flexible waste

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

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

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

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 • Flight • Mitochondria • Oxygen • Translation (ribosomes) • Glycolysis (2011 Science) Major transitions

7. Universal laws? fragile 100 Ideal robust efficient wasteful 1 10 fragile 10 2 .1 .2 .5 1 0 10 -1 0 1 Length, m 10 10 10 expensive

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

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

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

11. A pathway view DNA repair Mutation DNA replication Transcription Translation Metabolism Signal transduction … DNA RNA Protein

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

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

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

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

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

17. Proteins Metabolism Products Substrates

18. Core Protocols Gene Transcription mRNA Translation Proteins Metabolism Products

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

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

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

22. DNA repair Mutation DNA replication Transcription Translation Metabolism Signal transduction … Red blood cells Proteins Metabolism Products Signal transduction control feedback

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

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

25. Control 1.0 DNA repair Mutation DNA replication Transcription Translation Metabolism Signal transduction … Highly controlled Think of this as a “protocol stack”

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

27. RNA Gene RNAp Transcription Other Control mRNA

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

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

30. Mutation and repair Replication DNAp DNA Gene’ DNA RNA Gene Protein

31. Control 1.0 DNA repair Mutation DNA replication Transcription Translation Metabolism Signal transduction … Highly controlled Think of this as a “protocol stack”

32. Horizontal gene transfer (HGT) Replication DNAp DNA Gene’ New gene Gene New gene

33. 0. HGT DNA repair Mutation DNA replication Transcription Translation Metabolism Signal transduction … Gene RNA RNAp Transcription mRNA Amino Acids Other Control New gene Ribosomes DNA Translation Proteins Other Control Metabolism Products ATP Signal transduction control feedback

34. Control 1.0 0. HGT DNA repair Mutation DNA replication Transcription Translation Metabolism Signal transduction … Highly controlled Think of this as a “protocol stack”

35. Control 2.0 Evolution Adaptation Control 0. HGT DNA repair Mutation DNA replication Transcription Translation Metabolism Signal transduction … Highly controlled (slow) Highly controlled (fast) Think of this as a “protocol stack”

36. 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

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

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

39. Transmitter Transmitter Transmitter Transmitter Transmitter Transmitter Transmitter Transmitter Transmitter Transmitter Transmitter Transmitter Transmitter Receiver Receiver Receiver Receiver Receiver Receiver Receiver Receiver Receiver Receiver Receiver Receiver Receiver Variety of Ligands & Receptors Variety of Ligands & Receptors Variety of Ligands & Receptors Variety of Ligands & Receptors Variety of Ligands & Receptors Variety of Ligands & Receptors Variety of Ligands & Receptors Variety of Ligands & Receptors Variety of Ligands & Receptors Variety of Ligands & Receptors Variety of Ligands & Receptors Variety of Ligands & Receptors Variety of Ligands & Receptors 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 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

40. Flow of “signal” Shared protocols Ligands & Receptors Transmitter Receiver Responses 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

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

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

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

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

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

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

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

48. Any input Any other input Sensing the demand of the application layer Sensor domains 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

49. “Cross talk” can be finely controlled Any input Any other input Sensor domains • 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”

50. “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