Co-factors Fatty acids Sugars Nucleotides Amino Acids Catabolism Polymerization and complex assembly Proteins Precursors Autocatalytic feedback Taxis and transport Nutrients Carriers Core metabolism Genes DNA replication Trans* Regulation & control? E. coli genome Energy & materials

Co-factors Fatty acids Sugars Nucleotides Amino Acids Catabolism Polymerization and complex assembly Proteins Precursors Autocatalytic feedback Taxis and transport Nutrients Carriers Core metabolism Genes DNA replication Trans* Regulation & control E. coli genome

Co-factors Fatty acids Sugars Nucleotides Amino Acids Catabolism Polymerization and complex assembly Proteins Precursors Autocatalytic feedback Taxis and transport Nutrients Regulation & control Carriers Core metabolism Genes DNA replication Regulation & control Trans* Not to scale

essential : 230 nonessential:2373 unknown:1804 total: Gene networks?

Co-factors Fatty acids Sugars Nucleotides Amino Acids Catabolism Polymerization and complex assembly Proteins Precursors Autocatalytic feedback Taxis and transport Nutrients Carriers Core metabolism Genes DNA replication Trans* Regulation & control E. coli genome

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

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

Co-factors Fatty acids Sugars Nucleotides Amino Acids Catabolism Polymerization and complex assembly Proteins Precursors Autocatalytic feedback Taxis and transport Nutrients Carriers Core metabolism Genes DNA replication Trans* Regulation & control Knockouts often lose robustness, not minimal functionality Knockouts often lose robustness, not minimal functionality Knockouts often lethal

Co-factors Fatty acids Sugars Nucleotides Amino Acids Catabolism Polymerization and complex assembly Proteins Precursors Autocatalytic feedback Taxis and transport Nutrients Carriers Core metabolism Genes DNA replication Trans* Complexity is dominated by regulation & control

Genes Co-factors Fatty acids Sugars Nucleotides Amino Acids Proteins Precursors Core metabolism DNA replication Trans* Catabolism Carriers TransmitterReceiver Variety of Ligands & Receptors Variety of responses Regulation of protein levels Regulation of protein action

TCA Gly G1P G6P F6P F1-6BP PEPPyr Gly3p 13BPG 3PG 2PG ATP NADH Oxa Cit ACA Stoichiometry matrix S

Regulation of enzyme levels by transcription/translation/degradation TCA Gly G1P G6P F6P F1-6BP PEPPyr Gly3p 13BPG 3PG 2PG Oxa Cit ACA

TCA Gly G1P G6P F6P F1-6BP PEPPyr Gly3p 13BPG 3PG 2PG ATP NADH Oxa Cit ACA Allosteric regulation of enzymes

TCA Gly G1P G6P F6P F1-6BP PEPPyr Gly3p 13BPG 3PG 2PG ATP NADH Oxa Cit ACA Allosteric regulation of enzymes Regulation of enzyme levels

TCA Gly G1P G6P F6P F1-6BP PEPPyr Gly3p 13BPG 3PG 2PG ATP NADH Oxa Cit ACA Allosteric regulation of enzymes Regulation of enzyme levels Fast Slow

Regulation of protein levels Regulation of protein action Regulatory hourglass Huge variety of environments, metabolisms, functions Huge variety of components

Regulation of protein levels Regulation of protein action Environments, metabolisms, functions Components (genes) Huge variety Standardized mechanisms Highly conserved Huge variety Variety is within a specie (across time and space) and of course between species.

Huge variety Standardized mechanisms Highly conserved Huge variety assembly control Lego

Polymerization and complex assembly Proteins Autocatalytic feedback Regulation & control Genes DNA replication Trans*

DnaK rpoH Lon Other operons motif See El-Samad, Kurata, et al… PNAS, PLOS CompBio

DnaK rpoH Lon DnaK Lon Heat degradation foldedunfolded Other operons motif

RNAP DnaK RNAP  DnaK rpoH FtsHLon Heat  mRNA Other operons  Lon

RNAP DnaK  RNAP  DnaK rpoH FtsHLon Heat   mRNA Other operons  DnaK ftsH Lon

RNAP DnaK  RNAP  DnaK rpoH FtsHLon Heat   mRNA Other operons  DnaK ftsH Lon

RNAP DnaK  RNAP  DnaK rpoH FtsHLon Heat   mRNA  DnaK ftsH Lon Regulation of protein levels Regulation of protein action

TCA Gly G1P G6P F6P F1-6BP PEPPyr Gly3p 13BPG 3PG 2PG ATP NADH Oxa Cit ACA Allosteric Trans* RNAP DnaK  RNAP  DnaK rpoH FtsHLon Heat   mRNA  DnaK ftsH Lon Regulation of protein levels Regulation of protein action Regulation of protein levels Regulation of protein action Layered control architectures

RNAP DnaK  RNAP  DnaK rpoH FtsHLon Heat   mRNA Other operons  DnaK ftsH Lon

DnaK rpoH Lon Other operons motif

TCA Gly G1P G6P F6P F1-6BP PEPPyr Gly3p 13BPG 3PG 2PG ATP NADH Oxa Cit ACA RNAP DnaK  RNAP  DnaK rpoH FtsHLon Heat   mRNA  DnaK ftsH Lon Regulation of protein levels Regulation of protein action Allosteric regulation of enzymes Regulation of enzyme levels Regulation of protein levels Regulation of protein action

The Internet hourglass WebFTPMailNewsVideoAudiopingnapster Applications Ethernet SatelliteOpticalPower linesBluetoothATM Link technologies

The Internet hourglass IP WebFTPMailNewsVideoAudiopingnapster Applications TCP Ethernet SatelliteOpticalPower linesBluetoothATM Link technologies

The Internet hourglass IP WebFTPMailNewsVideoAudiopingnapster Applications TCP Ethernet SatelliteOpticalPower linesBluetoothATM Link technologies IP under everything IP on everything

IP TCP/ AQM Applications Link Top of “waist” provides robustness to variety and uncertainty above Bottom of “waist” provides robustness to variety and uncertainty below

IP TCP Application TCP Application TCP Application Routing Provisioning Vertical decomposition Protocol Stack

IP TCP Application TCP Application TCP Application Routing Provisioning Horizontal decomposition Each level is decentralized and asynchronous

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

Each layer is abstracted as an optimization problem Operation of a layer is a distributed solution Results of one problem (layer) are parameters of others Operate at different timescales Layering as optimization decomposition application transport network link physical Application: utility IP: routing Link: scheduling Phy: power

Examples application transport network link physical Optimal web layer: Zhu, Yu, Doyle ’01 HTTP/TCP: Chang, Liu ’04 TCP: Kelly, Maulloo, Tan ’98, …… TCP/IP: Wang et al ’05, …… TCP/power control: Xiao et al ’01, Chiang ’04, …… TCP/MAC: Chen et al ’05, …… Rate control/routing/scheduling: Eryilmax et al ’05, Lin et al ’05, Neely, et al ’05, Stolyar ’05, this paper detailed survey in Proc. of IEEE, 2006

I2LSR, SC2004 Bandwidth Challenge OC48 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 Harvey Newman’s group, Caltech “FAST” TCP/AQM implementation

5:Apps: Supply and demand of packet flux 4:TCP: robustness to changing supply/demand, and packet losses 3:IP: routes on physical network, rerouting for router losses 2:Physical: Raw physical network 1:Hardware catalog: routers, links, servers, hosts,… 5:Apps:supply and demand of nutrients and products 4:Allosteric regulation of enzymes: robust to changing supply/demand 3:Transcriptional regulation of enzyme levels 2:Genome: Raw potential stoichiometry network 1:Hardware catalog: DNA, genes, enzymes, carriers,… TCP/IPMetabolism/biochem

Huge variety Standardized mechanisms Highly conserved Huge variety assembly control Lego

Huge variety assembly Lego Limited environmental uncertainty needs minimal control

Uncertain environments Require additional layers Huge variety assembly control Lego

Variety of actuators Variety of sensors Real- time control NXT controller

2:Physical: Raw physical network 1:Hardware catalog: routers, links, servers, hosts,… 2:Genome: Raw potential stoichiometry network 1:Hardware catalog: DNA, genes, enzymes, carriers,… TCP/IPMetabolism/biochem This provides the raw physical network But it is not functional without some control

3:IP: routes on physical network, rerouting for router losses 2:Physical: Raw physical network 1:Hardware catalog: routers, links, servers, hosts,… 3:Transcriptional regulation of enzyme levels 2:Genome: Raw potential stoichiometry network 1:Hardware catalog: DNA, genes, enzymes, carriers,… This layer provides a minimally functional network It provides robustness and evolvability to changes in the layers below. In an environment lacking uncertainty (which is rare), this level of regulation is largely adequate.

5:Apps: Supply and demand of packet flux 3:IP: routes on physical network, rerouting for router losses 2:Physical: Raw physical network 1:Hardware catalog: routers, links, servers, hosts,… 5:Apps:supply and demand of nutrients and products 3:Transcriptional regulation of enzyme levels 2:Genome: Raw potential stoichiometry network 1:Hardware catalog: DNA, genes, enzymes, carriers,… TCP/IPMetabolism/biochem The presence of fluctuating demand and evolving applications requires additional layers of control

5:Apps: Supply and demand of packet flux 4:TCP: robustness to changing supply/demand, and packet losses 3:IP: routes on physical network, rerouting for router losses 2:Physical: Raw physical network 1:Hardware catalog: routers, links, servers, hosts,… 5:Apps:supply and demand of nutrients and products 4:Allosteric regulation of enzymes: robust to changing supply/demand 3:Transcriptional regulation of enzyme levels 2:Genome: Raw potential stoichiometry network 1:Hardware catalog: DNA, genes, enzymes, carriers,… TCP/IPMetabolism/biochem

Evolving evolvability? Structured Variation Structured Variation Structured Selection “facilitated” “structured” “organized” Architecture

Random variation Structured Selection Random and small Architecture Variation

Co-factors Fatty acids Sugars Nucleotides Amino Acids Catabolism Polymerization and complex assembly Proteins Precursors Autocatalytic feedback Taxis and transport Nutrients Carriers Core metabolism Genes DNA replication Trans* Architecture E. coli genome

Structured variation Structured Selection Structured and large Architecture Variation

So far Robust yet fragile Architecture Hard limits Small models Short proofs

Key concepts Robust yet fragile Architecture Hard limits Small models Short proofs CS complexity theory (P/NP/coNP/undecidable)

SmallLarge Robust/short Simplicity Organization Fragile/long Emergence Irreducibility Small/large descriptions, experiments, models, theorems Robust/fragile features of [*] in response to perturbations in descriptions, components, environment Short/long outcomes, proofs Much existing confusion is created by failure to grasp these distinctions (and lack of standard terminology). Ontology