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Polymerization and complex Autocatalytic feedback assembly Taxis and transport Proteins Catabolism Precursors Core metabolism Nutrients Ligand Receptor In GDP GTP Nucleotides Trans* G G GDP Carriers Genes DNA replication John Doyle John G Braun Professor Control and Dynamical Systems, BioEng, and ElecEng Caltech www.cds.caltech.edu/~doyle GTP P RGS In Out Collaborators and contributors (partial list) Biology: Csete,Yi, Tanaka, Arkin, Savageau, Simon, AfCS, Kurata, Khammash, El-Samad, Gross, Kitano, Hucka, Sauro, Finney, Bolouri, Gillespie, Petzold, F Doyle, Stelling, … Theory: Parrilo, Carlson, Paganini, Papachristodoulou, Prajna, Goncalves, Fazel, Liu, Lall, D’Andrea, Jadbabaie, Dahleh, Martins, Recht, many more current and former students, … Web/Internet: Li, Alderson, Chen, Low, Willinger, Vinnicombe, Kelly, Zhu,Yu, Wang, Chandy, … Turbulence: Bamieh, Bobba, Gharib, Marsden, … Physics: Mabuchi, Doherty, Barahona, Reynolds, Disturbance ecology: Moritz, Carlson,… Finance: Martinez, Primbs, Yamada, Giannelli,… Engineering CAD: Ortiz, Murray, Schroder, Burdick, … Current Caltech Former Caltech Longterm Visitor Other Multiscale Physics Network Centric, Pervasive, Embedded, Ubiquitous Core theory challenges Systems Biology Today’s focus Network Centric, Pervasive, Embedded, Ubiquitous Core theory challenges Systems Biology Status Consistent, coherent, convergent understanding. Core theory challenges Pervasive, Networked, Embedded Remarkably common core theoretical Core theory challenges. challenges Dramatic recent progress in laying the foundation. Yet also striking increase in unnecessary confusion??? Core theory challenges Systems Biology Feathers and flapping? Or lift, drag, propulsion, and control? The danger of biomemetics Wilbur Wright on Control, 1901 • “We know how to construct airplanes.” (lift and drag) • “Men also know how to build engines.” (propulsion) • “Inability to balance and steer still confronts students of the flying problem.” (control) • “When this one feature has been worked out, the age of flying will have arrived, for all other difficulties are of minor importance.” Core theory challenges • Hard constraints • Simple models • Short proofs • Architecture A look back and forward • The Internet architecture was designed without a theory. • Many academic theorists told the engineers it would never work. • We now have a nascent theory that confirms that the engineers were right. • For systems biology, future networks, and other new technologies, let’s hope we can avoid a repeat of this history. Architecture? • “The bacterial cell and the Internet have – architectures – that are robust and evolvable” • What does “architecture” mean? • What does it mean for an “architecture” to be robust and evolvable? • Robust yet fragile? • Rigorous and coherent theory? Hard constraints On systems and their components • Thermodynamics (Carnot) • Communications (Shannon) • Control (Bode) • Computation (Turing/Gödel) • Fragmented and incompatible • We need a more integrated view and have the beginnings Assume different architectures a priori. Hard constraints (progress) • Thermodynamics (Carnot) • Communications (Shannon) • Control (Bode) • Computation (Turing/Gödel) • We need a more integrated view and have the beginnings Work in progress • Thermodynamics (Carnot) • Communications (Shannon) • Control (Bode) • Computation (Turing/Gödel) • We need a more integrated view and have the beginnings Short proofs (progress) • Robust yet fragile systems • Proof complexity implies problem fragility (!?!) • Designing for robustness and verifiability are compatible objectives • Hope for a unifying framework? – SOS, Psatz (Prajna, P*) – Temporal specifications (Pnueli) – SAT (Selman) • Integrating simple models and short proofs? Simple models (challenges) • Rigorous connections between – Multiple scales – Experiment, data, and models • Essential starting point for short proofs • Microscopic state: discrete, finite, enormous – Packet level – Software, digital hardware – Molecular-level interactions • Macroscopic behavior: robust yet fragile Proteins Core metabolism Catabolism Precursors Nutrients Taxis and transport Polymerization and complex Autocatalytic feedback assembly Nucleotides Regulation Trans* & control Carriers Genes Regulation & control DNA replication The architecture of the cell. Bowtie: Flow of energy and materials Universal organizational structures/architectures Hourglass Organization of control Proteins Core metabolism Catabolism Precursors Nutrients Taxis and transport Polymerization and complex Autocatalytic feedback assembly Nucleotides Regulation Trans* & control Carriers Genes Regulation & control DNA replication The architecture of the cell. Proteins Taxis and transport Carriers Catabolism Nucleotides Carriers Regulation & control Proteins Proteins Catabolism Precursors Regulation Trans* & control Carriers Nucleotides Regulation & control DNA replication Polymerization and complex Autocatalytic feedback assembly Taxis and transport Proteins Regulation Trans* & control Catabolism Nucleotides Regulation Trans* & control Carriers Genes Regulation & control DNA replication Core metabolism Carriers Genes Regulation & control Genes DNA replication Core metabolism Nutrients Precursors Nutrients Nucleotides Regulation Trans* & control Carriers Polymerization and complex Autocatalytic feedback assembly Taxis and transport Core metabolism Catabolism Nucleotides Genes DNA replication Polymerization and complex Autocatalytic feedback assembly Taxis and transport Catabolism Precursors Genes Regulation & control Regulation Trans* & control Nutrients Regulation Trans* & control Proteins Core metabolism Nutrients Nucleotides Polymerization and complex Autocatalytic feedback assembly Taxis and transport Core metabolism Nutrients Catabolism Precursors Nutrients Core metabolism Proteins Precursors Taxis and transport Polymerization and complex Autocatalytic feedback assembly Precursors Polymerization and complex Autocatalytic feedback assembly DNA replication Regulation & control Multicellularity Genes Regulation & control DNA replication Robustness: Efficient and flexible metabolism Fragility: Obesity and diabetes Cell Cell Glucose and Oxygen Transport Cell Cell Cell Cell Cell Cell Cell Autocatalytic and regulatory feedback Robust Yet Fragile 1. Efficient, flexible metabolism 1. Obesity and diabetes and 2. Complex development and 2. Rich parasite ecosystem 3. Immune systems 3. Auto-immune disease 4. Regeneration & renewal 4. Cancer 5. Complex societies 5. Epidemics, war, genocide, … Human robustness and fragility Nightmare? Biology: We might accumulate more complete parts lists but never “understand” how it all works. Technology: We might build increasingly complex and incomprehensible systems which will eventually fail completely yet cryptically. Nothing in the orthodox views of complexity says this won’t happen (apparently). HOPE? Interesting systems are robust yet fragile. Identify the fragility, evaluate and protect it. The rest (robust) is “easy”. Nothing in the orthodox views of complexity says this can’t happen (apparently). Architecture? • “The bacterial cell and the Internet have – architectures – that are robust and evolvable” • What does “architecture” mean? • What does it mean for an “architecture” to be robust and evolvable? • Robust yet fragile? • Rigorous and coherent theory? rpoH Heat mRNA Regulation of protein levels Regulation of protein action • Cartoons and stories • No math + Taxis and RNAP DnaK ftsH Lon RNAP DnaK transport DnaK DnaK FtsH Autocatalytic feedback Lon + Proteins + Gly G1P Catabolism G6P F6P Precursors Core+metabolism Nucleotides Trans* F1-6BP Carriers Gly3p ATP 13BPG Genes 3PG 2PG Oxa PEP Pyr ACA TCA NADH Cit Regulation & control motif rpoH Other operons DnaK Lon motif Heat rpoH folded unfolded Other operons DnaK Lon degradation DnaK Lon rpoH Heat mRNA Other operons DnaK RNAP Lon RNAP DnaK FtsH Lon rpoH Heat mRNA Other operons RNAP DnaK DnaK DnaK ftsH Lon RNAP DnaK FtsH Lon rpoH Heat mRNA Other operons RNAP DnaK DnaK DnaK ftsH Lon RNAP DnaK FtsH Lon rpoH Heat mRNA Regulation of protein levels Regulation of protein action RNAP DnaK DnaK DnaK ftsH Lon RNAP DnaK FtsH Lon rpoH Heat mRNA Other operons RNAP DnaK DnaK DnaK ftsH Lon RNAP DnaK FtsH Lon motif rpoH Other operons DnaK Lon Variety of Ligands & Receptors Transmitter Receiver • • • • • • Ubiquitous protocol “Hourglass” “Robust yet fragile” Robust & evolvable Fragile to “hijacking” Manages extreme heterogeneity with selected homogeneity • Accident or necessity? Variety of responses Signal transduction Variety of Ligands & Receptors Gproteins Primary targets Variety of responses Bio: Huge variety of environments, metabolisms Universal control architecture Allosteric regulation Regulation of enzyme levels Huge variety of genomes Huge variety of components The Internet hourglass Applications Web FTP Mail Ethernet 802.11 News Video Power lines ATM Audio Optical Link technologies ping napster Satellite Bluetooth The Internet hourglass Applications Web FTP Mail News Video Audio ping napster TCP IP Ethernet 802.11 Power lines ATM Optical Link technologies Satellite Bluetooth The Internet hourglass Applications Web FTP Mail News Video Audio IP under everything ping napster TCP IP Ethernet 802.11 IP on Power lines ATM Optical everything Link technologies Satellite Bluetooth Bio: Huge variety of environments, metabolisms Internet: Huge variety of applications Huge variety of components Bio: Huge variety of environments, metabolisms Internet: Huge variety of applications Both components and applications are highly uncertain. Huge variety of components Bio: Huge variety of environments, metabolisms Internet: Huge variety of applications Huge variety of genomes Huge variety of physical networks Huge variety of components Hourglass architectures Bio: Huge variety of environments, metabolisms Internet: Huge variety of applications Feedback control Identical control architecture Huge variety of genomes Huge variety of physical networks Huge variety of components Bio: Huge variety of environments, metabolisms Universal control architecture Allosteric regulation Regulation of enzyme levels Huge variety of genomes Huge variety of components rpoH Heat mRNA Regulation of protein levels Gly Regulation of protein action RNAP DnaK DnaK DnaK ftsH G1P Lon G6P RNAP F6P DnaK FtsH Lon F1-6BP Gly3p ATP 13BPG 3PG 2PG Allosteric Oxa PEP Pyr ACA TCA NADH Cit Trans* TCP/IP Metabolism/biochem 5:Application/function: variable supply/demand 4:TCP 3:IP Feedback Control 4:Allosteric 3:Transcriptional 2:Potential physical network 1:Hardware components TCP/IP robustness/evolvability on many timescales • Shortest: File transfers from different users – Application-specific navigation (application) – Congestion control to share the net (TCP) – Ack-based retransmission (TCP) • Short: Fail-off of routers and servers – Rerouting around failures (IP) – Hot-swaps and rebooting of hardware • Long: Rearrangements of existing components – Applications/clients/servers can come and go – Hardware of all types can come and go • Longer: New applications and hardware – Plug and play if they obey the protocols TCP/IP fragility on many timescales • Shortest: File transfers from different users – End systems w/o congestion control won’t fairly share • Short: Fail-on of components – Distributed denial of service – Black-holing and other fail-on cascading failures • Long: Spam, viruses, worms • Longer: No economic model for ISPs? Robustness/evolvability on many timescales • Shortest to short: Fluctuations in supply/demand – Allosteric regulation of enzymes (4) – Expression of enzyme level (3) • Short: Failure/loss of individual enzyme molecules (3) – Chaperones attempt repair, proteases degrade – Transcription makes more • Long: Incorporating new components – Acquire new enzymes by lateral gene transfer • Longer: Creating new applications and hardware – Duplication and divergent evolution of new enzymes that still obey basic protocols Biochem fragility on many timescales • Shortest: Fluctuations in demand/supply that exceeds regulatory capability (e.g. glycolytic oscillations) • Short: Fail-on of components – Indiscriminate kinases, loss of repression, … – Loss of tumor suppressors • Long: Infectious hijacking • Longer: Diabetes, obesity Robust yet fragile (RYF) • The same mechanisms responsible for robustness to most perturbations • Allows possible extreme fragilities to others • Usually involving hijacking the robustness mechanism in some way • High variability (and thus power laws) Experimental (and network) biology • Laws: Conservation of energy and matter • Modules: Pipettes, Petri dishes, PCR machines, microscopes,… • Protocols: Rules and recipes by which modules interact to create function • All 3 must be understood. • Laws are immutable • Protocols are more important than modules Taxis and transport Polymerization and complex Autocatalytic feedback assembly Proteins • Laws: Conservation of energy, matter, and robustness/fragility Regulation Catabolism Nucleotides Trans* & control • Modules: Enzymes and metabolites • Protocols: Control, bowties and hourglasses Carriers • Principles??? Precursors Nutrients Core metabolism Genes Regulation & control DNA replication Bowtie: Flow of energy and materials Universal organizational structures/architectures Hourglass Organization of control Proteins Core metabolism Catabolism Precursors Nutrients Taxis and transport Polymerization and complex Autocatalytic feedback assembly Nucleotides Regulation Trans* & control Carriers Genes Regulation & control DNA replication The architecture of the cell. Bacterial cell Environment Huge Variety Environment Huge Variety Catabolism Precursors Nutrients Taxis and transport 20 same in all cells Core metabolism Nucleotides Carriers Huge Variety 100 same in all organisms Catabolism Precursors Core metabolism Nucleotides Carriers Nested bowties Precursors Catabolism Carriers Nucleotides Precursors Catabolism Carriers Gly G1P G6P Catabolism F6P F1-6BP Gly3p ATP 13BPG 3PG 2PG NADH Oxa PEP Pyr ACA TCA Cit Gly Precursors G1P G6P F6P F1-6BP Gly3p 13BPG 3PG 2PG Oxa PEP Pyr ACA TCA Cit Gly Precursors G1P G6P F6P Autocatalytic F1-6BP Gly3p Carriers ATP 13BPG 3PG 2PG Oxa PEP Pyr ACA TCA NADH Cit Gly G1P G6P F6P Precursors 20 same in all cells F1-6BP Gly3p Carriers ATP 13BPG 3PG 2PG Oxa PEP Pyr ACA TCA NADH Cit Gly G1P G6P Regulatory F6P F1-6BP Gly3p ATP 13BPG 3PG 2PG Oxa PEP Pyr ACA TCA NADH Cit Gly This is still a cartoon. (Cartoons are useful.) G1P G6P F6P F1-6BP Gly3p ATP 13BPG 3PG 2PG Oxa PEP Pyr ACA TCA NADH Cit Gly G1P G6P F6P F1-6BP Gly3p 13BPG 3PG 2PG Oxa PEP Pyr ACA TCA Cit If we drew the feedback loops the diagram would be unreadable. Gly G1P G6P F6P F1-6BP Gly3p ATP 13BPG 3PG 2PG Oxa PEP Pyr ACA TCA NADH Cit Gly Gly G1P G1P This cannot. G6P G6P F6P F6P F1-6BP F1-6BP This can be modeled to some 13BPG extent as a graph. Gly3p 3PG 2PG PEP Pyr ACA Gly3p ATP 13BPG 3PG 2PG PEP NADH Unfortunate and unnecessary confusion results from not “getting” this. Pyr ACA Biology is not a graph. Stoichiometry plus regulation dx Sv( x) dt Mass & Reaction d Mass&Energy Energy flux dt Balance dx S Sv( x) dt Mass & Reaction Energy flux Balance Gly G1P G6P F6P F1-6BP Gly3p ATP Stoichiometry matrix 13BPG 3PG 2PG Oxa PEP Pyr ACA TCA NADH Cit dx Sv( x) dt Mass & Reaction Energy flux Balance Gly G1P G6P F6P F1-6BP Gly3p Regulation of enzyme levels by transcription/translation/degradation 13BPG 3PG 2PG Oxa PEP Pyr ACA TCA Cit dx Sv( x) dt Mass & Reaction Energy flux Balance Gly G1P G6P F6P F1-6BP Gly3p ATP 13BPG Allosteric regulation of enzymes 3PG 2PG Oxa PEP Pyr ACA TCA NADH Cit Mass & Reaction dx Sv( x) Energy flux dt Balance Gly G1P G6P Allosteric regulation of enzymes F6P F1-6BP Regulation of enzyme levels Gly3p ATP 13BPG 3PG 2PG Oxa PEP Pyr ACA TCA NADH Cit Regulation of protein action Allosteric regulation of enzymes Regulation of protein levels Regulation of enzyme levels Polymerization and complex Autocatalytic feedback assembly Taxis and transport Proteins Catabolism Precursors Nutrients Core metabolism Nucleotides Regulation Trans* & control Carriers Genes Regulation & control DNA replication Gene networks? essential: nonessential: unknown: total: 230 2373 1804 4407 http://www.shigen.nig.ac.jp/ecoli/pec Polymerization and complex Autocatalytic feedback assembly Taxis and transport Proteins Catabolism Precursors Nutrients Core metabolism Nucleotides Trans* Carriers Genes DNA replication Regulation & control E. coli genome Precursors Fragility example: Viruses Carriers Viruses exploit the universal bowtie/hourglass structure to hijack the cell machinery. Trans* Fragility example: Viruses Catabolism Precursors Nutrients Core metabolism Nucleotides Proteins Viral proteins Trans* Carriers Genes Viral genes DNA Viruses exploit the universal bowtie/hourglass structure to hijack the cell machinery. replication Polymerization and complex Autocatalytic feedback assembly Taxis and transport Proteins Catabolism Precursors Nutrients Core metabolism Nucleotides Regulation Trans* & control Carriers Genes Regulation & control DNA replication Proteins Taxis and transport Carriers Catabolism Nucleotides Carriers Regulation & control Proteins Proteins Catabolism Precursors Regulation Trans* & control Carriers Nucleotides Regulation & control DNA replication Polymerization and complex Autocatalytic feedback assembly Taxis and transport Proteins Regulation Trans* & control Catabolism Nucleotides Regulation Trans* & control Carriers Genes Regulation & control DNA replication Core metabolism Carriers Genes Regulation & control Genes DNA replication Core metabolism Nutrients Precursors Nutrients Nucleotides Regulation Trans* & control Carriers Polymerization and complex Autocatalytic feedback assembly Taxis and transport Core metabolism Catabolism Nucleotides Genes DNA replication Polymerization and complex Autocatalytic feedback assembly Taxis and transport Catabolism Precursors Genes Regulation & control Regulation Trans* & control Nutrients Regulation Trans* & control Proteins Core metabolism Nutrients Nucleotides Polymerization and complex Autocatalytic feedback assembly Taxis and transport Core metabolism Nutrients Catabolism Precursors Nutrients Core metabolism Proteins Precursors Taxis and transport Polymerization and complex Autocatalytic feedback assembly Precursors Polymerization and complex Autocatalytic feedback assembly DNA replication Regulation & control Multicellularity Genes Regulation & control DNA replication Robustness: Efficient and flexible metabolism Fragility: Obesity and diabetes Cell Cell Glucose and Oxygen Transport Cell Cell Cell Cell Cell Cell Cell Autocatalytic and regulatory feedback Robust Yet Fragile 1. Efficient, flexible metabolism 1. Obesity and diabetes and 2. Complex development and 2. Rich parasite ecosystem 3. Immune systems 3. Auto-immune disease 4. Regeneration & renewal 4. Cancer 5. Complex societies 5. Epidemics, war, genocide, … Human robustness and fragility Polymerization and complex Autocatalytic feedback assembly Taxis and transport Proteins Catabolism Precursors Nutrients Core metabolism Nucleotides Trans* Carriers Genes DNA replication Regulation & control E. coli genome motif rpoH Other operons DnaK Lon motif Heat rpoH folded unfolded Other operons DnaK Lon degradation DnaK Lon rpoH Heat mRNA Other operons DnaK RNAP Lon RNAP DnaK FtsH Lon rpoH Heat mRNA Other operons RNAP DnaK DnaK DnaK ftsH Lon RNAP DnaK FtsH Lon rpoH Heat mRNA Other operons RNAP DnaK DnaK DnaK ftsH Lon RNAP DnaK FtsH Lon rpoH Heat mRNA Regulation of protein levels Regulation of protein action RNAP DnaK DnaK DnaK ftsH Lon RNAP DnaK FtsH Lon Polymerization and complex Autocatalytic feedback assembly Taxis and transport Proteins Catabolism Precursors Nutrients Core metabolism Nucleotides Trans* Carriers Genes DNA replication Regulation & control Bowtie: Flow of energy and materials Universal organizational structures/architectures Hourglass Organization of control Hourglass Organization of control The Internet hourglass Applications Web FTP Mail Ethernet 802.11 News Video Power lines ATM Audio Optical Link technologies ping napster Satellite Bluetooth The Internet hourglass Applications Web FTP Mail News Video Audio ping napster TCP IP Ethernet 802.11 Power lines ATM Optical Link technologies Satellite Bluetooth The Internet hourglass Applications Web FTP Mail News Video Audio IP under everything ping napster TCP IP Ethernet 802.11 IP on Power lines ATM Optical everything Link technologies Satellite Bluetooth Bio: Huge variety of environments, metabolisms Internet: Huge variety of applications Huge variety of components Bio: Huge variety of environments, metabolisms Internet: Huge variety of applications Both components and applications are highly uncertain. Huge variety of components Bio: Huge variety of environments, metabolisms Internet: Huge variety of applications Huge variety of genomes Huge variety of physical networks Huge variety of components Hourglass architectures Bio: Huge variety of environments, metabolisms Internet: Huge variety of applications Feedback control Identical control architecture Huge variety of genomes Huge variety of physical networks Huge variety of components Bio: Huge variety of environments, metabolisms Universal control architecture Allosteric regulation Regulation of enzyme levels Huge variety of genomes Huge variety of components rpoH Heat mRNA Regulation of protein levels Regulation of protein action RNAP DnaK DnaK DnaK ftsH Gly Lon G1P RNAP G6P DnaK FtsH Lon F6P F1-6BP Gly3p ATP 13BPG 3PG 2PG Allosteric Oxa PEP Pyr ACA TCA NADH Cit Trans* TCP/IP Metabolism/biochem 5:Apps: Supply and demand of packet flux 5:Apps:supply and demand of nutrients and products 4:TCP: robustness to changing supply/demand, and packet losses 4:Allosteric regulation of enzymes: robust to changing supply/demand 3:IP: routes on physical network, rerouting for router losses 3:Transcriptional regulation of enzyme levels 2:Physical: Raw physical network 2:Genome: Raw potential stoichiometry network 1:Hardware catalog: routers, links, servers, hosts,… 1:Hardware catalog: DNA, genes, enzymes, carriers,… TCP/IP Metabolism/biochem 5:Application/function: variable supply/demand 4:TCP 3:IP Feedback Control 4:Allosteric 3:Transcriptional 2:Potential physical network 1:Hardware components Protocols and modules • Protocols are the rules by which modules are interconnected • Protocols are more fundamental to “modularity” than modules TCP IP Vertical decomposition Protocol Stack Application IP Application Application Each layer can evolve TCP TCP independently provided: 1. Follow the rules 2. Everyone else does IP IP with IP “good enough” their layer Routing Provisioning Application Application TCP TCP IP Application IP IP TCP IP IP Horizontal decomposition Each level is decentralized and asynchronous Routing Provisioning Bowtie: Flow of energy and materials Universal organizational structures/architectures Hourglass Organization of control Robust yet fragile (RYF) • The same mechanisms responsible for robustness to most perturbations • Allows possible extreme fragilities to others • Usually involving hijacking the robustness mechanism in some way • High variability (and thus power laws) Facilitate regulation on multiple time scales: 1. Fast: allostery 2. Slower: transcriptional regulation (by regulated recruitment) and degradation 3. Even slower: transfer of genes 4. Even slower: copying and evolution of genes TCP/IP robustness/evolvability on many timescales • Shortest: File transfers from different users – Application-specific navigation (application) – Congestion control to share the net (TCP) – Ack-based retransmission (TCP) • Short: Fail-off of routers and servers – Rerouting around failures (IP) – Hot-swaps and rebooting of hardware • Long: Rearrangements of existing components – Applications/clients/servers can come and go – Hardware of all types can come and go • Longer: New applications and hardware – Plug and play if they obey the protocols TCP/IP fragility on many timescales • Shortest: File transfers from different users – End systems w/o congestion control won’t fairly share • Short: Fail-on of components – Distributed denial of service – Black-holing and other fail-on cascading failures • Long: Spam, viruses, worms • Longer: No economic model for ISPs? Robustness/evolvability on many timescales • Shortest to short: Fluctuations in supply/demand – Allosteric regulation of enzymes (4) – Expression of enzyme level (3) • Short: Failure/loss of individual enzyme molecules (3) – Chaperones attempt repair, proteases degrade – Transcription makes more • Long: Incorporating new components – Acquire new enzymes by lateral gene transfer • Longer: Creating new applications and hardware – Duplication and divergent evolution of new enzymes that still obey basic protocols Allosteric regulation Polymerization and complex assembly Nutrient Precursors Proteins Nucleotides Trans* Carriers Genes DNA replication Polymerization and complex Autocatalytic feedback assembly Nutrient Precursors Proteins Nucleotides Regulation Trans* & control Carriers Genes Regulation & control DNA replication Robustness/evolvability on many timescales • Shortest to short: Fluctuations in supply/demand – Allosteric regulation of enzymes (4) – Expression of enzyme level (3) • Short: Failure/loss of individual enzyme molecules (3) – Chaperones attempt repair, proteases degrade – Transcription makes more • Long: Incorporating new components – Acquire new enzymes by lateral gene transfer • Longer: Creating new applications and hardware – Duplication and divergent evolution of new enzymes that still obey basic protocols Robustness/evolvability on many timescales • Shortest to short: Fluctuations in supply/demand – Allosteric regulation of enzymes (4) – Expression of enzyme level (3) • Short: Failure/loss of individual enzyme molecules (3) – Chaperones attempt repair, proteases degrade – Transcription makes more • Long: Incorporating new components – Acquire new enzymes by lateral gene transfer • Longer: Creating new applications and hardware – Duplication and divergent evolution of new enzymes that still obey basic protocols What if a pathway is needed? But isn’t there? Slower time scales ( hoursdays), genes are transferred between organisms. This is only possible with shared protocols. Robustness/evolvability on many timescales • Shortest to short: Fluctuations in supply/demand – Allosteric regulation of enzymes (4) – Expression of enzyme level (3) • Short: Failure/loss of individual enzyme molecules (3) – Chaperones attempt repair, proteases degrade – Transcription makes more • Long: Incorporating new components – Acquire new enzymes by lateral gene transfer • Longer: Creating new applications and hardware – Duplication and divergent evolution of new enzymes that still obey basic protocols Slowest time scales ( forever), genes are copied and mutate to create new enzymes. Evolving evolvability? Variation Selection ? Evolving evolvability? Variation “facilitated” “structured” “organized” Selection transport metabolism assembly Robust?: Fragile to fluctuations Evolvable?: Hard to change Variety of producers Energy carriers Variety of consumers Biochem fragility on many timescales • Shortest: Fluctuations in demand/supply that exceeds regulatory capability (e.g. glycolytic oscillations) • Short: Fail-on of components – Indiscriminate kinases, loss of repression, … – Loss of tumor suppressors • Long: Infectious hijacking • Longer: Diabetes, obesity Robust yet fragile (RYF) • The same mechanisms responsible for robustness to most perturbations • Allows possible extreme fragilities to others • Usually involving hijacking the robustness mechanism in some way • High variability (and thus power laws) Bowtie: Flow of energy and materials Universal organizational structures/architectures Hourglass Organization of control Variety of Ligands & Receptors Transmitter Receiver • • • • • • Ubiquitous protocol “Hourglass” “Robust yet fragile” Robust & evolvable Fragile to “hijacking” Manages extreme heterogeneity with selected homogeneity • Accident or necessity? Variety of responses Signal transduction Variety of Ligands & Receptors Gproteins Primary targets Variety of responses Random walk Ligand Motion Motor Bacterial chemotaxis Biased random walk gradient Ligand Motion Signal Transduction Motor CheY Common energy carrier ++ Variety of receptors/ ligands Common signal carrier + + Common cytoplasmic domains From Taylor, Zhulin, Johnson Motor Transmitter Receiver Variety of Ligands & Receptors Variety of Ligands & Receptors Transmitter Receiver Motor Variety of Ligands & Receptors Transmitter Receiver Variety of responses • 50 such “two component” systems in E. Coli • All use the same protocol - Histidine autokinase transmitter - Aspartyl phosphoacceptor receiver • Huge variety of receptors and responses Signal transduction Applications TCP Variety of Ligands & Receptors Transmitter Receiver IP Link Variety of responses Variety of Ligands & Receptors Transmitter Receiver Motor • 50 such “two component” Variety of Ligands systems in E. Coli & Receptors Other Other Receptors Other& • All use the same protocol Receptors Other& Ligands Receptors Other& - Histidine autokinase Ligands Receptors Other& Ligands Receptors Other& transmitter Ligands Receptors Other& Ligands Receptors Other& Ligands Receptors Other& - Aspartyl phosphoLigands Receptors Other & Transmitter Ligands Receptors Other& acceptor receiver Ligands Receptors & Transmitter ReceiverTransmitter Ligands Receptors & • Huge variety of receptors Ligands Receiver Transmitter Ligands Receiver Transmitter and responses Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Receiver Transmitter Motor Other Receiver Transmitter Receiver Other Receiver Responses Other Responses Other Responses Other Responses Other Responses Other Responses Other Responses Other Responses Other Responses Other Responses Other Responses Responses Molecular phylogenies show evolvability of the bowtie architecture. conserved residues of interaction surface with phosphotransferase domains invariant active-site residues highly variable amino acids of the interaction surface that are responsible for specificity of the interaction conserved functional domains invariant active-site residues • Automobiles: Keys provide specificity but no other function. Other function conserved, driver/vehicle interface protocol is “universal.” • Ethernet cables: Specificity via MAC MAC addresses, function via standardized protocols. highly variability for specificity of the interaction Variety of Ligands & Receptors Transmitter Receiver • 50 such “two component” systems in E. Coli • Ubiquitous eukaryote protocol • Huge variety of – receptors/ligands – downstream responses Variety of responses • Large number of Gproteins grouped into similar classes • Handful of primary targets Variety of Ligands & Receptors Gproteins Primary targets Variety of responses Ligand GEF In In Receptor GDP GTP GDP GTP GDI G GDI G GDP GTP Out Rho Rho GDP P P RGS In In GAP GTP Out Receptors In GDP GTP G-proteins Out GDP GTP Primary targets P In Responses Speed, adaptation, integration, evolvability In GDP GTP Robustness GDP GTP Out Impedance matching: Independent of G of inputs and outputs P In Signal integration: High “fan in” and “fan out” Uncertain Variety of Ligands & Receptors Robust and highly evolvable Intermediates Variety of responses Uncertain Fragile and hard to change Fragility? • A huge variety of pathogens attack and hijack GTPases. • A huge variety of cancers are associated with altered (hijacked) GTPase pathways. • The GTPases may be the least evolvable elements in signaling pathways, in part because they facilitate evolvability elsewhere GEF In GDP GTP GDI GDI Rho Rho GDP GTP P In GAP Out Hijacking Ligand In Receptor GDP GTP G GDP G C-AMP GTP P Cholera toxin Cholera toxins hijack the signal transduction by blocking a GTPase activity. Bacterial virulence factors targeting Rho GTPases: parasitism or symbiosis? Patrice Boquet and Emmanuel Lemichez TRENDS in Cell Biology May 2003 Variety of Ligands & Receptors Transmitter Receiver Variety of responses But you already knew all this. • • • • • Ubiquitous protocol “Hourglass” Robust & evolvable Fragile to “hijacking” Manages extreme heterogeneity with selected homogeneity • Accident or necessity? Variety of Ligands & Receptors Gproteins Primary targets Variety of responses Theoretical foundations for networks • The most rigorous, sophisticated, and applicable of existing theories – Computation – Control – Communications • • • • Have become fragmented and isolated Failed attempts at unified “new sciences” Need new mathematics Recent progress has been spectacular, both in rigor and relevance A look back and forward • The Internet architecture was designed without a theory. • Many academic theorists told the engineers it would never work. • We now have a nascent theory that confirms that the engineers were right. • For MANETs and other new technologies, let’s hope we can avoid a repeat of this history. Multiscale Physics Network Centric, Pervasive, Embedded, Ubiquitous Core theory challenges Systems Biology