Keynote 6: Bernhard Palsson - "systems biology:... - ISMB 2008

PA plays "don't let the sun go down on me"... - Neil Saunders

systems biology of human metabolism - Roland Krause

Kicks off with an iphone joke :) - Neil Saunders

Who would start with an iPhone joke :) ? - Pedro Beltrao

1. paradigms 2. Links and nodes (network bioogy) 3. Maps and functional states 4. Workflows and knowledge bases 5 Reconstruction 6. Human reconstruction of the metabolic network 7. Application - Roland Krause

Talk outline looks mighty ambitious - Neil Saunders

components, networks, models, phenotypes (the paradigm) - Roland Krause

omics to knowledge base to in silico modeling to validation and discovery - Pedro Beltrao

Systems biology: components -> networks -> computational models -> phenotypes - Lars Juhl Jensen

Conversion of biochemical data to query-able format - Neil Saunders

1. maps to database, 2. knowledge base 3. query tools 4. validation and discovery of missing parts, synthetic biology - Roland Krause

So, his paradigm for sysbio maps to a large, structured and detailed knowledge base - Roland Krause

Various levels of modelling; detailed chemical kinetic knowledge the most specific - Neil Saunders

general property of cells - prototypical transformation are bi-linear. - Pedro Beltrao

Molecular biology links are fundamentally bi-linear, e.g. bimolecular reactions and interactions - Lars Juhl Jensen

Network links constrained by chemistry - Neil Saunders

Metabolic networks cannot be randomized for statistical evaluatiuon - no pyruvate will go to isocitrate just so. - Roland Krause

relative rates are fixed by thermodynamics but absolute rates are highly variable inside the cell. General comment, links are very constrained by the physical attributes of the nodes. Interesting comment about problems in creating a random network with little knowledge of atomic information. - Pedro Beltrao

Can now visualise pathways in context of entire metabolic network - Neil Saunders

nice thing about genome scale models is that we can look at pathways in the context of the whole model. "Pathways are models networks are reality" Uwe Sauer - Pedro Beltrao

Analogy between road maps and traffic (functional states) and biological networks. Getting closer to flux balance analysis - Pedro Beltrao

Network topology fixed, but functional states vary constantly - nice analogy with traffic on highways through the day - Neil Saunders

Cobra suite http://www.ncbi.nlm.nih.gov/pubmed... (a recent in Nature Protocols) - Roland Krause

contained based models work also because evolution creates systems that are optimized for some function. It is not easy to know what are these functions that are optimized. - Pedro Beltrao

COBRA software available as Matlab package - Neil Saunders

OK, vectors and matrix operations, sysbio at last - Roland Krause

I hope he does not say biblioome - Pedro Beltrao

Moving on from fluxes and matrix operations to workflows + knowledge bases; mentions EcoCyc as example - Neil Saunders

@pedro uwe sauer (eth)was the author of the pathways quote - Ildefonso Cases

Tables: rows are metabolites; columns are reactions; must be balanced (like balancing reactions in high school, but larger scale); you then map this to the metabolome as well as you can - Neil Saunders

@Ildefonso thanks - Pedro Beltrao

Metabolic reconstruction 1. Genome annotation 2. Model to perform tests (gaps etc) 3. Simulation, 4. Validation (go back to 2. if problems arise). - Roland Krause

The human metabolic and regulatory network is 10k by 15k today - Roland Krause

Feis 2008 Nature reviews Microbiology (new review on the subject) I don't think it is available - Pedro Beltrao

Showing plot of available genome-scale reconstructions over time - Neil Saunders

An idea for community effort for 2D annotation. Example of yeast reconstruction jamboree, accepted in Nature Biotech (out in a few months) Slamonella/Klebsiella jamboree September 2008 - Pedro Beltrao

Talking now about community annotation efforts; kind of like hackathons - Neil Saunders

Annotation jamborees to come: Salmonella and human (in 2008) - Roland Krause

2 years , 7 people to build the human metabolic network from literature 1134 genes, PNAS.. He could have mentioned another human reconstruction that was published in MSB - Pedro Beltrao

RECON 1 knowledgebase - is it available somewhere? - Lars Juhl Jensen

Dimensions: 3D (ultrastructural reconstruction); 4D - states over time - Neil Saunders

3D reconstruction of transcription in E. coli - spatial and temporal aspects of the network - Roland Krause

Last topic - what can we (the audience) do with reconstructions - Neil Saunders

"ask not what you can do for your reconstruction but what the reconstruction can do for your" ... phenotypic behavior, network analysis, bacterial evolution, metabolic engi, biological discovery. (http://www.nature.com/nbt...) - Pedro Beltrao

Ask not what you can do for reconstruction - Ask what reconstruction can do for you - Lars Juhl Jensen

Uses: metabolic engineering; evolution; network analysis; phenotypic behaviour; discovery (missing parts) - Neil Saunders

A lot more people working in these type of models. Mentions recent paper by Barabasi (http://www.ncbi.nlm.nih.gov/pubmed...) - Pedro Beltrao

Prediction of missing reactions or even missing pathways - Lars Juhl Jensen

Knowledge gaps: reactions, metabolites - Roland Krause

Covering some uses of the RECON 1 knowledge base - Neil Saunders

@Lars, I think Recon 1 is a reference to that human model in Duarte et al PNAS, and I think it is all available. - Pedro Beltrao

Q10 synthesis gaps http://www.ncbi.nlm.nih.gov/pubmed... - Roland Krause

@Pedro, that is also how I understand it now :-) - Lars Juhl Jensen

co-sets - Using metabolic networks to predict the cause of SNPs (concept MSB paper 2006). several examples of how SNPs associated with phenotypes that could be predicted by the network. Mentions again the Barabasi paper linked above - Pedro Beltrao

Recon 1 + gene expression map to localize the map by tissue. (lost me on nthe application ) I think the reference was Nature Biotech 2008 - Pedro Beltrao

Construction of tissue-specific models by combining Recon 1 and tissue expression data - Lars Juhl Jensen

Multi-omics data integration; basically mapping all sorts of datasets onto each other; gives example of mapping OMIM to expression profiles - Neil Saunders

Proud to be on time. - Roland Krause

Wrapping up. I thought it was a pretty impressive overview. - Neil Saunders

connectivity map data set (Lamb et al); expression data mapped to recon 1 metabolic network gen set; identified metabolic signatures for 540 expr. profiles; case study: anti diabetic drugs cluster very well; can see systemic down-=stream effects of drugs; one co-set includes HMG-CoA reductase (interesting to check other targets in the co-set if they are drug targets) - Michael Kuhn

Hypothesis: members of the same co-set should have identical effect on cell state -> implications for drug development by suggesting alternative targets - Lars Juhl Jensen

Well done everyone - this was an awesome coverage of the talk :-) - Lars Juhl Jensen

Yes, great coverage. Useful for me. - Michael Barton