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Nature’s logistical solution

Nature’s logistical solution. Zoltan Maliga MPI-CBG CCSS International Worksop June 8-12, 2009. ~10 Ma evolution. Biology : information, template, robust, adaptable. genetic blueprint. diversity. 6 x 10 9 bases in the genome 20,000 proteins 10,000 found in all cells

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Nature’s logistical solution

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  1. Nature’s logistical solution Zoltan Maliga MPI-CBG CCSS International Worksop June 8-12, 2009

  2. ~10 Ma evolution Biology : information, template, robust, adaptable genetic blueprint diversity 6 x 109 bases in the genome 20,000 proteins 10,000 found in all cells Robust developmental program • Trillions of cells • Phenotypic archetypes • Similar cognitive abilities • common cell machinery • cell-type specific genes

  3. Stroke Medicine : Fixing a molecular network No effect Therapeutic Toxicity Death Dosage-regime In patients COX-1 COX-2 Stomach ulcers Pain killer Blood thinner

  4. Can we look for control points in a process? DNA Tubulin

  5. Molecules hard-wired to interact Positive feed-back (amplification) Inducible negative feed-back Irreversible steps Quality control subroutines ensure correct cell division DNA attached? DNA separated? Cell divided?

  6. Capitalizing on checkpoints to treat cancer DNA Tubulin

  7. Scaling in biology Tubulin polymerization Nutrient uptake, cell division Cell movement, shape, organization Forming connections between cells Brain function, immunology, physiology Reductionism Integrationism

  8. conventional genomics Exploring an infinite-parameter space Predicted activity genes Function processes compartments Interactions

  9. How is a cell physically organized? parts list neuron brain

  10. Agents of cell organization : Motor proteins in cells DNA Tubulin Actin ACTIN TUBULIN What do they do? Where are they? What do they bind? 40 motors walk on actin 39 motors walk on tubuliln

  11. your favorite gene Experimental system : adding genes to cells Gene (DNA) GFP Into cells Localization Interaction Partner complex INTEGRATE WITH CURATED DATA SETS Gene GFP

  12. GENE OF STUDY GFP Known motors are properly targeted in cell division

  13. Each motor has a unique localization pattern

  14. A physical interaction map of the cell Virus infection Nutrient uptake Cell motion Cell division Kidney disease Mitochondrial disease Mental retardation DNA alignment

  15. From data to function : Understanding mitochondria

  16. Motor labels moving strings in cells MYO19 DNA

  17. Motor is not on filament 1 MYO19 Calnexin F-Actin

  18. Galectin MYO19 a-tubulin Motor is on filament 2

  19. Motor surrounds mitochondria (generates energy)

  20. Fis1 Gene Filament 1 Maintaining mitochondria for energy production branching fusion fission

  21. SUMMARY Systematic analysis of all motor proteins Different motor proteins define unique compartments New discoveries on the control of cell division Novel disease-relevant interaction networks

  22. ACKNOWLEDGEMENTS Mental Retardation Hilger Ropers (MPI-MG, Berlin) Cell Division Helder Maiato Stefano Maffini (U. Porto) Cell Motility Anna Akhmanova (U. Erasmus) Virology Beate Sodeik (U. Hannover) Drug Mechanism Nathanael Gray (Harvard Medical School) Merck, GmbH (Darmstadt)

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