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How Do Cells Compute? John J. Tyson Department of Biological Sciences Virginia Bioinformatics Institute Do Cells Compute? Computer bit string bit string N N2 x x 00 0 01 10 11 either A or B but not both 1 1 0 computations decisions Is the cell an Information Processing System? input IPS output nutrients repellants Cell growth & division movement hormones damage heat shock gene expression death Bacteria Glucose 1 glucose metabolizing enzymes 1 Lactose 0 lactose metabolizing enzymes 0 Bacteria Glucose 1 glucose metabolizing enzymes 1 Lactose 1 lactose metabolizing enzymes 0 Bacteria Glucose 0 glucose metabolizing enzymes 1 Lactose 1 lactose metabolizing enzymes 1 Bacteria Glucose 0 glucose metabolizing enzymes 1 Lactose 0 lactose metabolizing enzymes 0 Fission Yeast 7 mm 14 mm Wild type “size control” Mutant (wee1D) different “set point” Fibroblast cell cycle arrest repair Ionizing radiation damages DNA Fibroblast Programmed Cell Death Is a cell like a computer? Laptop Cell Silicon Carbon Solid state Digital Watery Analog Sequential Programmable Precise Parallel Hard-wired Sloppy Manufactured Designed DGaD Self-reproducing Evolved LoDD …in the last 5 years Cell Carbon “Molecular Systems Biology” Watery Analog Parallel Hard-wired Sloppy Self-reproducing Evolved 20 years ago… Cell Winfree & Kauffman Carbon Oster & Perelson Watery Analog Goldbeter & Segel Glass & Mackey Parallel Hard-wired Sloppy Self-reproducing Rinzel & Keizer Evolved Goodwin, Meinhardt, Odell, Tyson, … How do cells make decisions? WT Paul Nurse, Nature (1975) cdc wee Fission Yeast WT P Wee1 P cdc Wee1 CycB Cdc25 P ++ CycB cdc25ts Cdc25 MPF Mitosis Promoting Factor wee1ts wee1OP wee cdc25OP Fission Yeast Mitosis & Cell Division M 100 P Wee1 MPF Cdc2/Cdc13 P wee1D Wee1 CycB Cdc25 P ++ CycB 10-1 S/G2 DNA synthesis 10-2 SN 14mm 10-3 0 1 mass/DNA size Cdc25 size wee1OP 2 Size at Division 1.0 = WT size 2.0 1.4 1.6 1.0 1.2 0.8 3.0 cdc25ts WT 1 0 0 cdc25OP 0 . 3 .0 2 1.0 0.8 0.6 1.6 .2 1 .4 1 1 0 0.6 0.8 cut wee1ts 0.4 wee .2 1 1.0 Wee1 activity (%) cdc 0.6 wee1OP 1 0 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0 Cdc25 activity (%) 1 0 0 0 1 0 0 0 0 P Wee1 Cdc20 Wee1 CycB Cdc25 APC APC-P P CycB MPF Cdc25 1 MPF P ks 0.5 0 0 1 2 total cyclin total cyclin MPF Cell (2005) Joe Pomerening How do cells compute? Switches and Clocks M MPF Cdc2/Cdc13 100 10-1 MPF S/G2 10-2 10-3 0 1 mass/DNA size 2 ks The living cell is Rössler’s “flüssiges Automata”: a miniature, self-reproducing, nutrients growth & division water-soluble biochemical computer. repellants movement hormones damage heat shock gene expression death $$: DARPA, NIH, McDonnell Foundation
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