1. How Do Cells Compute? John J. Tyson Department of Biological Sciences Virginia Bioinformatics Institute

2. Do Cells Compute?

3. Computer bit string N N 2 x 01 00 10 11 1 0 1 0 either A or B but not both computations decisions

4. Is the cell an Information Processing System? IPS inputoutput

5. Cell nutrients repellants damage hormones heat shock growth & division movement gene expression death

6. Bacteria Glucose Lactose 1 0 glucose metabolizing enzymes 1 lactose metabolizing enzymes 0

7. Bacteria Glucose Lactose lactose metabolizing enzymes 1 1 0 glucose metabolizing enzymes 1

8. Bacteria Glucose Lactose lactose metabolizing enzymes 0 1 1 glucose metabolizing enzymes 1

9. Bacteria Glucose Lactose lactose metabolizing enzymes 0 0 0 glucose metabolizing enzymes 1

10. Fission Yeast 14 mm 7 mm Wild type Mutant (wee1D) “size control” different “set point”

11. Fibroblast Ionizing radiation damages DNA cell cycle arrest repair

12. Fibroblast Programmed Cell Death

13. Is a cell like a computer? LaptopCell Solid stateWatery ProgrammableHard-wired PreciseSloppy DigitalAnalog SequentialParallel ManufacturedSelf-reproducing DesignedEvolved SiliconCarbonSiliconCarbon DGaDLoDD

14. …in the last 5 years “Molecular Systems Biology” Cell Carbon Watery Hard-wired Sloppy Analog Parallel Self-reproducing Evolved Carbon

15. 20 years ago… Winfree & Kauffman Oster & Perelson Goldbeter & Segel Glass & Mackey Rinzel & Keizer Goodwin, Meinhardt, Odell, Tyson, … Cell Carbon Watery Hard-wired Sloppy Analog Parallel Self-reproducing Evolved Carbon

16. How do cells make decisions? WT cdc wee Paul Nurse, Nature (1975)

17. Fission Yeast P Wee1 P Cdc25 CycB Cdc25 MPF Mitosis Promoting Factor + + P WT cdc wee cdc25 ts wee1 ts wee1 OP cdc25 OP

18. Fission Yeast P Wee1 P Cdc25 CycB Cdc25 S/G2 M size MPF size SN 14  m wee1 OP wee1  P + + DNA synthesis Mitosis & Cell Division

19. WT Cdc25 activity (%) Wee1 activity (%) cdc cut wee quantized Size at Division 1.0 = WT size wee1 ts wee1 OP cdc25 OP cdc25 ts

20. P Cdc25 Wee1 P Cdc25 CycB P Cdc20 APC-P APC CycB MPF total cyclin ksks MPF

21. Joe Pomerening Cell (2005) MPF total cyclin

22. How do cells compute? Switches and Clocks ksks MPF S/G2 M size MPF

23. The class of chemical switching networks will be promising candidates for a possible new technology of chemical reaction systems.

24. nutrients repellants damage hormones heat shock growth & division movement gene expression death The living cell is Rössler’s “flüssiges Automata”: a miniature, self-reproducing, water-soluble biochemical computer.

25. $$: DARPA, NIH, McDonnell Foundation