1. Noise and Bistability 12/10/07

2. Noisy gene expression at single cell level Elowitz 2002

3. Noise distribution of protein concentration Bar-Even 2006

4. Dependence of noise level on protein concentration Bar-Even 2006

5. Proteins are produced in bursts Cai 2006

6. Proteins are produced in bursts Cai 2006

7. Intrinsic and extrinsic noise extrinsic noise: fluctuations in the amounts or states of other cellular components lead indirectly to variation in the expression of a particular gene intrinsic noise: The inherent stochasticity of biochemical processes such as transcription and translation Elowitz 2002

8. Intrinsic and extrinsic noise extrinsic noise: fluctuations in the amounts or states of other cellular components lead indirectly to variation in the expression of a particular gene intrinsic noise: The inherent stochasticity of biochemical processes such as transcription and translation Elowitz 2002

9. Distinguishing intrinsic from extrinsic noise Average over cell population For a fixed time t, Total noise level, Average over time Swain 2002

10. Distinguishing intrinsic from extrinsic noise Average over cell population For a fixed time t, Total noise level, Average over time Swain 2002

11. Measuring intrinsic and extrinsic noise Swain 2002

12. Measuring intrinsic and extrinsic noise Simultaneously measure the expression levels of two copies of a single gene, controlled by the same promoter. Elowitz 2002

13. Measuring intrinsic and extrinsic noise Elowitz 2002

14. Controlling noise Noise can hamper the precision of decision making by a cell. Noise can be controlled by using negative feedback loops. Essential genes are less noisy than other genes, suggestive of selection pressure. AB A B t t

15. Benefit of noise Noise can diversify phenotypic responses. Different pheontypes may be adapted for different environmental conditions. Population diversity can help the population to survive as a whole.

16. Alternative ways to adapt to environmental changes Leibler 2005

17. Noise-induced drug resistance Balaban 2004

18. Noise-induced drug resistance Observation No mutation is identified. “Resistant” cells can be further killed by antibiotics. Balaban 2004

19. Noise-induced drug resistance Observation No mutation is identified. “Resistant” cells can be further killed by antibiotics. Explanation Genetically identical cells have different responses to environment due to noise. A subpopulation of cells “persisters” escape the antibiotics by initiating the “right” response. Balaban 2004

20. Bistability Veening 2006 Gene activities can be regulated by on- off switches. Large-scale continuous response can be due to change of proportions of responsive cells.

21. Bistability Bistability is characterized by bimodal distribution. Single stable state corresponds to a unimodal distribution. Veening 2006

22. Positive feedback loops and bistability AB A B t t

23. AB A B t t

24. Ordinary differential equations y t

25. y1y1 t y2y2 y1y1 phase diagram

26. Steady states y2y2 y1y1

27. y2y2 y1y1 unstable y2y2 y1y1 stable

28. Bistability y2y2 y1y1

29. Modeling positive feedback loops AB The positive feedback loops can be modeled by ODEs

30. AB The solution is The only possible stable states are 0 and infinity. Therefore, nonlinear models are required to model bistability. Modeling positive feedback loops

31. Ferrell & Xiong 2001

32. Single stable steady states in simple Michaelis-Menen systems Ferrell & Xiong 2001

35. Hysterisis Ferrell & Xiong 2001

36. Readling List Elowitz et al. 2002 –Defined intrinsic and extrinsic noise Balaban et al. 2004 –Noise-induced drug resistance Ferrell and Xiong 2001 –Introduction to bistability