2. Size DOES Matter!

3. HHMI Geneticist and his mouse and fly. Size Does Matter! HHMI Geneticist Vs. Dinosaur

4. Size Feature Is One of the Fundamental Characters of Living Organisms Fruit flies: ~1 mm 1 ~1 mg 1 Mice: ~10 cm 10 2 ~10 g 10 4 Humans: ~1 m 10 4 ~100 kg 10 8 Dinosaurs: ~10 m 10 5 ~10 MT 10 10

5. Size DOES matter!

6. Biological Significance of Size Features Bone/Body Mass The Length of the Legs Roots/Trunk Heart/Body Mass Proportionality Ratio of Organ Sizes The Golden Ratio & Fibonacci Series

7. Phi = A/B = B/C = 1.618… P = B/A = C/B = 0.618… Phi: the Golden Ratio and Fibonacci Series BC A http://goldennumber.net

8. Human Beauty Is Based on Phi

9. Animal Body Is Based on Phi

10. Fibonacci Series in Plants

11. Biological Significance of Size Features Mating Segregation Predator/Prey Enlarged Roots/Store Water Longer Fish Swims Faster Size & Function Egg Sizes/Maturation Time Body Size/Surface-Mass/Body Temperature/ Metabolic Rates/Longevity Fixed Adult Size/Continue Growing Leave Sizes/?

12. Evolution Question: Why Did Animals Become Bigger Early And Are Now Getting Smaller? O2 Food Supply Land Area

13. Size Property Is Intrinsic to an Organ Primodium Graft Exchange Amblystoma tigrinum A. punctatum Twitty and Schwind, 1928 Proc. Soc. Exper. Bio. Med. 25:686

15. Size Control Mechanism

16. Implication of Regeneration

17. Wing Size Is Unchanged When Pattern Is Disrupted Wild Type col Mutant Vervoort, M. et al., 1999

18. Overexpression of E2F Increases Cell Numbers, but Does Not Change Wing Size Neufeld T. et al., 1998

19. What Determines the Sizes of the Organs/Organisms? What Genes? Genes!

20. Identify Tumor Suppressors in Mosaic Flies RB + - - Xu et al. 1995 Development Tumors? / + /

21. Xu et al., 1995, Development Tumors in Drosophila Eye

22. Xu et al., 1995, Development

23. Lats Mutants Deregulate Organ Size Xu et al. 1995 Development Tao et al. 1999 Nature Genetics

24. Identify overgrowth mutants by comparing twin-spot clones Xu et al., 1995 Development W + W + Replication W + W + Segregation W + W + W W Mutant Cell + + Wild Type Twin-spot Cell

25. Identify Overgrowth Mutants by Comparing the Sizes of Twin Clones Xu et al. 1995 Development -/- +/+

26. Tsc1, Tsc2, and PTEN Mutations Deregulate Organ Size Potter et al. Cell 2001

28. Size DOES matter!

29. Lats Homologs Function as TS in Flies and Mice St John et al. 1999 Nature Genetics

30. Tumorigenesis Requires Deregulation of Size-Control Mechanism Tumor development requires increasing total mass Multiple tumor suppressors and oncogenes affect Mechanisms of size control Molecules participating in size-control could be targets for anti-cancer drugs Potter and Xu 2001

31. S6k Tor Akt (PKB) InR PI3K Tsc1Tsc2 Active Potter et al. Cell 2001 Potter et al. Nat Cell Bio 2002 Inoki et al. G & D 2003 PTEN Rapamycin S6K Tor Inactive Tsc1 PP Tsc2 TSC Pathway Provides A Basis for Therapeutic Intervention Rheb

32. Clinical Trails for TSC and LAM 2003 Kwiatkowski, Harvard; Yeung, U of W Clinical trails 2003.4 US: Drs. McCormack, Franz, Bissler England: Drs. Simpson and Kingswood Germany: Dr. Weinke Pathway conserved, S6K activated in patients TSC pathway and drug target TSC animal trial 2002-2003 Many groups 2001,2002 Potter & Xu

33. How Organisms Measure Size?

34. Drosophila TSC genes affect cell size, but not ploidy Potter et al Cell 2001

35. Wild-Type Organisms build structures by measuring physical distance or cell number? Distance Cell Number Tom Ni, Undergrad