Size DOES Matter!

1. Size DOES Matter!

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

3. Size Feature Is One of the Fundamental Characters of Living Organisms Dinosaurs: ~10 m 105 ~10 MT 1010 Humans: ~1 m 104 ~100 kg 108 Mice: ~10 cm 102 ~10 g 104 Fruit flies: ~1 mm 1 ~1 mg 1

4. Size DOES matter!

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

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

7. Human Beauty Is Based on Phi

8. Animal Body Is Based on Phi

9. Fibonacci Series in Plants

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

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

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

14. Size Control Mechanism

15. Implication of Regeneration

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

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

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

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

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

21. Xu et al., 1995, Development

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

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

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

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

27. Size DOES matter!

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

29. 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

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

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

32. How Organisms Measure Size?

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

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