Size DOES Matter Size Does Matter Geneticist Dinosaur

Size DOES Matter!

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

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

Size DOES matter!

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

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

Human Beauty Is Based on Phi

Animal Body Is Based on Phi

Fibonacci Series in Plants

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

Evolution Question: Why Did Animals Become Bigger Early And Are Now Getting Smaller? Land Area Food Supply O 2

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

Size Control Mechanism

Implication of Regeneration

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

Overexpression of E 2 F Increases Cell Numbers, but Does Not Change Wing Size Neufeld T. et al. , 1998

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

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

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

Xu et al. , 1995, Development

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

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

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

Tsc 1, Tsc 2, and PTEN Mutations Deregulate Organ Size Potter et al. Cell 2001

Size DOES matter!

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

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

TSC Pathway Provides A Basis for Therapeutic Intervention In. R PI 3 K PTEN Akt (PKB) Inactive Active P P Tsc 1 Tsc 2 Potter et al. Cell 2001 Rheb Rapamycin Tor S 6 k S 6 K Potter et al. Nat Cell Bio 2002 Inoki et al. G & D 2003

Clinical Trails for TSC and LAM TSC pathway and drug target 2001, 2002 Potter & Xu Pathway conserved, S 6 K activated in patients 2002 -2003 Many groups TSC animal trial 2003 Kwiatkowski, Harvard; Yeung, U of W Clinical trails 2003. 4 US: Drs. Mc. Cormack, Franz, Bissler England: Drs. Simpson and Kingswood Germany: Dr. Weinke

How Organisms Measure Size?

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

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