size does matter! hhmi geneticist and his mouse and fly. size does matter! hhmi geneticist vs....
TRANSCRIPT
Size Feature Is One of the FundamentalCharacters of Living Organisms
Fruit flies: ~1 mm 1 ~1 mg 1
Mice: ~10 cm 102 ~10 g 104
Humans: ~1 m 104 ~100 kg 108
Dinosaurs: ~10 m 105 ~10 MT 1010
Biological Significance of Size Features
Bone/Body Mass
The Length of the Legs
Roots/Trunk
Heart/Body MassProportionalityRatio of
Organ Sizes
The Golden Ratio & Fibonacci Series
Phi = A/B = B/C = 1.618…
P = B/A = C/B = 0.618…
Phi: the Golden Ratio and Fibonacci Series
B C
A
http://goldennumber.net
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/?
Evolution Question:Why Did Animals Become Bigger Early
And Are Now Getting Smaller?
O2
Food Supply
Land Area
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
Transplant
Fetal digestive track tissue Stop growth after forminga cyst of a constant size
Leitina et al., 1971Transplantation11,499
Transplant
Young disc Stop growth afterreaching normal size
Bryant, 1978.Genet. & Bio.of Drosophila
Size Control Mechanism
Michalopoulos &DeFrances, 1 99 7
Science
Surgical removalof a part of the liver
Mammal
Regeneration
Implication of Regeneration
Disc Regeneration
French et al.,1978. Science
Surgical removal
Drosophila
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 TypeTwin-spotCell
Identify Overgrowth Mutants by Comparing the Sizes of Twin Clones
Xu et al. 1995 Development
-/-
+/+
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
S6k
Tor
Akt (PKB)
InR
PI3K
Tsc1Tsc2Active
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
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