size does matter! hhmi geneticist and his mouse and fly. size does matter! hhmi geneticist vs....

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Size DOES Matter!

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Size DOES Matter!

HHMI Geneticist and his mouse and fly

.

Size Does Matter!

HHMI Geneticist Vs. Dinosaur

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

Size DOES matter!

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

Human Beauty Is Based on Phi

Animal Body Is Based on Phi

Fibonacci Series in Plants

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

Wing Size Is UnchangedWhen Pattern Is Disrupted

Wild Type

col Mutant

Vervoort, M. et al., 1999

Overexpression of E2F Increases Cell Numbers,but Does Not Change Wing Size

Neufeld T. et al., 1998

What Determines the Sizes of the Organs/Organisms?

What Genes?

Genes!

Identify Tumor Suppressors in Mosaic Flies

RB+

RB-

RB-

Xu et al. 1995 Development

Tumors?

/ + /

Xu et al., 1995, Development

Tumors in Drosophila Eye

Xu et al., 1995, Development

Lats Mutants Deregulate Organ Size

Xu et al. 1995 DevelopmentTao et al. 1999 Nature Genetics

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

-/-

+/+

Tsc1, Tsc2, 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

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

How Organisms Measure Size?

Drosophila TSC genes affect

cell size, but not ploidy

Potter et al Cell 2001

Wild-Type

Organisms build structures by measuring physical distance or cell number?

Distance

Cell Number

Tom Ni, Undergrad