Big lessons from little worms

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Apoptosis By Douglas R. Green

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Presentation transcript:

Big lessons from little worms Apoptosis worm Image from Mingxue Cui

The worms are transparent

Worms are transparent <1000 cells One can follow the individual lineage of each of the cells

Deciphering the cell lineage of C. elegans

Deciphering the cell lineage of C. elegans

Cell death is also a “cell fate”

Specific cells are dying in a programmed manner Programmed cell death Specific cells are dying in a programmed manner

Programmed cell death (PCD) The mechanism: apoptosis Also associated with the fight of our body against cancer tumors Is this an active process?

We know there is apoptosis We know it is important in development and possibly in cancer We don’t know whether it is an active process We don’t know of any genes involved Let alone, a pathway (if exists) What do we do?

Forward Genetics: random mutations Mutagenesis Forward Genetics: random mutations

They found the guy who gets rid of the body Next, they found the murderer

ced-3 acts to promote cell death

The gene is mapped and sequenced Is it murder or suicide? ced-3 ced-1 Mutant analysis The gene is mapped and sequenced Next step: does it have human homologes or is this just a worm-specific pathway?

Is it a worm-specific gene or do we have human homologs?

- The ced-3 gene encodes a protease, conserved in evolution - It kills cells by degrading their proteins Apoptosis is carried out by proteins. It is an active process, not a passive death Now we also know that human caspase is involved in apoptosis

A new mutation was isolated: ced-9 ced-9(-): ectopic cell death (cells that normally live, undergo apoptosis)

More and more mutants are isolated Epistasis analysis and biochemical studies allow the scientists to build a pathway

Genetic control of programmed cell death ced-9 ced-4 ced-3 Cell death CED-4 CED-4 is inactive CED-9 No death signal Activates CED-3 caspase for the killing CED-9 CED-4 Death signal

Gain of function mutations in bcl-2 were associated with human cancers (bcl= b cell lymphoma resulting from a translocation event) Our body uses the same apoptotic mechanisms used in PCD, for killing “bad” cells Identify mutants in worms (with the simplest assay) and find human homologs

Nobel Prize Lineage and programmed cell death Physiology and Medicine 2002 Bob Horvitz John Sulston Sydney Brenner Bob Horvitz

- Pro-apoptotic signals open up the channels, allowing cyt C to be released to the cytoplasm

A simplified representation of apoptosis Proapoptotic (BH3-only) Noxa Antiapoptotic Bcl-2 Procaspase Apaf Proapoptotic (multidomain) Bax Caspase Cytochrome C Mitochondria All the regulators are from the same protein family (containing BH domains)