Apoptosis - pre-programmed cell death...      (2002 Nobel Prize)

   Apoptosis, or programmed cell death, is a normal cell suicide process in response to cell signals.
It is mediated by a group of gene coded protein-digesting enzymes called caspases that in an
ordered series of events dismantles the interior of a cell.
 Caspases are a family of cysteine
proteases, which are activated whenever a cell plans or is signaled to activate its self-destruction
Cell death is characterized by an overall compaction (shrinking) of the cell & its nucleus,
and the orderly dissection of chromatin by unique endonucleases.  Death is finalized by a rapid
engulfment of the dying cell by phagocytosis of neighboring cells.

   Organisms consist of hundreds of cell types, all originating from a fertilized egg cell. During
development cell numbers increase dramatically, as they form the various tissues and organs.
Parallel with new cell formations, cell death is a normal process regulating an appropriate number
of cells in the tissues. Controlled elimination of cells is called programmed cell death or apoptosis.

   The 2002 Nobel's in Medicine are for discoveries of  the genetic regulation of programmed cell
. The laureates identified key genes regulating organ development and programmed cell death
& have shown that corresponding genes exist in higher species, including man. The discoveries are
important for cancer research via trying to treat disease by turning on "programmed cell death".
If one can create drugs that may trigger the "self-destruct" programs to kill off these abnormally
dividing cells cures may be effected.

   An example of programmed cell death occurs when tadpoles undergo tail metamorphosis to become
adult frogs. In humans inter-digital mesoderm initially formed between fingers and toes is removed by
programmed cell death

Sydney Brenner of the Salk Institute used the nematode Caenorhabditis elegans, which became
a multicellular model experimental system, to follow cell division and differentiation from the
fertilized egg to the adult via microscopic observation.  He demonstrated that a specific gene
mutation, induced by ethyl methane sulfonate, could be linked to a specific effect in nematode
organ development. His work on nematodes created an experimental system that laid the foundation
for the study of apoptosis.

John Sulston of the Wellcome Trust Institute in England mapped cell lineages, where every cell
division and differentiation could be followed in the development of C. elegans.   There are only
cells in an adult nematode. He showed that specific cells lineages (nerves) undergo programmed
cell death, as an integral part of the normal differentiation process. He also identified the first
mutation of a gene participating in the cell death process. Sulston also showed that a protein encoded
by the nuc-1 gene is required for degradation of the DNA of the dead cell.

Robert Horvitz of MIT discovered and characterized key genes controlling cell death in C. elegans.
He identified the first two bona fide "death genes", ced-3 and ced-4. Functional ced-3 & ced-4 genes
are a prerequisite for cell death to be executed. Another gene, ced-9, protects against cell death
by interacting with ced-3 and ced-4.   He has shown how these genes interact with each other in the
cell death process and that corresponding genes (a ced-3-like gene) exists in humans.  

Experimental model

Some Apoptosis Resources:
    J. Kimball's Biology book - apoptosis site
    NIH Apoptosis Interest Group Site
    Cell Death Society
    1st Int'l Meeting on Yeast Apoptosis, Oct. 4, 2002