Imagine a society in which the ultimate in cooperation was the rule.Crime wouldn't exist. Someone would always be there to help, atwork or home. No one would ever be alone. Of course, this societywould also be one in which every action taken would be for thecommon good. By definition, no one could stand out from the crowd.

That ultimate cooperative society exists inside every person in theform of cellular associations that form the tissues and organs thatmake up each individual. While a human's ultimate goal in life is topass on a legacy, a cell's goal is to sacrifice everything for the goodof the organism, allowing the whole to survive.

The fact that cells must cooperate closely in order for a person tofunction and survive requires them to have some very specificattributes. One of the more unique characteristics that cells mustpossess is the ability to know how to remove themselves from thescene at the appropriate time. They must die on cue so that thegrowth of abnormal cells can be avoided or room can be made forother cells.

In the past few years, scientists have begun to study the process bywhich cells undergo this programmed cell death or suicide, known asapoptosis. In the March 10 Science, several researchers summarizeour current understanding of apoptosis.

During apoptosis, the nucleus and cytoplasm of the cell condense.Fragments of the cell become membrane-bound and these so-calledapoptotic bodies are then readily taken up by macrophages orneighboring cells and digested. Thus, dead cells are efficiently andrapidly removed without leakage of intracellular contents. In contrast,cell death by necrosis results from cellular injury which causes cellsto break open, releasing their cytoplasmic contents and causing ageneralized inflammatory response.

The basic machinery to carry out apoptosis appears present in thecell's cytoplasm and ready to act in essentially all mammalian cells atall times. When cell nuclei are removed and the remaining so-calledcytoplasts are deprived of survival factors, they undergo all of thechanges that are characteristic of apoptosis. In essence, nuclear deathappears secondary to essential cytoplasmic death events.

However, not surprisingly, the initiation of apoptosis is carefullyregulated. Many different signals, originating both from within andoutside cells, influence the activation of the cell death program.These diverse signals can either promote or suppress cellular suicide,sometimes having opposing effects on different cell types. Growingevidence indicates that cells are primed for cellular suicide and mustcontinuously receive signals from other cells in order to prevent theinitiation of apoptosis.

Cellular Suicide Genes

Hermann Stellar, a molecular biologist at the Howard HughesInstitute at Massachusetts Institute of Technology, discusses thegenes controlling apoptosis in nematode worms and fruit flies andhow they are related to human genes in his article entitled,"Mechanisms and genes of cellular suicide." Genetic studies in theseorganisms have led to the isolation of genes that are specificallyrequired for programmed cell death. These genes and many of thecomponents of this process appear to be conserved in humans.

Specifically, the ced-9 gene from nematodes encodes a protein that issimilar to the Bcl-2 family of cell death regulators in highervertebrates, such as rodents and humans. The ced-9 gene is requiredto protect cells in these worms that need to survive from undergoingprogrammed cell death. Interestingly, the expression of human Bcl-2can inhibit cell death in nematodes and can even partially substitutefor the loss of ced-9 function.

Work in nematodes and fruit flies has shown that apoptosis is centralto the development and maintenance of all animals. It is a major forcein the formation of organs and tissues during embryonic growth, inremoving unwanted or dangerous cells, and in killing viral-infectedcells and tumors.

Fas Death Factor

Also in the apoptosis section of Science, Shigekazu Nagata of theOsaka Bioscience Institute and Pierre Golstein of INSERM-CNRS inMarseille, France, discuss the biology of Fas, a prominent player inapoptosis in the immune system. In their article entitled, "The Fasdeath factor," they give an overview of the biology of this specificcellular suicide agent.

Fas is a cell surface protein recognized by cytotoxic antibodies. It isthe receptor for the Fas ligand (FasL), a previously unknown cytokinebelonging to the tumor necrosis factor family. When FasL binds toFas, the target cell undergoes apoptosis.

Many cells express Fas, but FasL is expressed predominantly inactivated T cells. The Fas-FasL system is involved in the process ofcytotoxic lymphocyte-mediated cell death and down-regulation of theimmune system response. Loss-of-function mutations of Fas or FasLcan cause activated lymphocytes to accumulate, resulting inautoimmune disease in mice.

Finally, Craig Thompson, a molecular geneticist at the HowardHughes Medical Institute at the University of Chicago, looks at thetherapeutic potential in cell death processes in his article entitled,"Apoptosis in the pathogenesis and treatment of disease." Abnormalactivation of the programmed cell death pathway appears to play arole in a variety of diseases, including cancer, autoimmune diseases,viral infections, AIDS and neurodegenerative disorders.

In principle, the genes involved in apoptosis, such as Bcl-2, and theirprotein products could provide targets for therapeutic intervention.However, the genes currently known to be involved in apoptosisappear to act more centrally, thus specificity of inhibitor agentswould likely be a considerable problem. But these central mediatorsof apoptosis may still be able to be manipulated in a cell-specificfashion. Clearly, significant therapeutic development is still somedistance away, but with increasing knowledge about cell-specificfactors involved in apoptosis should come agents that truly will beable to modulate cell death. n

-- Chester Bisbee Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.

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