Cells die to keep you alive

McClatchy NewspapersMay 28, 2008 

Robert Horvitz at the Massachusetts Institute of Technology won a Nobel Prize for his discovery of suicide genes.

DONNA COVENEY / MIT / MCT

WASHINGTON — In an act of ultimate self-sacrifice, millions of human cells commit suicide every day, making your life better by their death.

Some cells kill themselves so that developing embryos don't grow webs between their fingers and toes. In teenagers, unused brain cells are pruned away. Other cells kill themselves after damage by radiation or smoking.

Now scientists are learning to control this biological demolition process and enlist it in the war on cancer. It's called "programmed cell death" (PCD) or, in scientific jargon, apoptosis (ah - pop - TOE - sis). Mistakes during apoptosis can lead to cancer or keep anti-cancer therapy from working.

"In one-third to one-half of all cancers, a major component of the malignancy is the ability of the cancerous cell to resist apoptosis," Richard Lockshin, a biology professor at St. John's University in New York City, said in an e-mail interview.

Programmed cell death is directed by a flock of about 25 related genes, some with morbid names like Reaper, Grim, Bad and Scythe. These genes contain instructions to create certain proteins — strings of biological molecules — that launch cascades of chemical events ending in the annihilation of unwanted cells.

Government, academic and commercial laboratories are racing to develop drugs that control PCD genes. Several biotechnology companies are conducting preliminary human trials of such drugs for lung and colorectal cancer, among others. As yet, none have been approved for medical use.

"The first attempts to manipulate cell death directly have not proved very effective," Lockshin said. The problem is that researchers tried to use broad-based weapons — he called them "bludgeons" — that were not directed precisely at the cells that needed to be destroyed.

"There is considerable attention now to finding means of targeting these bludgeons to specific cells," Lockshin said. "In other words, bullets are very effective killers, but you have to aim them at the right targets."

Other researchers are more optimistic about the prospects for controlling cellular suicide.

"I believe that clinically useful therapeutic interventions on apoptotic checkpoints will be available by 2012," Guido Kroemer, a prominent cell death researcher at the French Medical Research Council in Paris, said in an e-mail message. "It's just a question of perseverance (and luck)."

"Basic research has paved the way," Kroemer explained. "The field is now advancing from its initial stages, at the level of fundamental discovery, to a ... stage at which drug discovery becomes a priority."

Programmed cell death has been spurring research efforts over the last 10 years, since Robert Horvitz, a cell biologist at the Massachusetts Institute of Technology in Cambridge, Mass., discovered a "family" of genes in tiny laboratory worms that cause cells to die or protect them from dying.

Horvitz and two British colleagues received a Nobel Prize in 2002 for their work. The worm genes have human parallels that are the now the subject of intensive research.

Here's how it works: Some death genes produce proteins that break open vital organs inside cells called mitochondria. The damaged mitochondria release floods of chemicals that would eventually destroy the host cell. At the same time, other proteins in the same family try to block apoptosis, keeping the cell alive.

As Horvitz explained on his laboratory's website, the balance between these competing proteins decides "which cells are to live and which are to die."

"The execution of cellular suicide, or apoptosis, is indisputably under the dominion of one group of proteins, the Bcl-2 family," Richard Youle, a neurologist at the National Institutes of Health in Bethesda, Md., wrote in the journal Science last year. Within this family, he wrote, there are "factions (that) are at odds with each other, as they rival to promote or block cell death."

PCD researchers are also seeking techniques to prevent unwanted or unnecessary cell suicide.

"I am confident that these efforts will ultimately pay off and generate pharmacological treatment for the avoidance of unwarranted cell death, for instance in stroke or in heart attack," Kroemer wrote.

Horvitz, Lockshin, Kroemer and hundreds of PCD researchers will gather at a conference of The International Cell Death Society in Shanghai, China, next month (June 6-9) to discuss the latest findings. Chinese drug companies are very interested in developing medicines using programmed cell death, Lockshin said.

For more on programmed cell death:

www.celldeath.de/encyclo/aporev/aporev.htm

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html

McClatchy Newspapers 2008

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