Johns Hopkins Gazette: July 21, 1997

Halting The Impulse
To Die

Betenbaugh studies
how to keep cells
from committing

Phil Sneiderman
News and Information

Every day, for reasons that are not clearly understood, some human cells commit suicide. Some cells, such as those that have been infected by a virus, kill themselves to preserve the health of the body as a whole. Others self-destruct simply because they sense that a threat to their survival or merely something unfamiliar is lurking nearby.

This process, called apoptosis or programmed cell death, is a normal biological occurrence that can promote proper organ development and help to prevent cancer. But it's unwelcome in modern biotech labs, where scientists turn living cells into miniature pharmaceutical factories that produce proteins, enzymes, antibodies and viruses to help patients with an array of illnesses. Apoptosis prompts many of these microscopic workers to put physiological "guns to their heads" after just a few days on the job. Working closely with molecular biologists, Hopkins engineer Michael J. Betenbaugh is trying to disable these guns and allow the drug-making cells to lead longer, more productive lives.

"Ideally, we'd like to extend the lifetime of these cells and increase their efficiency in making biotech products that save people's lives," says Betenbaugh, an associate professor in the Department of Chemical Engineering.

His research has important implications. If scientists find a way to stop cellular suicide, they may be able to keep some cardiac cells from killing themselves after a heart attack. They may also be able to extend the life of artificial organs made from animal tissue.

The key is to halt apoptosis, which is often triggered by changes in a cell's environment. "It may be a viral infection, the loss of a key nutrient, radiation or a chemical toxin_all at sub-lethal levels," Betenbaugh explains. "These would not kill the cell by themselves. Nevertheless, the cell turns on this physiological chain of events that causes it to self-destruct."

In biotech labs, however, researchers want genetically engineered cells to thrive and produce medicines for as long as possible--a goal that is thwarted by programmed cell death. To remove this stumbling block, Betenbaugh installs "stop signals" at specific points along a cell's road toward self-destruction. To find these signals, he works with researchers led by J. Marie Hardwick, an associate professor of molecular microbiology and immunology at the School of Public Health. Hardwick's team is mapping out the genetic path that a cell follows toward self-destruction. In his own biotech lab, Betenbaugh uses these findings to figure out the best way to block the cell's progress along this path.

"There is a point of no return as the cell goes through the process of killing itself," Betenbaugh explains. "But at some point you can stop it. I'm collaborating with the biologists who are figuring out what those stop signals are. Then, as an engineer, my job is to apply those stop signals to the cell lines that I'm developing."

One potential stop signal is membrane protein called bcl-2. When this material is inserted during the genetic engineering of a new cell line, it appears to shut down the suicidal impulses, Betenbaugh says. He is also experimenting with chemicals that mimic the effects of bcl-2 when added to cells that are already growing in the lab.

"Maybe our cells see the signals that tell them to commit suicide," Betenbaugh says. "But we can halt that process before it hits the point of no return. Instead of dying after two days, our cells might live for six or seven days, making pharmaceuticals for a longer period of time."

In his initial experiments, Betenbaugh has more than doubled the life span of some biotech lab cells. Thus far, however, each of these hardier cells has not produced as much medicine as the ones that died quickly. By trying new genetic and chemical strategies, the researcher seeks to improve the system significantly in the near future. "We want to find the combination that will allow these cells to work more efficiently and live longer," Betenbaugh says. "That's what this research is all about."

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