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How does one define the borderline between life and death?” asks Prof. David Wallach of the Biological Chemistry Department. Most doctors agree that cessation of heartbeat or brainwaves is the standard indication of human death. For the body’s cells, too, scientists have clear ideas as to the signs that indicate death. For instance, they can point to specific molecules that are intimately associated with the cell death process. But, as Wallach and an international team of researchers have recently demonstrated, at least one of the molecules most closely linked to cell death may be just as necessary for maintaining cell life.
Caspase-8 is a member of the caspase family of enzymes, known to play a central role in the complex process leading to cell death, also called apoptosis. This enzyme’s activation is, in itself, taken as a sign that the cell is on an irreversible path to suicide.
In the 20 years that Wallach has been studying apoptosis, he has brought to light some of the more important biological molecules and processes involved, including caspases. Around six years ago, he and his research team used a technique called “gene knock-out” to create mice lacking the gene that produces caspase-8. However, rather than breeding mice with immortal cells, as would be the case if caspase-8 was merely a link in the cell-suicide chain, they found their mice didn’t make it past the embryo stage. Apparently, this “cell death” enzyme also had important roles to play in growth and development.
“Unfortunately, when knocking out a gene causes so much havoc in the organism, it's very hard to study its function,” says Wallach. But a recent advance in knock-out technology inspired the team to try once again to unravel caspase-8's role. Called conditional knock-out, it allowed the scientists to delete the gene in only one organ at a time or to turn it off at a specific time.
When the caspase-8 gene was knocked out from the liver, the result was, indeed, the creation of cells that refused to die, giving scientists further proof that caspases are crucial to apoptosis in living mammal cells. In contrast, knocking out the caspase gene from the circulatory system produced nearly opposite results. Cells did not grow and develop properly, and the fine capillary blood vessels failed to form as they should. Similarly, knocking out the caspase gene from the stem cells that become various types of blood cells resulted in the complete arrest of blood-cell generation, while deleting it in unformed macrophages (a type of white blood cell) kept them from maturing, showing the “death” gene may be a “life” gene after all.
While this study raised some new questions about the mechanisms that control life, another study recently published by Wallach and his team settled the long-standing question of how a protein they had previously discovered helps the cell resist death. Called NIK, this protein relays messages from the immune system outside the cell to an intracellular “messenger service” called NF-kB, which sparks the production of proteins that, among other effects, endow cells with death resistance. But NIK works only some of the time, and the circumstances of its employment were the subject of scientific controversy. Wallach’s team showed that NIK comes into play only if specific receptors on the cell membrane - those tied to the functioning of white blood cells known as lymphocytes - are activated. Because an accumulation of death-resistant lymphocytes is tied to such problems as graft rejection and various autoimmune diseases, NIK is a promising target for new drugs to treat a variety of conditions.
Prof. David Wallach’s research is supported by the Kekst Family Center for Medical Genetics; the Dr. Josef Cohn Minerva Center for Biomembrane Research; the David and Fela Shapell Family Center for Genetic Disorders; the Joseph and Bessie Feinberg Foundation; and the Alfred and Ann Goldstein Foundation.