Understanding of Brain Development and Cancer Growth Also Advanced

A key enzyme that acts as a "suicide weapon" causing cells to self-destruct has been discovered by Weizmann Institute researchers.

This finding, reported in the June 14 issue of Cell, may help in the design of treatments for autoimmune disorders caused by abnormal cellular self-destruction, such as juvenile diabetes and multiple sclerosis. It also advances the understanding of a variety of other normal and abnormal processes involving cell suicide.

"We've identified a crucial step in the self-annihilation of cells and may now be able to control this process," says Prof. David Wallach of the Institute's Department of Membrane Research and Biophysics, whose research team included graduate students Mark Boldin, Tanya Goncharov and Yury Goltsev.

Our body's cells commit suicide regularly in a normal process that enables organs to renew and repair themselves. But in certain autoimmune diseases, the immune system erroneously commands healthy cells to exterminate themselves.

Scientists have known for several years that in these disorders certain cells receive the self-destruct message through three recepto molecules on their surface, known as Fas/Apo-1and two tumor necrosis factor (TNF) receptors.

Now Institute researchers have discovered the "suicide weapon" that translates this message into action -- an enzyme they called MACH. This enzyme cuts up certain vital proteins inside the cell, thereby disrupting its normal functions and causing it to die.

The scientists also found that the transmission of the suicide message is surprisingly direct. Unlike many other cellular processes that involve multiple stages and messengers, it is relayed directly from the receptor to the suicide machinery inside the cell.

"We were amazed to discover how little it takes to trigger cellular self-destruction -- it's as if cells always live on the brink of suicide," Wallach said.

The new understanding of the suicide mechanism may make it possible to block it in autoimmune disorders. Moreover, since the death signals are primarily transmitted via Fas/Apo-1 and TNF in the case of disease, it may be possible to selectively block only these abnormal signals while allowing other cell suicide processes to continue in tissues where they are needed.

The discovery of the MACH molecule also advances our understanding of the development of the brain and other organs because this enzyme belongs to a family of proteins that play a crucial role in cellular self-destruction involved in these and numerous other body processes. In addition, the new finding may help us understand the growth of cancerous tumors, in which the cellular suicide mechanisms responsible for maintaining the normal growth of tissues are sometimes disturbed.

Prof. Wallach has studied TNF receptors for some 14 years and -- together with his Weizmann Institute colleagues -- was among the first researchers in the world to clone them.

This research was supported in part by Inter-Lab, Nes Ziona, Israel; Ares Trading S.A., Switzerland, and Israel's Ministry of Science and the Arts.