Coming to Terms with Death

Article excerpt

Accurate descriptions of a cell's demise may offer clues to diseases and treatments

Death is a part of living--and an essential one. From conception onward, cells divide over and over again. Their endless proliferation would quickly lead to elephantine bodies were it not for a compensating death of cells.

But cells' deaths can achieve far more than just crowd control. During fetal development, a symphony of cell deaths sculpts the body. During sickness, cascades of biochemical events euthanize diseased cells. Even healthy cells, as they age and lose vigor, commit suicide for the good of the organism.

The typical adult may create 10 billion new cells every day--and kill off an equal number. Indeed, cancers stem from cells that have foresworn the natural suicide plan that's programmed into an organism's genes. The progeny of these renegade masses of prolific immortals eventually set up squatter colonies that crowd out healthy tissues and siphon off resources.

Until recently, most biologists classified cell deaths into two categories. In apoptosis, genetically programmed suicide shapes an organism or rids it of diseased cells. Necrosis, in contrast, includes cell deaths resulting from some outside force.

During the past few years, however, several biologists and pathologists have begun to challenge this bimodal classification, arguing that it's both overly simplistic and misleading. For instance, some researchers have found a type of programmed cell death that bears little resemblance to apoptosis. Others report a novel form of cell homicide that targets malignant cells.

Recently, a panel of scientists reconsidered the classification of cell death and argued for more precise descriptions.

At stake is more than nomenclature, however. By misdiagnosing how cells die, some scientists argue, the medical community risks overlooking new ways to halt untimely deaths--or to foster them for the sake of cancer therapy.

Two years ago, a California scientist stumbled onto evidence for one of these new types of cell death while she was attempting to measure rates of apoptosis in genetically modified human cancer cells.

Sabina Sperandio of the Buck Institute for Age Research in Novato, Calif., inserted into lab-cultured cell lines various genes that would make the cells dependent on a particular hormone or protein. She expected that in the absence of this chemical partner, the cells would undergo apoptosis.

In one experiment, Sperandio made a line of human cells dependent on insulin-like growth factor 1. As predicted, when she incubated these cells without the factor, they began dying. However, they didn't exhibit predictable features of apoptosis.

Concerned that she was doing something wrong, Sperandio consulted her boss, Dale E. Bredesen. He says that after one glance, he saw that Sperandio had triggered in the cells a process that "didn't look anything like apoptosis."

Typically in apoptosis, the membrane of a dying cell softens and blebs balloon out. Meanwhile, the cell's nucleus shrinks and then divides. Eventually, the cells break into large fragments, which the body's roving cleanup crews discard. Enzymes, called caspases, trigger this apoptosis.

However, the cells that Sperandio created were doing something different. There was no membrane blebbing, no fragmentation of the nucleus, and no cell breakup. Moreover, chemicals that inhibit apoptosis didn't prevent the cells' suicide.

Instead, the cells were swelling and developing large bubbles, or vacuoles, with liquid inside them. These cells, Bredesen recalls, resembled a condition that other biologists had periodically described as "type 3 cell death" since at least the early 1970s.

In the Dec. 19, 2000 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, Sperandio, Bredesen, and their colleagues declared this a novel kind of cell suicide, dubbing it paraptosis. …