The human body is composed of 10 trillion cells. Each day billions of cells die and are replaced by fresh cells. The birth and death of cells must be perfectly balanced. If cell birth exceeds death, organs enlarge and cancer results. If death exceeds birth, organs degenerate, as in Alzheimer’s disease. The factors controlling cell birth have been studied for many decades and much has been learned. In contrast, cell death was considered a random event until the studies of Horvitz in roundworms revealed a gene-determined control mechanism called programmed cell death. Although the phenomenon was recognized, the biochemical mechanism was obscure until Xiaodong Wang showed that the executioner is an internal organelle, the mitochondrion, which was previously thought to function only as an energy generator.

Every nucleated animal cell contains many mitochondria, which are tiny membrane-bound structures filled with enzymes that oxidize foodstuffs and generate high-energy chemicals. When a cell is programmed to die, the mitochondria release proteins that trigger cell death. One such protein, cytochrome C, was long known as an essential component of the energy-generating system. Using clever biochemical measurements, Wang showed that mitochondria-derived cytochrome C binds to a cytosolic protein, Apaf-1, thereby activating a protease called caspase-3. Activated caspase 3 triggers a cascade of reactions that lead to fragmentation of nuclear DNA, dissolution of the cell membrane, and engulfment of the dying cell by neighboring scavenger cells. Cells resist the suicidal action of cytochrome C by producing proteins called IAPs that block the caspase. Wang showed that mitochondria overcome this resistance by releasing another protein, Smac, which neutralizes the IAPs, permitting cell death to proceed to completion. Wang also discovered a mitochondria-derived nuclease that assists in the fragment of nuclear DNA.

Wang’s discoveries have profound implications for therapeutics. Companies are hard at work developing drugs that block the lethal actions of the mitochondrial proteins. Such drugs might prevent cell death in conditions like myocardial infarction and ischemic strokes where cells are programmed to die in response to hypoxia. At the other extreme, cancer cells survive by producing proteins that block the mitochondrially derived proteins, thereby preventing programmed cell death. Pharmaceutical companies are developing drugs that mimic the mitochondrial death-inducers, thereby overcoming the resistance of the cancer cells and eliminating the cancer.

Because of Wang’s work and that of others in the field (most notably the late Stanley Korsmeyer) programmed cell death is now understood mechanistically as well as programmed cell birth, thereby restoring the balance necessary for a complete understanding of animal life.

Life Science and Medicine Selection Committee
The Shaw Prize

12 September 2006, Hong Kong