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Cells die so that other cells may live. Every day in an orderly, programmed way, cells commit suicide in a vital physiological process known scientifically as "apoptosis," from the Greek word that means the yellowing and falling of leaves from a tree. The molecular programming of the death of cells is neither random nor left to chance. But when apoptosis fails, disease often follows.
The study of apoptosis is currently among the most exciting in molecular biology. Programmed cell death or suicide is now thought to play an important role in cancer and AIDS, in the development of the nervous system and in such immune system disorders as rheumatoid arthritis. Although scientists have known about apoptosis for years, interest in this phenomenon, which is biology's way of assuring cell renewal, lay dormant until the 1970s. Today, it seems, nearly every laboratory that is studying molecular medicine is thinking about apoptosis in one way or another.
Apoptosis occurs in virtually all species of mammals, from worms to humans, and is controlled by a class of genes whose function is to induce or prevent cell death. The suicide gene, called Fas, produces a protein that sits on the surface of a cell, ready to trigger the cell's demise when it receives the appropriate biological signal. The phenomenon is fascinating to watch -- or imagine. The dying cells shrink, as their membranes or outer walls fill with fluid. Nearby cells then digest their dying neighbors. Because of technological developments, it is possible to measure apoptosis in the laboratory, either by determining the percent of dead cells in a given population or by counting the number of cells that contain the Fas gene, which tells us they are genetically programmed for destruction.
Let me describe the role of apoptosis in two fields where the sense of scientific drama is especially high: viral diseases, including AIDS and some forms of cancer, and autoimmune diseases in which the body turns against itself.
AIDS is the result of infection by the human immunodeficiency virus (HIV) -- a virus with a remarkable ability to change its molecular shape at a rapid pace. Many cells undergo apoptotic death when they are exposed to viruses. The cell, once it becomes "aware" that it has been penetrated by a virus, commits suicide. In the process, it kills not only itself but also the virus, thereby stopping the virus from replicating and spewing forth new viruses to spread infection to other cells within the body. By a mechanism we only partially understand, HIV often subverts or outwits this natural protective process. The same is true in some cancers which produce proteins that disable the Fas gene that would otherwise cause healthy cell death.
One of the bad signs for a person with AIDS is a decline in the number of immune cells when they are infected and killed by HIV. But early in the course of the disease, this direct killing of what are known as T cells by the AIDS virus is insufficient by itself to account for the profound drop in cell count and the loss of immune function that follows.
Recently, we have learned that apoptosis gone awry also plays a part in the destruction of the normal immune response. A protein produced by cells that are infected by HIV is thought to enter uninfected T cells and induce cell suicide. Thus, to the misfortune of the patient, the AIDS virus is able to kill more T cells through apoptosis that it does through direct infection. Therefore, drugs directed not only at killing the virus but also at blocking the protein that induces apoptosis could be beneficial in the treatment of patients with AIDS. It is exciting, though unpredictable, research.
In my own area of research specialty (autoimmune disease), apoptosis is also an idea whose time has come, leading us to new appreciation of the mechanisms by which the immune system reacts against itself. These disorders include multiple sclerosis, rheumatoid arthritis and a less common disease known as Sjogren's Syndrome, which is a main target of research in my laboratory. In multiple sclerosis, the immune system, mistaking itself as "foreign" to the body, attacks and destroys areas of the brain, causing neurological deterioration. In rheumatoid arthritis, it is the joints that suffer. In Sjogren's Syndrome, the autoimmune attack destroys the glands that make tears and saliva.
There have been many unsuccessful attempts to isolate a virus or other agent as the cause of autoimmunity, but new leads in programmed cell death may take us farther along. An unusual strain of inbred mouse, known as MRL/pr, develops an autoimmune disease that combines the features of rheumatoid arthritis, Sjogren's Syndrome, and another disorder (systemic lupus erythematosus). The white blood cells in the MRL/pr mouse contain a mutated or abnormal version of the Fas gene and that, in turn, inhibits the natural process of apoptosis. These abnormal lymphocytes accumulate instead of dying off. The lymphocytes infiltrate the lining of the joints in rheumatoid arthritis and the tissues of the salivary and tear glands in Sjogren's Syndrome.
The discovery of the defective Fas gene in the MRL/pr mouse leads naturally to studies of apoptosis in patients. In my research with Sjogren's patients, we take a biopsy of the salivary gland for diagnostic purposes. The autoimmune process revealed in these tissues is the battleground where the immune system and its opposing force (still unknown) are fighting it out. The majority of the attacking lymphocytes in the patients' glands are the same cells affected in AIDS. We find that, in Sjogren's, these T cells contain the Fas protein, indicating a commitment to cell suicide. However, by measuring apoptosis in the tissues, we know that these cells are unable to die.
The consequences of blocked apoptosis are significant for the gland's destruction. The lymphocytes are stuck in the gland like a fly on flypaper. They appear to become relatively ineffective as immune defense cells and also block the entry of other helper T cells that, if able to enter the gland, could be more effective at defense. The mechanisms by which this process works currently occupy our scientific thinking.
Apoptosis opens up a new field of inquiry into some of the most important afflictions of humankind. Defective apoptosis now seems to be even more important than uncontrolled cell growth in explaining some malignancies. For instance, researchers have recently learned that many of the chemotherapeutic drugs used to treat cancer patients actually work by causing apoptotic cell death. In other words, they stimulate an intrinsic, natural cell process. In all the diseases we study, the hope is that because agents we may develop to affect apoptosis will affect a natural biological phenomenon, they may have few side effects. I hope we are right.
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