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Abstract
Researchers still can't agree on how to pronounce it, and many continue to argue over its definition, but with 10,000 new papers published about it each year, apoptosis - a form of programmed cell death - is one of the hottest topics in biology.
Since Andrew Wyllie and colleagues coined the term in 1972, the pace of research aimed at elucidating how and why cells decide to kill themselves has grown exponentially. Each day about 10 billion cells in a human body must die simply to make room for new cells produced for ordinary maintenance. The name for those that refuse to die or to stop multiplying on schedule is cancer.
If apoptosis were fully understood, new treatments for cancer, heart attack, stroke, Alzheimer's, and hepatitis - and even ways of postponing such aspects of aging as menopause, wrinkles, and baldness - might be developed.
But the process is extraordinarily complex, and even the 50,000 papers so far published on the topic don't fully explain it. Scientists have a pretty good handle on the central process by which many cells die and have identified some of the signals that tell a cell to commit suicide; but how these signals trigger the central mechanism, how particular types of cells are targeted for death or for protection from death, and at what point a cell is beyond salvation are still unclear.
"We now have a good understanding of the core execution programs," says Barbara Osborne, professor of biology in the Department of Veterinary and Animal Sciences at the University of Massachusetts at Amherst. "And by that I mean cells get signaled to die and something happens. We don't understand what, but we do know the central core pathway, and elucidating that is the most important advance in the last few years."
Apoptosis was first described based on morphology, as a series of events that lead a cell to die in an orderly way - as opposed to chaotic death or necrosis, which results from injury or cell malfunction. Apoptosis can start either with a message from a "death receptor" (in humans, tumor necrosis factor receptors) or with a message from within the cell. The cell's energy stores, the mitochondria, then leak cytochrome c, which binds Apaf-1 (apoptosis-activating factor). Next, caspase enzymes take over: The "caspase cascade" triggers a protein called caspase-activated DNase to cleave the cell's DNA, which can then be seen as tiny "ladders" floating in the cell.
Osborne describes watching the process in lymphocytes, which are very sensitive to cell death signals - presumably because many lymphocytes have the potential to attack the body if not controlled. "It's beautiful," she says. "The cells are normally round, and little pieces pinch off; you see little bubbles at the surface." This process is called blebbing, a word that seems to capture perfectly what it looks like.
Once the DNA has been cut, the cell sends signals to attract nearby immune cells, which consume the dead cell. Apoptosis prevents harmful contents of the dying cell from leaking out and hurting surrounding cells - unlike necrotic death, which leads to inflammation and can trigger apoptosis in previously healthy neighboring cells.
In fact, many of the cell deaths in heart attacks, liver disease, and stroke occur because damaged cells set off apoptosis in surrounding cells. Research in rats suggests that half the cells that ordinarily die in the course of a stroke can be saved by treatment with caspase inhibitors. Some research also suggests that arteriosclerosis may be due in part to the failure of certain cells to undergo apoptosis - and, conversely, that death from the massive infection septicemia may result from excessive apoptosis.
Apoptosis also plays a role in many neurodegenerative conditions, such as Alzheimer's disease. Neurons are particularly sensitive to apoptosis via the process of excitoxicity, which occurs when too many excitatory neurotransmitters are sent from one cell to the next. Various types of brain damage, whether caused by head injuries or disease, might be alleviated by interfering with this process.
The potential for cancer treatments based on controlling programmed cell death is also immense, since many tumors result from the failure of damaged cells to kill themselves. New drugs and gene therapies are being developed (and in some cases, are already in clinical trials) to target those cells and direct them to die. This could eliminate most of the side effects associated with ordinary chemotherapy and radiation treatments, which are relatively nonspecific and kill healthy as well as cancerous cells.
Developing organisms also rely heavily on apoptosis to remove cells that aren't needed, such as those making up the webs between fingers in fetuses, or excess brain cells that serve only to guide others or that fail to make the connections required for function.
Malfunctions in apoptosis may also play a role in schizophrenia, which is now believed to be largely a neuro-developmental disorder. If the signaling required for neural apoptosis were thoroughly understood, perhaps this and other developmental defects could be prevented or mitigated.
Researchers have long wondered about the role of apoptosis in aging and whether aging results from cell suicide. It's clearly more complicated than that - for instance, worms engineered to lack apoptosis actually die earlier than normal worms - but such signs of aging as wrinkling and hair loss, among others, do involve large-scale apoptosis.
Aptly, in modern Greek "apoptosis" means balding or hair loss, though the word was taken from ancient Greek, where it refers to the dropping of leaves from trees.
Though it is still hard to imagine how a "death program" could evolve, one theory posits that it developed soon after proto-mitochondria merged with other single-celled organisms to create multicellular life. When resources are low, some bacteria emit toxins in order to kill off their neighbors and reduce competition for food. If mitochondria had a similar ability, multicellular organisms could have commandeered the process as a way to get rid of unneeded cells.
However it evolved, apoptosis is now an important link between sex and death. To become complex and specialized, organisms had to segregate their reproductive DNA from that used in day-to-day living. To regulate such complexity, it was inevitable that some cells would need to be sacrificed for the good of the whole - so a process like apoptosis was required.
In place of the effective immortality of early single-celled creatures, which produce offspring identical to their predecessors, multicellular organisms began to reproduce by sexual recombination. And, according to William Clark, emeritus professor of immunology at the University of California at Los Angeles and author of A Means to an End: The Biological Basis of Aging and Death, the reproductive DNA "doesn't give a fig" what happens to the somatic cells (our bodies) once sufficient offspring have been produced.
And fertility itself is also regulated by apoptosis. A woman is born with all the eggs she will ever have. Though she starts with millions, she usually runs out by her forties, and the apoptosis of her last egg sets off menopause. Jonathan Tilly, associate professor of obstetrics, gynecology, and reproductive biology at Harvard University School of Medicine, was able to block a similar process in mice by preventing their oocytes from killing themselves; the mice later gave birth to normal litters. Research with human egg cells is under way.
Researchers are currently trying to elucidate the role of mitochondria in apoptosis - which is still unclear, according to Doug Green, director of the division of cellular immunology at the La Jolla Institute for Allergy and Immunology. Green asks, "Is the mitochondrion a machine [in this process]? Is it a switch, or is it just a bag of cytochrome c floating around? We still don't know."
Tilly's group published a paper in Nature [1] last year that showed that adding just 5 percent more mitochondria to mouse eggs, which normally have a high rate of apoptosis, cuts their death rate nearly in half. "Mitochondria can certainly impact the decision to die," he says.
Interestingly, researchers investigating a fertility technique that mixes the cytoplasm of an oocyte from a young woman with nuclear DNA from an older woman have recently found that the resultant babies have mitochondrial DNA from both women - in essence, they have three parents.
If effective control of apoptosis is achieved, it could be put to a number of other creative uses. Tilly suggests, for instance, that apoptosis-based contraceptives could send cell death signals to only the eggs a woman would normally ovulate in a particular month, leaving her free of pregnancy risk for that month but able to conceive later.
Programmed cell death also plays a key role in the immune system, which must constantly generate and eliminate cells for particular tasks and which frequently creates dangerous cells as the result of recombinations undertaken to provide maximum diversity of disease-fighters. There is some controversy over the role of apoptosis in HIV disease - but learning to control apoptosis could lead to a variety of treatments for viral and autoimmune disorders.
Says Zahra Zakeri, professor of biology at Queens College in New York, "If we had our dream and understood all about cell death, you could kill cells you didn't want, like cancers [or] cells with viral infections. You could prevent deaths in cells you wanted in degenerative diseases, infarctions, and stroke. [The enormous number of possibilities] is what makes it so interesting."
But William Clark is less enthusiastic about the prospects of controlling apoptosis to fight human disorders. He thinks it's better to interfere before cells start dying.
"Apoptosis is such a widespread phenomenon in the body," he says. "It's used in so many places and we don't know how to affect one place without screwing up another. Any drug developed that influences apoptosis throughout the body may end up doing more harm than good." For example, a drug that prevented apoptosis to save brain cells from stroke might cause cancerous cells elsewhere that would ordinarily die to live and thrive.
"It's like the story a few years ago about telomerase," Clark says. "People thought, Restore the ends of telomeres, immortality at last. But if you reactivated telomerase, you'd turn into a giant tumor. It's like apoptosis, so widespread. It's worth studying and learning about, but I think in terms of practical uses, it may be very limited."
Only time, clinical trials, and another 50,000 or so papers will tell.
Maia Szalavitz is a health/science journalist who has written for the New York Times, the Washington Post, Newsday, New York Magazine, Salon, and other major publications.
Cary Barnhard grew up in New Jersey, where his senior class voted him "most unique." He maintains that honor is a polite way of being voted "most likely to need therapy." After a few misadventures in the music industry, he started pretending to be a graphic artist. Eventually it became the truth.
Apoptosis - a general overview from Kimball's Biology Pages.
Apoptosis (Programmed Cell Death) - annotated links from the WWW Virtual Library of Cell Biology.
Apoptosis-DB.org - "a bioinformatics resource for apoptosis researchers," includes annotated databases of proteins involved in programmed cell death.
Cell Death Society - a resource for researchers, with job listings, meeting information, and more.
Mouse Strain Keeps Ovaries Running Into Old Age, Can Women? - an article about the work of Jonathan Tilly and others. From the February 5, 1999 issue of Focus.
W.R. Clark Books - includes articles written by William R. Clark on aging and cell death and information about his books.
The Role of Molecules that Mediate Apoptosis in T-cell Selection - discusses programmed cell death in the generation of the T-cell repertoire. From Trends in Immunology, 2001, 22(2)107-111. Full text available from BioMedNet.
Molecular Mechanisms of Apoptosis in the Cardiac Myocyte - reviews recent findings and their potential to help in the treatment of heart disease. From Current Opinion in Pharmacology, 2001, 1:2:141-150. Full text available from BioMedNet.
A Mitochondrial Perspective on Cell Death - discusses current research efforts and hypothetical mechanisms of mitochondrial action. From Trends in Biochemical Sciences, 2001, 26:2:112-117. Full text available from BioMedNet.
Life-or-Death Decisions by the Bcl-2 Protein Family - reviews the complex roles played by Bcl-2 family members. From Trends in Biochemical Sciences, 2001, 26:1:61-66. Full text available from BioMedNet.
Selective Inhibitors of Apoptotic Caspases: Implications for Novel Therapeutic Strategies - focuses on non-peptide inhibitors of caspases 3 and 7. From Drug Discovery Today, 2001, 6:2:85-91. Full text available from BioMedNet.
Drug Discovery Opportunities from Apoptosis Research - considers how recent findings may lead to new treatments. From Current Opinion in Biotechnology, 2000, 11:6:586-592. Full text available from BioMedNet.
Mitochondria as the Central Control Point of Apoptosis - considers the role played by mitochondria and the Bcl-2 family of proteins. From Trends in Cell Biology, 2000, 10:9:369-377. Full text available from BioMedNet.
Mechanisms of Programmed Cell Death in the Developing Brain - reviews evidence for multiple roles of apoptosis during brain development. From Trends in Neurosciences, 2000, 23:7:291-297. Full text available from BioMedNet.
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