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We tend to think of biology as the study of life, but a growing number of biologists are dancing with the devil to uncover the players in a game called cell death. An injury kills cells by physical damage that sets off related discomfort in surrounding tissues, but the vast majority of the body's cells die painlessly in altruistic suicides that benefit the organism. During this programmed cell death - coined apoptosis in 1972 - a cell destroys itself from within, preserving its plasma membrane to prevent the inflammation that accompanies necrotic, or traumatic, cell death. This mechanism plays a role in such diverse processes as brain development, how the immune system fights foreign materials, and ways to treat and beat cancer.
To get familiar with this field, Apoptosis Online serves as a good starting point. This site provides several informative categories to explore: Apoptosis Forum offers discussions of recent research, Career Connection provides searchable postings, and Reference Library contains reviews of books and journals. Perhaps the most useful section is Community Center, which compiles information on funding opportunities, including available grants and deadlines. This site also lists upcoming scientific meetings relevant to the field, identifies funded research projects and their administrators, and includes its own set of Web links. This site is interactive in that it encourages user submissions of information or links.
Initially apoptosis became obvious during development when tadpoles systematically lose their tails. Over the last 20 years, however, scientists discovered the pervasive nature of cell death in multicellular organisms, and the field of apoptosis research exploded. One barometer of this burgeoning interest in programmed cell death is the increasing availability of information and resources on the Web. Cyberspace provides links to every aspect of apoptosis, from the most recent discoveries in the field to the products used to make these discoveries, and everything in between.
The Apoptosis Interest Group at the National Institutes of Health provides another general interest site. In addition to a terrific introduction to the field of apoptotic mechanisms, this site provides information on the Washington, D.C. area meetings of the group. If New York City lies closer to home, the Cell Death Society's site offers several kinds of information, including summaries of recent meetings, book reviews, and links to apoptosis journal articles and reviews (see this issue's Site Review for more information).
The normal development and function of an organism, as well as protection against pathogenesis, depends crucially on apoptotic cell death. Embryonic apoptosis saves humans from being born with webbed fingers and toes, and as many as half of the brain's neurons die as the developing nervous system forges proper connections. Even as adults, our cells die constantly and get replaced according to a grand pattern. For example, dramatic cell death occurs in women following lactation, when breast tissue gets reabsorbed. Apoptotic death also destroys cells that threaten an organism.
Extracellular signals also control the fate of cells. An apoptosis-inducing
signal, for example, can kill even seemingly healthy cells. The harbingers
of doom to cells include small molecules, such as tumor necrosis factor and
the Fas ligand, that bind to surface receptors. For more information on any
of these molecules, visit John Kimball's online summary.
Despite the universal involvement of caspases, multiple routes lead to
apoptosis. These often include a cascade of signals, which are susceptible
to multiple levels of control. Viruses often throw wrenches into the system,
and many cancers disable apoptosis on the route to malignancy. Humans want
to get in on this game, and a number of biotech companies are making it
their aim to outsmart cells. Protecting against unwanted cell death might
treat neurodegenerative diseases, including Parkinson's and Alzheimer's, and
it might also contribute to the cocktail of therapies being used to combat
HIV's attack on immune system cells. LXR
Biotechnology aims to prevent the apoptosis that results from heart
attacks and strokes, possibly due to the lack of oxygen available to cells
in these circumstances.
Many biological supply companies sell reagents for dissecting the details of
apoptotic signaling. Companies make a wide variety of kits for diagnosing
apoptosis through a number of methods including detecting DNA fragmentation
and quantifying downstream apoptotic markers, as well as caspase assays with
varying degrees of specificity. Laura DeFrancesco recently reviewed the kits
on the market in The
Scientist, and her article is available online. In addition, there are a number of
apoptosis promoters and inhibitors on the market. For a list of companies
that offer apoptosis products and links to their Web sites, visit the SciWeb Center for
Apoptosis Information. To get a handle on these methods, turn to
Beohringer Mannheim's Guide to Cell Proliferation and Apoptosis Methods, which provides
downloadable methods files available directly from its table of contents.
This is only a sample of what's available in the online world of apoptosis.
Cell death is alive and well on the Web.
Cells accomplish apoptosis in various ways. For one thing, internal
circumstances can trigger the cell death program. For instance, a cell with
severely
damaged DNA initiates an apoptotic pathway that depends on a tumor
suppressor called p53. Another
example arises from the progressive shortening of telomeres at the
chromosome tips, which occurs with each round of cell division. This
phenomenon might provide an intrinsic biological clock that limits the
longevity of a cell lineage. In laboratory cell cultures, most cells divide
only about 50 times before undergoing apoptosis. Nevertheless, these
intrinsic mechanisms fail in cancer cell lines that are immortal.
How do these diverse signals result in the same program of cell death? A soil nematode known as Caenorhabditis elegans offered the first molecular clues to apoptotic signaling. The successful apoptosis of 131 specific cells of the adult worm depends upon several cysteine proteases known as caspases. Although the founding members of this family belong to the worm, all known apoptotic signals result in the aggregation and activation of similar enzymes. These proteases activate each other, as well as additional substrates, and cause characteristic self-destructive events, including cell shrinkage, membrane blebbing, and DNA degradation. One can see what this looks like at CellsAlive!.
More research, however, centers around inducing apoptosis to kill unwanted cells as part of treating cancer. Current nonsurgical therapies often use DNA-damaging agents to induce apoptosis in all the body's dividing cells. This indiscriminant cell death causes a number of unpleasant and dangerous side effects, including immune suppression. Therefore, considerable interest surrounds the search to understand and harness the specificity of apoptotic
signaling that allows for the survival of some cells and the death of
others. By inhibiting the growth of blood vessels, for example, companies
such as TAP Holdings and Ixsys hope to target
cancers with oxygen deprivation, which can cause cells in a tumor to undergo
apoptosis. Cell Pathways and Genentech are developing drugs that activate
receptor-mediated apoptosis specifically in cancer cells. Idun Pharmaceuticals hopes to find drugs that
will activate downstream caspases.
Kate Winkler is a graduate student in the Department of Pharmacology and the Cell and Molecular Biology Program at Duke
University, where she studies the cell division cycle.
Endlinks
Apoptosis Activity - this article in The Scientist, by Ricki Lewis, gives an overview of the development of cell death research.
Apoptosis Research Group - the National Research Council of Canada's Institute for Biological Sciences provides details on various areas of ongoing research.
Cell Cycle Mailbase - a news, chat, and mail site that covers cell-cycle-related concerns, including apoptosis.
Dynamic Development's Brief Introduction to Apoptosis - this text/lecture supplement, maintained by the University of Calgary, pays special attention to a few molecular participants: bcl-2/ced-9, ice/ced-3, p53, and the Fas ligand.
PharMingen - offers a colorful, free poster entitled "Apoptosis Signals." Visit their Web site to preview and order it. They also sell products for apoptosis research.
SciWeb's Center for Apoptosis Information - compiles information for apoptosis researchers. Includes a discussion group, meeting announcements, and links to companies' apoptosis Web pages. Uniquely, it also offers information on apoptosis-related patents, clinical trials, and FDA documents.
Web sites mentioned in this column:
Forensic Biology 
Molecular Modeling: Internet Resources for Biologists
Science News on the Net: Fast Food, Bistro, or Order In
Pixels at an
Exhibition
Complex Systems
in Biology
A Billion Base
Pairs
Up for Grabs