Programmed Cell Death is Alive and Well
Time was, in the late 1990s, when you could barely move in the Biology Top Ten without tripping over papers about apoptosis. That’s the mechanism whereby cells die (or commit suicide) in a tidy, regulated fashion, as opposed to the far messier cell death described as necrosis. Apoptosis is crucial in development, for example killing off the cells between the fingers and toes to separate the individual digits. It is also vital in day-to-day human life, with an estimated 50 to 70 billion cells dying neatly each day, an annual turnover that roughly equals body weight. And when out of kilter, it is responsible for cancers and other diseases. Today, papers on apoptosis are much rarer in the Top Ten, but according to Douglas R. Green, one of the most highly cited researchers on the topic, “this is hardly surprising.”
Apoptosis, as a word, has seen some controversy over how to pronounce it. The authors of the original 1972 paper that coined the term were in no doubt (J.F.R. Kerr, et al., Brit.J. Cancer, 26: 239-57, 1972). In a footnote, they noted that “the stress should be on the penultimate syllable, the second half of the word being pronounced like ‘ptosis’ (with the ‘p’ silent), which comes from the same root ‘to fall’, and is already used to describe the drooping of the upper eyelid.”
Green, chair of the immunology department at St. Jude Children’s Research Hospital in Memphis, Tennessee, tells ScienceWatch that “when the mechanisms of apoptosis were ‘new’ they received widespread citation, most often in the introductions of papers on other topics. As the field matured, the cutting-edge papers were cited predominantly by other experts in the field, and thus the ‘impact’ declined. Apoptosis has reached a state ... where it is no longer necessary to reference the term or specific publications.”
The attached graph, tracking occurrences of the word “apoptosis” in Thomson Reuters-indexed papers since 1990, would seem to support this observation. The graph separately charts the word as a “topic” term in the Web of Science (that is, in a paper’s title, abstract, or keywords) compared against appearances strictly in the title.
From beginnings well shy of 100 papers in 1990, both lines on the graph rise steeply through the decade, reflecting the interest and attention that made apoptosis such a Top Ten fixture for those years. Toward the end of the1990s, however, the “title only” line begins to flatten, thereafter rising modestly to a high near 6,000 reports in 2005 before slipping back below 5,000 on an apparent downward trajectory. The “topic” line, meanwhile, climbs continuously, racking up ever-increasing numbers that exceeded 23,000 in 2011. The graph suggests that, although perhaps waning as a principal topic of investigation, the phenomenon of apoptosis continues to figure robustly in large and increasing numbers of reports each year.
MOMP AND CIRCUMSTANCE
The mechanisms of apoptosis are indeed no longer new, and are now reasonably well understood. A pivotal event is known as MOMP, for mitochondrial outer membrane permeabilization. Mitochondria are the energy factories inside cells. MOMP causes molecules from inside the mitochondria to leak out into the cytoplasm. Indirectly, this can kill cells by disrupting energy metabolism. A more targeted pathway sees cytochrome c, a crucial element in energy metabolism, interacting with apoptotic protease activating factor 1 (Apaf-1), which then activates a cascade of caspases that destroy most of the cell’s important molecular machinery. The broken-up bits of the cell are bundled up into chemically labeled apoptotic bodies, which enables the immune system to recognize and remove them quickly and efficiently.
Apoptosis is a feature of all vertebrates, and although similar processes had been noted in invertebrates (indeed, apoptosis in the nematode worm Caenorhabitis elegans was the subject of the 2002 Nobel Prize in Physiology and Medicine), MOMP did not appear to play a role in nematodes or Drosophila. A 2012 paper by Green and his colleagues shows that the mitochondrial pathway is present in a planarian worm and in sea urchins. Furthermore, apoptosis-regulating proteins from the planarian are functional in yeast and in mammalian cells. Most likely, the full mitochondrial pathway is ancestral to all multicellular animals, parts of it having been lost in nematodes and Drosophila.
As for plants, the word apoptosis is derived from a Greek root, which denotes the dropping off of petals from flowers or leaves from trees, and processes very like animal apoptosis are important in plants. Mitochondria are equally important in plant programmed cell death, although there is no immune system to remove the bits of dead cell. Programmed cell death may play an important role in preventing inbreeding in some plant species, where a protein in the pistil interacts with a receptor in the pollen tube of incompatible pollen, resulting in the death of the pollen.
Many different stimuli converge on the mitochondria to trigger MOMP. These include extracellular signals such as toxins, growth factors, and hormones, as well as factors associated with T lymphocytes fighting off infection. Intracellular stimuli are generally related to damage caused by heat, radiation, viral infection, lack of oxygen and many other factors. Crucial roles in the apoptotic pathways are played by members of the Bcl-2 family of proteins, some of which promote apoptosis and some of which inhibit it. These Bcl-2 family proteins have been implicated in certain types of cancer, and changed the prevailing view of cancers. Before the identification of Bcl-2, cancer was thought to be a process of runaway cell proliferation, too much growth; the accelerator, if you will, was stuck on. Oncogenic mutations to Bcl-2 genes that promote apoptosis showed that “proliferation” could also be the result of too little death; the brakes are not working.
Small molecules that can affect the apoptotic pathways, often by acting on Bcl-2 family proteins, have thus been a major target of approaches to therapy, not only of cancers but also of neurodegenerative diseases, HIV-AIDS, and some of the consequences of ischemic heart disease and stroke. Bax and Bak, two members of the Bcl-2 family that promote apoptosis by allowing molecules to escape from the mitochondria, are being intensively studied. And new types of programmed cell death are being uncovered. Necroptosis is a caspase-independent type of programmed cell death that seems to be particularly important in regulating the very rapid turnover of cells lining the gut, and that may be important in maladies like Crohn’s disease, as discussed in these papers from Nature Medicine and Gut. Another well-organized cell-death process that does not resemble apoptosis requires the presence of iron in the cell, for reasons still unknown, and has been called ferroptosis. This process may have a role in killing cancer cells when active and in protecting against neurodegenerative diseases when blocked (e.g., Cell.)
So the field is by no means dead, even if it is no longer getting the citations needed to propel it into the Top Ten. In addition to the maturity of the basic science, as applications of apoptosis move into the clinical realm (see, for example, Nature), citations to the original discovery literature decline. Simply put, there’s no need. Douglas Green calls this “an unfortunate aspect of citations.” Unfortunate, perhaps, but also normative: Sociologists and historians of science, using the phrase credited to Robert K. Merton in the late 1940s, have long referred to this phenomenon as “obliteration by incorporation.”
As Green tells ScienceWatch, “Scientists do not sufficiently tout the extent to which basic developments lead to cures, since the time lag from basic findings to ‘on target’ clinical application is often so long that the basic findings have entered the textbooks and are no longer ‘surprising’. This leads to the general idea that basic research may not be absolutely fundamental to clinical advance, which is a sad misinterpretation of the reality.”
Dr. Jeremy Cherfas is Senior Science Writer at Bioversity International, Rome, Italy.
The data and citation records included in this report are from Thomson Reuters Web of ScienceTM. Web of ScienceTM is a registered trademark of Thomson Reuters. All rights reserved.