Apoptosis and elephants

Apoptosis, the molecular biology of programmed cell deathEdited by Michael D. Jacobson and Nicola McCarthy.Oxford University Press, 2002. US$60.00 (304 pages)ISBN 0 199 63849 7We've all heard the Sufi parable of the blind men and the elephant – how each describes the beast as something different – and we've seen it applied as a cautionary tale when we seek to unravel scientific mysteries. But there might be an alternative version that is just as cautionary: several blind mullas are told they are touching an elephant. In reality, each has been presented with a completely different item (a tree, a snake, the wall of a house, a rhinoceros), but they all believe that they have their hands on the same beast. Similarly, some widespread biological processes might have divergent mechanisms even when they have a common evolutionary origin.Cell death has been a subject of study for at least a century, and of intense (and very successful) investigation for more than a decade. Tens of thousands of papers have been written on the subject, and the neophyte who enters this veritable morass of information is in danger of sinking, or at the very least losing their way. A popular solution to the problem (in this and many other boisterously active fields) is to obtain an up-to-date guide – usually in the form of a collection of short review chapters – to gain perspective and navigate the tricky terrain. One such collection is the volume considered here. As in all collections of this kind, the tacit assumption is that each chapter deals with at least one part of the elephant.This volume, edited by two respected workers in the field, represents a collection of reviews dealing (for the most part) with the process of apoptosis. In general, the contributors are specialists in the field they overview, and although coverage is uneven, they are largely successful in providing a fairly detailed discussion of aspects apoptosis, at least for research extending through 2000.This is a problem. The time necessary to write, assemble, edit, and print such a volume (as opposed to a much more rapid publication type), which hopes to cover up-to-the-minute developments in a fast moving field, renders many of the reviews out of date before the collection hits the presses. In only one case was an attempt made (and a good one) to update the developments to 2001, and this in a chapter addendum. Throughout much of the book there are errors and miscalculations that we now regard as unlikely or fully wrong. A newcomer to the field (for whom this was allegedly written) might become confused in the process of separating fact from some of the fiction (the last is too harsh, it is not ‘fiction’, but rather ‘based on a true story’).There are some outstanding reviews in this compilation, and it is not my goal to belittle the very real (and often successful) efforts of the authors and the editors. But in this era of ready-access to a myriad of rapid publications, including innumerable review articles, it might be time to consider whether works of this type continue to serve an important purpose. The goal (as stated) was to produce a highly accessible overview of the field for the unenlightened, keeping it as current as possible and filled with new (or fairly new) observations. However, science generally doesn't work like that: new findings and ideas are risky, and could turn out to be wrong. Overviews of recent developments can be very useful, provided we have them in hand while they are still recent, but with time we often have to discard some findings as spurious (or at least, not ready for prime-time).Unfortunately, at no point is an attempt made in this book to indicate which statements and positions are widely accepted, versus opinions of the authors (and by now, possibly no longer opinions); or which statements are stand-alone observations versus well documented findings. This is a weakness that is by no means unique to this volume. Arguably, it is unfair of me to indict this collection when it clearly follows the model established by so many of its kind.Let us return to our elephant: the process of apoptotic cell death, especially as presented here. Are we all studying the same beast, or do the parts only appear to fit together? The field of apoptosis emerged from the observations of pathologists on different types of cell death and their consequences. The classic work of Kerr, Wyllie and Currie that defined apoptosis, arose on a foundation of embryology that established roles for cell death in animal development. In the late 1980s, as molecular approaches to the elucidation of the mechanisms underlying the cell cycle paved the way to dissection of other cellular processes, the study of apoptotic cell death entered a renaissance that continues today. This has been fueled by outstanding biochemical, genetic, and cellular studies that began to unravel the complexities of the process. Undoubtedly, one key set of investigations was the elucidation of the genetic basis of programmed cell death in Caenorhabditis elegans, which (among other notable discoveries) gave us the caspase proteases and their role in apoptosis. In one of the best overviews in the volume and one of the best I've read on the topic, Xue et al. review the genetic control of cell death in C. elegans. Several other chapters also review the topic in a superficial way as a prelude to their main topics, even though it contributes little to the subject (especially when an excellent and detailed account is provided in the same volume).Another notable contribution is the chapter on cell death in Drosophila by Bergeron and Steller, which is lucid and fairly complete (again, considering the time problem), and which takes some pains to present contrasting viewpoints. Similarly, the chapter on Bcl-2 family proteins by Tsujimoto successfully covers the area, but with a strong author's bias. Other chapters are somewhat less successful, for example, the chapter that covers the TNF-receptor family by McCarthy and Bennett. It actually provides a very good overview on each receptor. However, because the majority of these have little or nothing to do with apoptosis, much of this chapter will not be valuable to those hoping to understand how (and when) the subset of receptors that do effect cell death function physiologically. The review on caspases by Roy and Cardone goes into considerable detail in identifying caspase substrates, but does not consider that many of these might play little or no role in apoptosis (as the cell is dying anyway, irrelevant substrate cleavage might be, well, irrelevant). A more detailed discussion of the biochemical basis of specificity (and guidelines for identifying such sequences) would have been welcome. Perhaps most disappointing in some ways, was the introductory chapter: ‘Why be interested in death?’ The answer seemed to be because (a) it is essential for life (but often, it isn't); and (b) because lots of people seem to study it. Hopefully, someone who picks up this book would not need to ask this question!Some important omissions include: consideration of the process of phagocytosis in apoptotic cells (discussed for the nematodes, but not other organisms); caspase-independent cell death (discussed in passing in the chapter on mitochondria, but perhaps deserving of more attention); the inhibitor of apoptosis proteins (superbly reviewed by Vaux in other works, but only fairly superficially here in his chapter on viruses); and apoptosis in mammalian systems other than the brain (well discussed in a chapter by Jacobson and Bergeron).Apoptosis exists in all animal cells, but is all apoptosis the same? Caspases are essential for many cell deaths in C. elegans and Drosophila, but might be largely dispensible for cell death in vertebrates. Mitochondrial outer-membrane permeabilization and death-receptor pathways are extremely important in vertebrate cell death, but might not have roles in nematodes or insects. Anti-apoptotic Bcl-2 proteins block the caspase adapter protein Ced-4 in worms, but do not inhibit its homolog, Apaf-1, in vertebrates, and might not even exist in insects.As we continue to probe the process of apoptosis, each examining our own part of the elephant, we might yet find that we are elucidating related, but essentially different processes that do not necessarily inform us about apoptosis in other animals. Once we appreciate this, the richness of the process and its evolution will start to reveal itself and could lead us in exciting new directions.This volume, like many of its kind, will be of the most interest to specialists who might like to see what their colleagues were thinking a couple of years ago. But in a rapidly developing field like this, it would better serve students and other interested newcomers to peruse recent reviews in the field.