The Grand Finale

The formation of cells, tissues, and organisms is analogous to the construction of a building; it requires building blocks. Therefore, it is somewhat counterintuitive that the formation and maintenance of animals also requires massive demolition by cell death. Perhaps this is why the link between cell death and animal development lagged behind the appreciation of cell division's impact by many years. A new book by Douglas R. Green, Means to an End: Apoptosis and Other Cell Death Mechanisms, highlights discoveries of the past 30 years on the mechanisms that control programmed cell death.Green states in the Preface that this book is neither a monograph, nor an historical account, nor an exhaustive description of a field. Rather, the author focuses on the mechanisms underlying mammalian apoptosis, a form of cell death. This book gracefully covers a wide variety of subjects and, in my opinion, distills our knowledge of cell death into an accessible text that is both enjoyable to read and appropriate for a broad audience. Do not misunderstand the Preface, as readers will experience much more than a description of mammalian apoptosis. Although this may have been the original motivation behind the book, Green integrates our knowledge of cell death in diverse biological contexts and periodically detours into “just so stories” that present the author's entertaining thoughts about the evolution of apoptosis.The term programmed cell death is based on the observation that dying cells go through an ordered series of morphological changes. This, combined with a need for RNA and protein synthesis, suggested that cell death is controlled by a genetic program. Descriptive studies of normal and cancerous cells led to the definition of morphological forms of cell death. Apoptosis (type I cell death) requires two cells: the dying cell and the phagocyte that digests the dead cell with the help of the phagocyte lysosome—the equivalent of the cell trash can. Autophagic (type II) cell death depends on the dying cells' own lysosomes and a self-degradation process known as autophagy. Nonlysosomal (type III) cell death, also known as necrosis, is associated with membrane leakage and inflammation without any role for the lysosome.View Large Image | View Hi-Res Image | Download PowerPoint SlideThe revolution in our understanding of cell death, which Martin Raff in the book's Foreword accurately equates with the Big Bang, occurred when Robert Horvitz and colleagues performed screens to identify the genes that are required for programmed cell death in the worm Caenorhabditis elegans. These studies provided many important advances in our understanding of apoptosis, including a genetic parts list for cell death and an ordered pathway for how these parts interact and control distinct steps of these processes.Green confronts a description of the problem of how cells die by immediately “stepping into the deep end of the molecular pool of biochemical mechanisms that control cell death.” I had my doubts about this approach but confess that it works. A key advance that emerged directly from the pioneering studies of worms is that caspase proteases are key regulators of apoptosis in all organisms. These caspase enzymes cut cell proteins in a highly ordered manner resulting in the controlled disassembly of the cell. Work in many laboratories has led to an understanding of many of the proteins that are cut by caspases and of the biochemical mechanisms that control their activation. This subject occupies more than half the book, and this is appropriate given the importance of caspases and their regulation to cell death. The description of this complex subject is clear, comprehensive, and considers what is known about caspases in other organisms. This is an important side point, as it does not escape the author's attention that much can be learned by studying cell death in different organisms, and during the development of these animals—the topic of an entire chapter. Although the focus of this book is on cell death in mammals, our knowledge of cell death in other organisms is integrated at appropriate points, and the author weaves a tight and entertaining story that all biologists with a basic understanding of the principles of biochemistry and molecular and cell biology will appreciate.If wood, mortar, and bricks are equivalent to the cell cytoskeleton frame, then mitochondria are the furnace that converts fuel to heat our home. In addition to being the center of cell bioenergetics, mitochondria are important regulators of cell death, and many proteins have been reported to influence mitochondria and cell death. Among them are the Bcl-2 family of proteins that alter mitochondria by poking holes in their membranes. This process, known as mitochondrial outer membrane permeabilization (MOMP), releases key activators of the death-activating caspases, including cytochrome c.MOMP is central to the intrinsic cell death pathway, but this is not the only way that cells activate caspases. Cells also have death receptors on their surface that control the extrinsic death pathway. As with MOMP, the author describes in considerable detail these proteins and how they contribute to cell death. The understanding of caspase activation is important for many reasons, including that this may be exploited for disease therapies, such as in cancer.No book on cell death is complete without a discussion of how dead cells are cleared. This is an important issue, as the failure to recognize and digest apoptotic cells may have a profound impact on our immune system. The author accurately describes how apoptotic cells are recognized by the phagocytes that eat them, as well as the complex communication between these two cell types that culminates in delivery of the dead cell into the phagocyte trash can for degradation and recycling.Apoptosis dominates this text, and this is appropriate for multiple reasons. Although our knowledge of the mechanisms that control apoptosis are quite sophisticated, the study of nonapoptotic forms of cell death is in its infancy. In fact, the first mechanisms for the regulation of autophagic and programmed necrotic cell death have just been discovered. Although these forms of cell death must be important based on their presence in animals, we know little to nothing about their occurrence in mammals under physiological conditions. As a leader in the cell death field, Green recognizes that this is one of the up-and-coming areas of cell death research, and his inclusion of this topic is timely.Altered cell death has implications for numerous human disorders. Disease contexts for cell death are introduced throughout the text, including subjects such as autoimmune disorders. There is also a chapter dedicated to cell death and cancer, which seems appropriate given the intense research efforts at the intersection of these fields. The best example is work on the tumor suppressor p53. Although this could be the subject of an entire book, the author focuses on several important highlights that are appropriate to the broad target audience of this text.The book ends with a vision for the future. Here the focus is on testing models of cell death and the development of ways to make cells live and die. These issues are critical to the development of disease therapies, and a reasonable way to end a book about this field.A major strength of the book, in addition to its writing style, is the breadth of coverage, which I think accurately reflects the current status of our understanding of cell death. It is worth noting that the illustrations and figures are appropriate and helpful, and the reading lists at the end of each chapter are useful additions for readers that want to learn more about specific topics. Green covers more territory than many specialized books and does this by elimination of detail. Because of this approach, the book is a must read for students, clinicians, and experts in other fields wanting to learn more about cell death. Although the content may be very familiar to experts in the field, my suspicion is that they too will enjoy and benefit from reading this entertaining book.