Ganini, Carlo

Melino, Gerry

Zampieri, Carlotta

English

Apollo (Cambridge)

Zampieri et al. Cell Death and Disease          (2020) 11:259 https://doi.org/10.1038/s41419-020-2465-5 Cell Death & DiseaseBOOK REV I EW Open Ac ce s sThe biochemistry of cell deathCell Death: Apoptosis and Other Means to an End, SecondEdition by Douglas R. Green, St. Jude Children’s ResearchHospital, Cold Spring Harbor Laboratory Press, New York, 2018Carlotta Zampieri 1, Carlo Ganini 1 and Gerry Melino 1Can we impress you with a mind-blowing revelation?“Cells are not eternal in our bodies, but rather theyencounter death!”1.If someone pronounces this sentence at a biology class,students will laugh. Why? Because cell death has beenstudied since the 60s of the last century. When we speakabout apoptosis nowadays, we regard it as a well-knowntruth. Anyway, this truth did not catch the attention ofscientists until the 1980s, where the interest in the fieldexploded, leading to a dramatic increase of publications.Cell death passed “from neglect to hysteria” in only a fewyears, citing Martin Raff2, one of the founders of the field.Undoubtedly, cell death is fundamental in our organismthroughout the whole lifespan of a human being3: duringbody development, in tissue remodeling, and in manydiseases like cancer, auto-immune, or infectious diseases.Many of these morbidities may originate from an incor-rect apoptosis process: either from an excessive removalof essential cells for the body or from a defective elim-ination of potentially damaged cells. Our knowledge onapoptosis and cell death in general has reached an inter-esting point and we have a broad understanding of themechanisms that are crucial to its regulation and of theirconsequences, making it reasonable to look at them in atherapy-oriented fashion.Since we know so much about this field and the dif-ferent forms of cell death4, does it make sense to write abook on cell death? Moreover, does it make sense to writea “second edition” to a previously published work? Theanswer is undoubtfully yes… and who better than DouglasGreen could do it?Douglas Green is one of the worldwide leading expertson apoptosis and cell death. He has dealt with the role ofcell death in the regulation of cancer and immuneresponse, studying the molecular events that drive theprocess, focusing on the induction-activation of apoptosisin T cells and the role of Myc, death receptors and Bcl-2in this context. His deep understanding of the fieldallowed him to write the first edition of this book in aclear and straightforward manner, enriched by extremelyinformative figures. His talent as a biologist, as well as acommunicator, has been condensed in this second edi-tion, as you will discover by reading it from the beginningto the end, “in a few sittings”… and again, as in the pre-vious edition, some “aha!” moments will not be missing!In this edition of “Cell Death: Apoptosis and OtherMeans to an End”1, the author extensively described thestudies carried out on apoptosis so far, with outstandingclarity (Fig. 1). The theme has been addressed mostlyunder a biochemical point of view, starting from thedescription of the molecular mechanisms driving apop-tosis, using an innovative bottom-up approach, as hepointed out, dissecting at first the extreme end of a cell’slife, tracing it back to the state of a healthy cell to discoverwhat caused it to die. Nevertheless, this book might not besolely regarded as a comprehensive review about thebiochemistry of the way cells die, since Douglas did notonly focus on the molecular and cellular mechanismsdriving cell death, but also described them with a glance atevolutionary biology, neuroscience, oncology, andimmunology.As a starting point, the author describes the caspases,the essential proteins responsible for the activation andthe execution of apoptosis. From Douglas very words, weunderstand that the structure of the book is to be read© The Author(s) 2020OpenAccessThis article is licensedunder aCreativeCommonsAttribution 4.0 International License,whichpermits use, sharing, adaptation, distribution and reproductionin any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate ifchangesweremade. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to thematerial. Ifmaterial is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Correspondence: Gerry Melino (melino@uniroma2.it)1Department of Experimental Medicine, TOR, University of Rome Tor Vergata,00133 Rome, ItalyOfficial journal of the Cell Death Differentiation Association1234567890():,;1234567890():,;1234567890():,;1234567890():,;from the beginning to the end, as each chapter builds upnotions that will guide any reader to complete the picturepresented in the following one, therefore allowing a per-sonal reconnection of the dots, leading to the promised“aha!” moments. After the introduction on the caspases,the book moves on to the explanation of the main path-ways responsible for their activation, the mitochondrialand the death receptors pathways. Anyway, cells do notonly die by apoptosis: the other not apoptotic cell deathtypes are briefly discussed alongside with the mechanismsby which the organism cleans the remaining from deadcells4. The various aspects of cell death described so far,are then used to summarize its role in specific contextssuch as development and cancer.The book ends with the future: the future of cell death!5The author concludes with a formal approach applyingmathematical models to discuss about the correctness, orincorrectness, of what we know on the topic and with aninformal and more practical one, to understand how wecould use our knowledge to engineer cell death. All theabove is contained in a short didactic book with chal-lenging topics, written in a pleasant key in less than 250pages! A few details about each chapter will follow in thenext paragraphs…Chapter 1 is fundamentally an intriguing synopsis oncell death. If cell death’s increase can lead to cancer6, onthe other hand its decrease can lead to infections orneurodegeneration. The organism must always maintain abalance between mitosis and apoptosis. In this chapter,the author outlines the molecular mechanisms that areregulating cell death: he explains the differences betweenpassive death, occurring when the cell does not participatein the mechanism of death, and active death, when insteadcells play an active role in the process.Green’s bottom-up approach starts with the study of thebiochemistry of apoptosis, which is elegantly presented inChapters 2 and 3. Chapter 2 focuses on the key enzymesresponsible for the activation and the execution ofapoptosis, the caspases, through a chemical look (i) attheir structure, (ii) at their domains (in diverse organ-isms), and (iii) at the structure of their substrates. Chap-ter 3 is more focused on the regulation of caspases activityby activators or inhibitors, grouping caspases into twotypes, depending on their function: initiator caspases(caspase-2, -8, -9, -10) or effector caspases (caspase-3, -6,-7). The power of these chapters relies on the linearity ofthe presentation of more than 30 years of the molecularcharacterization of apoptosis into a straightforward text,supported by highly informative figures… a good way tostart learning about cell death (if you are facing it for thefirst time) or to make a point after a few yearsworking on it!Already at this point, the reader has a clear picture ofhow apoptosis occurs in a cell… but when is it activated?And how does the programmed cell death build up?Chapters 4 and 5 are there to answer our questions,focusing on the mitochondrial pathway of apoptosis, fol-lowing the cytochrome c release by the mitochondrion,giving start to apoptosis in a process called mitochondrialouter membrane permeabilization (MOMP)7. MOMP,and consequently apoptosis, is closely regulated by afamily of proteins, Bcl-2 whose importance is highlightedin Chapter 5 and fully described in its ability to mediatevarious signals inducing cell death7.Anyway, the mitochondrial pathway is not a unique wayto trigger apoptosis: a full chapter is therefore dedicated tothe death receptors, which are activated by the deathligands. Death ligands are part of a family of proteins, theTNF (tumor necrosis factor) family, and death receptorsare part of the tumor necrosis factor receptors (TNFRs)family. The chapter does not only focus on the descriptionat a structural level of this alternative apoptosis triggeringpathway, but also shows contacts between the activationof the death receptors and the mitochondrial pathway ofapoptosis. A quick look at other modalities of apoptosisengagement is given in Chapter 7, where theFig. 1 Cover of the second edition of the book “Cell Death: Apoptosisand Other Means to an End” by Douglas R. Green, edited by ColdSpring Harbor Laboratory Press, New York.Zampieri et al. Cell Death and Disease          (2020) 11:259 Page 2 of 3Official journal of the Cell Death Differentiation Associationinflammasome and other caspases activation platformsare described, remanding us about the close link betweenapoptosis and immunity, so dear to Douglas Greenthroughout his entire career.Nevertheless, apoptosis is not the only way for a cell todie4. Therefore, in this comprehensive book on cell death,Green dedicates an entire chapter to describe the varioustypes of cell death (necrosis, necroptosis, autophagy).Indeed, apoptosis and necrosis were the first cell deathtypes studied. Necrosis is presented as an accidentaldeath, caused by cell damage, although we now know thatit can occur in a regulated fashion, called necroptosis,which is briefly discussed. Along with necrosis andnecroptosis, the chapter also overviews the survivalmechanism of autophagy.The book, in addition to the biochemical side, includesthe evolutionary aspects of cell death. It presents, asGreen says, a “Just So Story”, a scenario of how themitochondrial pathway of apoptosis could have evolvedduring eukaryotic evolution.At this point a question in the readers’ brain might arise,one of those questions human beings have always askedthemselves: what does happen after (cell) death? InChapter 9, Douglas talks about “the burial, the disposingof the corpse” briefly focusing on phagocytosis whichprevents the inflammatory response and cleans the tis-sues. The cell which is about to die releases “find-me”signals to be recognized. On the surface of the apoptoticcell the “don’t eat me” signals are blocked, and instead“eat-me” signals are activated by the dead cell-phagocyteinteraction, leading to cell incorporation and degradation,not without any “consequences”.Now the reader has a broad perspective on cell deathand apoptosis. Therefore, it is about time to describecell death regulation either during embryonic devel-opment, where apoptosis is also implicated in neuronaland lymphocytes selection. This topic is covered inChapter 10, where the signals engaging cell deathpathways are described in their role in the sculptingembryo.Finally, talking about defective cell death, a chapterneeds to talk about cell death and cancer, of course6.Much of the focus is on p53 and on its key role inapoptosis8; the author describes how p53 regulatesapoptosis and inserts a clear and schematic panel on theprotein regulation. But most of all, this chapter explainshow “damaged” apoptosis can lead to cancer and how thismechanism might be exploited for cancer prevention.Once again, Douglas gives us a didactical and rationalexplanation of how cancer might be considered a diseasecaused by defective cell death.The true ending of the book is outstanding. After a greatdeal of information in the previous chapters, the readernow understands how a cell engages cell death pathways,their regulation, how death occurs and how it is pro-cessed. But is the “big picture” we are looking at, reallycomplete? To answer this question, the first part of thefinal chapter applies a mathematical approach to under-stand if the models we generate conform to our obser-vations. But the true conclusion is a practical one: howcan we use the information we have to engineer celldeath? You just have to read the book, and you will alsoget to this point!The book’s strength relies on its linearity, with a clearand consequential division of the chapters. It deals withcomplex and vast topics, but it remains easy-to-read andpleasant. It is a good reading for those who need ageneral overview of cell death. Douglas Green has in factmanaged to schematize the engaged processes to theright point and in less than 250 pages, without beingrepetitive and without making it as a boring list ofreactions.The molecular interactions are well schematized inthe figures—even if sometimes with synthetic legends—through stylish and plain images, not too colorful.Whilst also beginners are able to read this book, it issuitable for a diverse audience (without neglecting therich “additional reading” section, full of keystone paperson cell death). Why should we read “Cell Death:Apoptosis and Other Means to an End”? Becausereading this book: “cannot tell us whether we are rightor wrong but, instead, where our ignorance lies andwhere our knowledge is useful”1.Received: 22 February 2020 Accepted: 12 March 2020References1. Green, D. R. Cell Death: Apoptosis and Other Means to an End. 2nd edn (ColdSpring Harbor Laboratory Press, New York, 2018).2. Raff, M. C. Social controls on cell survival and cell death. Nature 356, 397–400,(1992).3. Melino, G. The Sirens’ song. Nature 412, 23, (2001).4. Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of theNomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541,(2018).5. Green, D. R. The coming decade of cell death research: five riddles. Cell 177,1094–1107, (2019).6. Carbone, M. et al. Consensus report of the 8 and 9th Weinman Symposia onGene x Environment Interaction in carcinogenesis: novel opportunities forprecision medicine. Cell Death Differ. 25, 1885–1904, (2018).7. Kalkavan, H. & Green, D. R. MOMP, cell suicide as a BCL-2 family business. CellDeath Differ. 25, 46–55, (2018).8. Levine, A. J. Reviewing the future of the P53 field. Cell Death Differ. 25, 1–2,(2018).Zampieri et al. Cell Death and Disease          (2020) 11:259 Page 3 of 3Official journal of the Cell Death Differentiation Association

The biochemistry of cell death : Cell Death: Apoptosis and Other Means to an End, Second Edition by Douglas R. Green, St. Jude Children's Research Hospital, Cold Spring Harbor Laboratory Press, New York, 2018.

https://www.repository.cam.ac.uk/bitstream/handle/1810/306181/The%20biochemistry%20of%20cell%20death%20%20Cell%20Death%20Apoptosis%20and%20Other%20Means%20to%20an%20End%2c%20Second%20Edition%20by%20Douglas%20R.%20Green%2c%20St.%20Jude.pdf?sequence=1&isAllowed=y

The biochemistry of cell death : Cell Death: Apoptosis and Other Means to an End, Second Edition by Douglas R. Green, St. Jude Children's Research Hospital, Cold Spring Harbor Laboratory Press, New York, 2018.

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