20 Years of Cell Death

Richard A Lockshin, Zahra Zakeri

• Publisher: Richard A Lockshin
• Year: 2015
• ISBN:
  9780989467445
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Cell Biology
• Index: Biological Sciences

In 1994, when the International Cell Death Society was founded, programmed cell death and apoptosis had just recently been recognized as major factors in medicine, important in diseases such as cancer, neurodegenerative diseases, autoimmune diseases, and developmental anomalies. The biomedical world had accepted the idea that most cells do not die by accident: under specific conditions, they commit suicide, leading either to protection of the organism or damage to it. In the last 20 years, we have come to understand a great deal about cell death. It is a major research field, and one that is considered in all medical research. In this book, many of the pioneers and leading researchers recount, in often personal terms, how their particular specialties developed, where the field is today, and what it promises for the future, both in our understanding of human and animal development and for our control of these diseases and even of viral infection. The authors address apoptosis, programmed cell death, necroptosis, autophagy, and many other versions of cell death. This comprehensive work presents the state of the art in the field, yet is written in language that makes it accessible to specialists, to students, and to non-specialists interested in understanding the field. As a resource for the history of the field as well as for its current status and the direction into which research is heading, it serve as a standard for many years.

Chapter 1: Introduction (Lockshin and Zakeri)

Richard A. Lockshin1,2, Ph.D. Zahra Zakeri2, Ph.D.

1Dept. of Biological Sciences, St. John’s University, Jamaica, NY USA (Emeritus)

2Dept. of Biology, Queens College of CUNY, Flushing, NY USA

[email protected]

The year 2014 marks several anniversaries. This book was compiled with the intent of commemorating the 20th anniversary of the International Cell Death Society, but it also marks the 50th anniversary of the appearance of the term “programmed cell death” in the visible1 scientific literature. Although there were many valuable experiments and observations that preceded that point, especially some of the experiments by John Saunders (Saunders and Gasseling, 1962; Saunders, 1966; Fallon and Saunders, 1968), in a sense it marks the beginning of a new era. However, interest built only slowly. 1972 marked the culmination of a thoughtful approach initiated by the pathologist John Kerr, with the publication of the recognition by Kerr, Wyllie, and Currie that the, at that time inexplicable, mode of cell death was quite common if not universal. Kerr had previously pointed out that cell shrinkage and blebbing, combined with condensation and margination of chromatin, was very common but not not interpretable by any obvious osmotic mechanism. Intending to highlight that generality, they christened the mode “apoptosis”(Kerr, 2002; Kerr et al., 1972). Even so, interest continued to grow slowly. It was not until the 1990’s that the manner in which cells die began to attract attention. What happened was a series of discoveries: The genetics of a major path to cell death was worked out for Caenorhabditis, leading to the recognition that the primary effector of cell death was a protease that was evolutionarily conserved, with an apparently similar role in humans(Horvitz, 2003); recognition that at least two types of cancer could be attributed to mutations of genes that affected cell death, the genes ultimately proving to be members of larger families now known as the bcl-2 and tumor necrosis factor families (see Vaux, 2002), with the gene most commonly mutated in cancer (p53) also being shown to affect the ability of cells to undergo apoptosis (Yonish-Rouach et al., 1993); and, finally, the description of a simple and cheap technique by which the existence of apoptosis could be documented in many types of cells.

The impact of these discoveries was immediately obvious. Within a few years of each other, conference series on cell death were founded at the Gordon Conferences, the Keystone Symposia, Cold Spring Harbor Laboratories Conferences, the International Cell Death Society, and the European Cell Death Organization. From that point the field grew exponentially, to the extent that by 2013, 75 papers on various aspects of cell death were appearing every day.

In 1994 Raymond Birge, Michael Hengartner, Richard Lockshin, and Zahra Zakeri founded The International Cell Death Society (ICDS), nicknamed also “The Death Poet’s Society” as small group in New York at Rockefeller University. The society promulgates a better understanding of the mechanisms of cell death, establishing communication among the various branches of the research and communicating and coordinating the application of research findings. Soon after we got started, others learned of our activities, come to our meetings, and asked if we had considered the possibility of taking the meetings to other parts of the world. The society first had biannual meetings, which were later changed, due to demand, to annual meetings. So far the society has directed 20 meetings. In conjunction with the meetings, the ICDS has established specific workshops on the topic of cell death as well as advice for young scientists, women, and scientists from the third world. We have also honored distinguished contributions to the field. as subsequently has also been done by other organizations. We celebrated our 20 years of establishment at a meeting in South Africa in 2014.

Like all topics in the sciences, excitement grew to certainty; troubling observations, some previously well-known but ignored, began to gnaw at that certainty; alternative hypotheses were erected, vigorously contested, and modified; a new level of complexity was admitted; and that complexity has led us to recognize that there is another layer to the onion, and that we need to know much more about the prodromal as opposed to what are essentially the final phases of cell death. We can summarize what has happened since 1994 as a series of steps, each of which is more specifically addressed by the authors of the several chapters, many of whom develop their subject in a very personal style, with anecdotal descriptions of the birth of the field. Altogether they provide not only an accurate and highly readable statement of the state of the art, but also a personalized sense of history as it is lived.

Thanks to the contributors, this overview of the last 20 years addresses most of the issues that have appeared and are now under consideration. In Part 1, “Components and Pathways of Apoptosis,” Patrizia Agostinis describes how we came to understand how endoplasmic reticulum stress and the unfolded protein response influence the fate of cells. Bodvael Pennarun, Octavian Bucur, and Roya Khosravi-Far describe an important negative regulator for programmed cell death, and go on to point out how this knowledge is being exploited for cancer therapy. Mauro Piacentini continues, telling the story of how transglutaminase came to be recognized as a marker for apoptosis, how it works, and how it affects the fate of apoptotic cells. Finally in this section, Boris Zhivotovsky addresses the issue of the other functions of caspases, including those that function in the differentiation of lymphoid tissues and functions of the apoptotic caspases that have nothing to do with the death of the cell. This theme is expanded by J. Marie Hardwick, who has used highly innovative approaches to question the alternative roles of many proteins that are presumed to function primarily for apoptosis. In Part 2, “Processes of Apoptosis,” we turn to mechanisms by which cells are killed. Zakeri and Lockshin, reviewing the modern history of the field, emphasize how understanding has gone from a rather narrow certainty to a broader recognition of the importance of many overlapping and sometimes competing processes, such as autophagy and necroptosis. Birge describes a currently very active field, the role of the dying and fragmenting cell in invoking (or not invoking) an immune response. How the immune system responds to a dying cell can determine the difference between autoimmune disease and health, or between health and cancer. Domagoj Vucic tells the story of the discovery of inhibitor of apoptosis proteins and the progress of the exploration to its current status as a target for therapy. Doug Green looks at the centrality of mitochondrial metabolism in determining cell fate, and asks why very similar cells differ in terms of timing or extent of their response to perturbation.

In Part 3, “Autophagy and Necroptosis,” we explore alternatives to apoptosis. De Zio and Cecconi lead this section by asking what the genes Apaf1 and Ambra do; they find that both genes are very important for both apoptosis and autophagy, and that their activities determine the extent to which either process proceeds. Gozuacik and Kig follow with a review of how autophagy came to be closely analyzed, and how we now understand its role in cell fate and its interaction with apoptosis. Next, Ben Loos reflects, in a manner similar to Green, on how the energy is handled and how availability of energy affects apoptosis, autophagy, and cell fate. He emphasizes the newest, extremely high resolution microscopy tools. Junying Yuan recounts the discovery of necroptosis and evaluates its meaning and importance for today’s research.

In Part 4, “Viruses and Cancer,” Zakeri et al describe the battles waged between cells and viruses for control of their destinies. Viruses often protect cells against other stresses, most commonly by activating autophagy, thereby preserving the cells to ensure the reproduction of the virus. Ultimately however the vi...

Table of contents

• Table of Contents
• Dedication and Acknowledgment
• IntroPage
• Chapter 1: Introduction (Lockshin and Zakeri)
• PART 1
• Chapter 2: Endoplasmic Reticulum stress in Cancer and Cell Death: a time lapse (Agostinis)
• Chapter 3: c-FLIP: A negative regulator of programmed cell death and a target for cancer therapy (Pennarun, Bucor, and Khosravi-Far)
• Chapter 4: Transglutaminase Type2 and Cell Death: an historical overview. (Piacentini)
• Chapter 5: Caspases: helpers and killers (Zhivotovsky)
• Chapter 6: Seeking day jobs for all apoptosis-related factors – inside one perspective (Hardwick)
• PART 2
• Chapter 7: Modern history of the study of cell death: 1964...1994...2014 (Zakeri and Lockshin)
• Chapter 8: Efferocytosis: Molecular Mechanisms and Immune Signaling from Dying Cells (Kumar, Smith, and Birge)
• Chapter 9: From caterpillars to clinic: IAP proteins and their antagonists (Vucic)
• Chapter 10: How do cells stay alive? (Green, Llambi, and Fienberg)
• PART 3
• Chapter 11. Apoptosis and Autophagy face to face: Apaf1 and Ambra1 as a paradigm (De Zio and Cecconi)
• Chapter 12. Cell Death and Autophagy: A Historical Perspective (Gozuacik and Kig)
• Chapter 13: Autophagic flux and cell death (Loos)
• Chapter 14: Discovery of key mechanisms of cell death: from apoptosis to necroptosis (Yuan)
• PART 4
• Chapter 15: Cell death and virus infection – a short review (Zakeri et al)
• Chapter 16: Harnessing apoptosis pathways for childhood cancer (Fulda)
• Chapter 17: South African medicinal plants inducing apoptosis in cancer cells: a treasure trove of anti-cancer agents? (vand der Walt and Cronjé)
• Index