It became obvious that Peter Vandenabeele was a troublemaker when, after establishing himself as one of the early researchers on cell death, he challenged the dichotomy argued by others that programmed or regulated cell death consisted of autophagy and apoptosis. While others argued that cell deaths were either uncontrolled necrosis or variants of autophagy or apoptosis, he argued that other types of death were sufficiently consistent in pattern and characterized by distinct enzymatic pathways to merit their own categorization and name. Among the patterns that he and his group identified were necroptosis, previously categorized as necrosis but for which he identified distinct roles for kinases and a constrained leakage from cell membranes, releasing Damage-Associated Molecular Patterns that induced responses by the immune system and thereby led to a more aggressive response by the immune system, an important element in defeating cancer. His pursuit of this topic led him to accept and emphasize yet another form of cell death, ferroptosis, an iron-requiring form of cell death that is characterized by the accumulation of lipid droplets in cells. At meetings and conferences, he can always be counted on to ask stimulating, challenging, and provocative questions. He directs a large group at one of Europe’s largest and best-known cell death centers. Given his broad interests, he has developed a large library to screen for the responses of tumors to many drugs and to silencing of kinases, ubiquitylating enzymes, and other enzymes with short hairpin and short interfering RNAs. Thus, his group has become a leader in the search for molecules that can suppress cancers through modulation of apoptosis, phagocytosis, necrosis, ferroptosis, and immune responsiveness. We look forward to many years of contributions from this laboratory regarding the numerous general and specific biochemical mechanisms of cancer and many other diseases, the vulnerable pathways that they manifest, and how to treat them.
From her beginning career in Padua as a biochemist, Patrizia Agostinis has always been seeking the connection between one process and another, or among several simultaneous or sequential processes. She started by asking how photodynamic therapy worked. This query led her, by the time that she had moved to Leuven, to the field of cell death, where she began considering cancers such as melanoma and gliomas. She was among the first to examine how ER stress connected to mitochondria, and how cell surface signaling connected to autophagy. Following these questions led her to consider Damage Associated Molecular Patterns, or DAMPs, and their connection to Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), taking her to the study of ER-Plasma Membrane and ER-mitochondria contact sites, a study in which she became one of the leaders and principal players. Still active in these areas, in the last ten years she has turned her attention also to immunologically-induced cell death, examining how targeted cells invoke Unfolded Protein Responses and ultimately die, and is now examining the possibility of immunotargeting dendritic cells to limit the devastation of glioma. Her current research aims to connect the unfolded protein response, reactive oxygen and endoplasmic reticulum pathways, with autophagy, cell death and the immune response to dying cells, currently a very exciting area of study. Given her interest in damage-associated molecular patterns, she has successfully explored many of the more subtle consequences of damage to malignant cells by photo- or chemotherapy, including the pathways from the initial reaction, involving a kinase (phosphorylating enzyme) called PERK, and tracing how the response moves from the endoplasmic reticulum (ER) to mitochondria and the cell membrane. Through very careful and focused work, she has identified the contact sites through which the ER communicates to these other organelles, establishing a mechanism whereby injury initiates autophagy (self-eating) and to a different pattern of death. While maintaining these projects, Patrizia is an unfailingly helpful collaborator and supporter of others, and her students and collaborators have prospered. As a Past President of ECDO and full Professor and group leader of the Cell Death Research & Therapy lab at the Department of Cellular and Molecular Medicine & Center for Cancer Biology of the VIB-KU Leuven, she cooperates with laboratories throughout Europe and the world, and the breadth of her insight has been important to the whole field.
Marie Hardwick first appeared on the cell death scene as a broad-scope scientist, interested in both mammalian cells and yeasts, the genetics of which offered means of asking different questions about cell death. In a sort of quirky way, she asked questions that either never occurred to those of us in the field too excited about the latest discoveries about apoptosis or that we did not dare to challenge: in the sequence for intrinsic (metabolic) apoptosis–[something happens] → Bax, Bak displace Bcl2 from mitochondrial membrane → mitochondrial membrane depolarization → leakage of cytochrome c and Apaf-1 → activation of apoptosome→caspase-driven degradation of cell, what is meant by [something happens]? What happens to the cytoplasm? Why are the cytoplasmic Bcl-2 family members in the cytoplasm in the first place? Do they possibly have any function other than to lay in wait for eventual apoptosis? Does Bcl-2 have a function other than helping to seal mitochondria against potential leakage? And is it possible that caspases, in active (proteolytic) or inactive form, do something other than act as executioners lurking in reserve? After all, organisms die in many ways, but it is rather uncommon to find situations in which organisms activate specific toxins or other specific means of destroying themselves. Even lysosomes, so named because they were seen to rupture in CCl4-induced hepatotoxicity, proved soon enough to be not suicide bags for cells but rather intracellular digestive and housekeeping organelles.
Among the observations that Marie has forcefully put forward and documented by yeast genetics and manipulation of mammalian cells, she and her laboratory have established that Bcl-2 family members influence metabolism, mitochondrial structure and therefore function, and neuronal growth and activity. She has demonstrated that the common means of studying function, by knockout or knockdown of specific genes, has an intrinsic flaw: As old-time biochemists or biologists might have suggested, but we rarely consider today, alteration of a central metabolic component generates complex feedbacks, so that the surviving altered cell is very different in many respects, with genome-wide up- or down-regulation of many other obviously-compensatory and not-so-obviously-compensatory genes. Therefore, at best, we have to be circumspect in our interpretation of the results. She has also, along with researchers such as Jean-Claude Ameisen, asked what caspases were before they were caspases–in other words, did they and do they serve other functions? Following this line of argument, she has generated models for the function of a programmed cell death even in unicellular organisms and its relationship to the earliest phases of tumorigenesis, and she has demonstrated that caspases can be active in cells that do not die. All of these studies provoke questions and ultimately lead to a more profound understanding of the meaning and purpose of organized cell death, rather than the more facile assumptions that tend to dominate discussions of apoptosis.
Marie is the first David Bodian Professor at Johns Hopkins. David Bodian, also a mid-westerner, was the first to establish that formaldehyde-killed polio virus could still immunize chimpanzees, an important step in the eventual development of polio vaccine. With her wide-ranging and catholic approach to biomedical questions, she is a worthy recipient of that post. She is modest and unassuming, yet witty and sharp. I was not at all surprised to learn that she has a twitter handle @JMHtweetsrarely. For all of her provocative contributions to our field, we are pleased to honor her with this award for her contributions.
Rehovot, Israel, 2017: Barbara Conradt
BARBARA CONRADT is a Professor of Biology at the Ludwig-Maximilians-Universität München (LMU Munich). Her mottos in science are that “little things make big differences” and that “one can always learn something from negative data.” She received a PhD in molecular biology from UCLA where she worked on reconstitution of the fusion of vacuoles in yeast under the supervision of Prof. William T. Wickner. She recalls experiencing more than 200 failed attempts before she finally came up with a protocol that worked – a breakthrough that helped establish the current understanding of the molecular mechanism of vacuole fusion. To this day, she recalls not the frustration of failure after failure but her enthusiasm to get back into the lab every day to try again.
She moved to MIT for her postdoctoral training with Prof. H. Robert Horvitz (Horvitz together with Sydney Brenner and John Sulston received the Nobel Prize for Medicine in 2002 for their discoveries concerning genetic regulation of organ development and programmed cell death). During this period, she made several seminal discoveries published in two sequential Cell papers (Conradt & Horvitz), in which she characterized the BH3-only protein EGL-1 in C. elegans and its interaction with the Bcl-2 homolog CED-9, and identified the sex determination zinc finger protein TRA-1A as a transcriptional repressor of egl-1, which mediates developmental cell death of the hermaphrodite-specific neurons (HSNs) in males.
She subsequently served as an Independent Junior Group Leader at the Max-Planck-Institute of Neurobiology, Munich-Martinsried and as Professor of Genetics at the Geisel School of Medicine at Dartmouth. During these periods, she continued making important contributions to the field of programmed cell death, including the discovery and thorough characterization of the role of Bcl-2 family members in the regulation of mitochondrial dynamics.
She moved to LMU Munich in 2011, and her research currently focuses on the regulation of programmed cell death and mitochondrial dynamics. Her group recently reported that components of the engulfment pathways promote programmed cell death by enhancing the polar localization of apoptotic factors in mothers of cells programmed to die. In a more recent paper, her group discovered the regulation of EGL-1 and programmed cell death by microRNAs, thus demonstrating that even after almost two decades since the first EGL-1 paper, exciting discoveries about the regulation of this pro-apoptotic protein are still waiting to be uncovered. This example perfectly describes Conradt’s way of doing science. She believes that “good science just takes time,” and that “one has to be patient and open-minded to follow the biology rather than the model in one’s mind.”
Conradt’s passion for science isn’t unusual, but her commitment to actually working at the lab bench is. Whereas many principal investigators gradually move away from the bench during the course of their careers and spend more and more time on the administrative work of running their lab, Barbara still continues to do experiments. “I just love it,” she says. “That is the part that’s the most fun.” It keeps her up to date on the latest technologies and is also “the best way to see how others in her lab are doing and to communicate with them.”
It is therefore a pleasure for the ICDS to recognize the achievements of Barbara Conradt, who has already won several distinctions and awards, including the EMBO Young Investigator (2001 – 2004) and the Leukaemia & Lymphoma Society’s Special Fellow Award (1997 – 2000). It is an honor to present one of our 2017 prizes for Lifetime Achievement to Barbara Conradt.
Rehovot, Israel, 2017: David Wallach
DAVID WALLACH has always been curious. As he says, “..from the day I crawled on the sand and saw something next to me. It never stopped interesting me. It never changed…I want to thank my parents, of blessed memory…” That characteristic served him well. Throughout his life, David has sought mechanisms, how things worked. Training under Michael Schramm and Ira Pastan, his curiosity led him to the question of what drove inflammation, leading him to the elucidation of the mechanism of action of tumor necrosis factor. His work with TNF led to several important advances, including the development of drugs against several severe chronic inflammatory diseases. This basic research has eased considerable pain in this world.
Realizing that TNF was a cytokine that bound to specific cell-surface receptors, Dr. Wallach expanded these observations to elucidate the extrinsic cell death pathway. He identified the “death domain,” a region in the TNF and other cell death receptors that, upon self-association, triggers cell death. This observation established for cell death cascades a means of enzyme activation different from phosphorylation, cleavage, or ion change. He cloned caspase-8 (the protease that, in the extrinsic pathway ultimately activates caspase-3) and its adapter protein FADD/MORT1. This work was crucial in establishing the importance of a caspase cascade to effect apoptosis.
He also recognized cFLIP/CASH as a natural antagonist of caspase-8, and thus a means of keeping apoptosis under control. This inhibition revealed that caspase-8 had activities that could not be directly tied to apoptosis: differentiation of the hematopoietic system including the yolk vasculature and differentiation of macrophages; and binding to the cell membrane and translocation to the nucleus of the pseudokinase MLKL (mixed lineage kinase domain-like), leading to the controlled necrosis-like form of death called necroptosis. A third surprising function of Caspase-8 is to prevent escaping nucleic acid oligomers from activating inflammatory responses as keratinocytes terminally differentiate. We look forward to his wide-ranging curiosity producing many more such surprises in the coming years.
It is therefore a pleasure to join many others in celebrating the achievements of David Wallach. David has already won many prestigious prizes including the Teva Founders Prize (1997), Rappaport Prize in Biomedical Sciences (2012), Merck-Serono Prize (2012), and Emet Prize (2014). He was Councilor (2007) and President (2011) of International Cytokine Society, and has served on the editorial boards of a dozen journals. He is currently the Joseph and Bessie Feinberg Chair of the Department of Biological Chemistry here at the Weizmann. An outstanding scientist, he is also a modest and wonderful and gentle human being. It is an honor to present one of our 2017 prizes for Lifetime Achievement to David Wallach.
Cork, Ireland, 2016: Hermann Steller
HERMANN STELLER lives comfortably in many worlds. He completed his undergraduate and doctoral studies in Germany (undergraduate in Frankfurt, working on the genetics of bacterial sporulation) and Ph.D. (summa cum laude, using gene transfer to study regulation of genes in Drosophila at the European Molecular Biology Laboratory in Heidelberg). He then took these skills in genetics to the University of California, Berkeley, where as a postdoctoral fellow he used genetics of Drosophila to analyze neuronal specificity. This research was sufficiently promising that he moved next to the Department of Brain and Cognitive Sciences and the Department of Biology at MIT, where he rose to the ranks of Professor and Investigator at the Howard Hughes Medical Institute.
Meanwhile, his research led deeper into the study of apoptosis in Drosophila. He started by developing the now widely used technique of using acridine orange to scan for cell deaths in embryos. He continued by defining a controllable situation of cell death, the eyeless series of mutants and, by genetic screening and anatomic localization of mutants, identified the regulation and control of a seemingly new pathway of cell death, involving grim, reaper, and Hid. Many researchers were frightened away by these discoveries. Whereas the Caenorhabditis cell death pathway was remarkably similar to that of vertebrates including mammals, this was different. Characteristically, though, he used this difference as a provocation and stimulus, working out where the pathways were similar and asking what could be learned from their similarities. From these comparisons he began to understand the complex negative and positive feedback loops that limit the randomness of the decision to die. This was another level of different worlds: to keep focused on mammalian and insect cell death mechanisms, hunting for the generalities that connected them.
These studies, in addition to spawning the current heads of many fine laboratories throughout the world, led him into another important area: when caspases or other proteases are activated without necessarily killing cells. Such studies led him to apoptosis-like processes such as sperm differentiation and to recognition of apoptosis signaling mechanisms cells undergoing apoptosis can stimulate other cells, at some distance, to respond by initiating division or, surprisingly, also initiate apoptosis. As was logically necessary but needed to be proved, the transmission of these signals required very tight control of the activity of cytoplasmic proteases. All of these findings have pronounced implications for future drug development.
In 2000, he moved again into a new era of different worlds. After spending a year at the Weizmann Institute of Science in Israel, he spent the next several years between Rockefeller, where he is Strang Professor and Head of Laboratory, and as a Visiting Professor at the Technion in Israel. During this period he developed his interest in the communication and regulation of death signals, as well as acquiring a collaborator and life partner.
For his unstinting and uncompromising insistence on knowing the communication sequences within and among cells, the International Cell Death Society is proud to honor Dr. Steller’s achievements.
Cork, Ireland, 2016: Seamus Martin
Seamus Martin began working on apoptosis as a young PhD student in the late 1980s and was so captivated by this process that he has continued to work on cell death ever since. His early work in Tom Cotter’s lab in Ireland explored the nature of the triggers that could promote apoptosis (which in those days were thought to be few and far between) and he quickly found that many standard chemotherapeutic drugs promoted this process, and also that the ‘death machinery’ was constitutively present in most cells, which was very much against the dogma at that time. His subsequent post-doctoral training periods in the laboratories of Ivan Roitt at UCL, London and Doug Green at La Jolla, California, saw Seamus working on many aspects of cell death control, including how HIV induces apoptosis, how caspases coordinate cell death, and devising a cell-free approach for studying mammalian apoptosis. He has made a number of key contributions to the field including: introduction of the annexin V-labeling method, which has become the gold standard for measuring apoptosis, unraveling the cytochrome c and granzyme B-initiated caspase activation cascades, identification of multiple caspase substrates, and the recent discovery that ‘death receptors’ Fas and TRAIL can also promote inflammation that may be exploited by certain cancers. His current passion is exploring the molecular connections between cell death and inflammation and identifying the key drivers of sterile inflammation.
Seamus also lectures extensively at Trinity College in Dublin, where he holds the endowed Chair of Medical Genetics, he has co-written the past three editions of the best-selling Immunology textbook ‘Essential Immunology’, and is Editor-in-Chief of The FEBS Journal. He has received several awards for his work including The GlaxoSmithKline Award of The Biochemical Society UK (2006) and The Boyle Medal (2014) and was elected to the Royal Irish Academy in 2006, the European Molecular Biology Organisation (EMBO) in 2009 and is president-elect of the European Cell Death Organization (ECDO).
Prague, Czech Republic, 2015: Scott Lowe
In 1990, we thought we understood cancer. It was a disease of cell proliferation and migration. Proliferation of mutated cells could be blocked by p53. Failure or mutation of p53 could be documented in half of all cancers. However, other arguments were beginning to appear. In 1991, Stan Korsmeyer published that the Bcl-2 protein, known for its activity in B-cell lymphoma, was reduced in cells that underwent apoptosis; in 1989 Peter Krammer realized that a specific protein, which he called Apo-1, could induce apoptosis in tumor cells; and in 1991 Shige Nagata recognized that the Fas-AntiFas system could induce apoptosis, with the synonymy of Apo-1 and Fas being recognized shortly thereafter. At this time Scott Lowe, working serendipitously with several doctoral mentors, recognized that functional p53 worked not only in the negative sense of preventing mitosis of cells with damaged DNA, it also worked in the positive sense of provoking apoptosis in those damaged cells that nevertheless initiated mitosis. The discovery, first published in 1993, led to a paradigm shift. Cancer was no longer a disease of unregulated cell replication. It also, and perhaps even mostly, was a disease or diseases in which cells failed to heed the normal physiological commands to die.
Since that time, Scott has led the field in research concerning p53 and especially its effect in controlling apoptosis as well as cell senescence. This research has led him to recognize that cells in which specific genes are permanently knocked-out or upregulated often compensate for the defect. He therefore has developed models in which genes can be temporarily and reversibly shut off. Using these models, as well as RNAi and mouse mosaic models, he and his group have pursued those few genes whose activity discourages tumor development. This has become an exciting new model for the study of the appearance of cancers, leading his group to study cancer genomics in samples from human patients. In these and other studies his group keeps generating new insights such as establishing that a therapeutic target could be translational control of cell survival. His laboratory has been the leader in combining cancer genomics, RNAi, and mouse models to undertake the functional annotation of the cancer genome.
Dr. Lowe received his Ph.D. at MIT and moved to Cold Spring Harbor Laboratory, where he remained for 15 years before moving in 2011 to Memorial Sloane Kettering Cancer Center, where he is a Howard Hughes Medical Institute Investigator, and Chair of the Cancer Biology and Genetics Program as well of the Geoffrey Been Cancer Research Center. He has won the AACR Award for outstanding achievement in cancer research, the MSKCC Paul Marks Prize for important contributions to the understanding of cancer, the Colin Thomson Memorial Medal of the International Association for Cancer Research, the Alfred G Knudsen Award of the National Cancer Institute, and many other awards. It is our pleasure and honor to recognize today his contribution to our understanding of how tumors are suppressed through apoptosis.
South Africa, 2014: Vishva Dixit
Vishva Dixit returns to Africa to receive this recognition. Of course, he has been to Africa many times, but he was born in Kenya and received his medical degree from there. He might have followed in the footsteps of his parents, who were both physicians, but he was always curious and wanted to find out how things worked. He had been the best student in Pathology as well as the best student in Obstetrics and Gynecology, and the best overall medical student; and his reputation was good enough for him to win a Josiah Macy Postdoctoral Fellowship Award to come to St. Louis, where he started to work on cell-matrix signaling in the immune system. However, as he mentions in a charming interview available on YouTube®, he seems to have had a charming form of attention deficit, as he could not help becoming curious about other problems. It was the late 1980’s, and two exciting stories had started to break in the field of apoptosis. Nagata and Krammer had independently identified the Fas-Fas Ligand interaction as a trigger for cell death in the immune system, which was quickly generalized to the the tumor necrosis family, and the Horvitz group had sequenced a primary killer gene and identified it as a protease with homologs in mammals. Vishva wondered if he could connect these two, the initial activation of cell death and the final, destructive proteolysis. This curiosity led to his elucidation of the several interconnecting links that we now recognize as the sequence by which the binding of a ligand to a receptor leads to the activation of an initiator caspase and thence to the activation of the effector caspase.
In over 400 publications, Vishva and his group have continued to explore the pathways and the control of cell death, as well as the function of the pro-inflammatory caspases. Since 1997, when he moved to Genentech, he has continued these explorations, but adding a translational direction to his research. Starting as Director of Molecular Oncology, as which he oversaw the development and release of some of the first antibody-based anti-cancer drugs, he has now moved to the position of Vice President, Physiological Chemistry, where he continues his interest in many aspects of apoptosis, including ubiquitin pathways, necroptosis, and many other areas, while allowing his imagination to wander to questions such as why the proteins that control phototropism in plants are conserved in animals.
He has won many honors, including the Warner-Lambert/Parke-Davis Award in Experimental Pathology, and he is a Fellow of the American Academy of Arts and Sciences, an Associate Member of EMBO, and a Member of the National Academy of Sciences (USA). The International Cell Death Society is pleased to recognize one of its own, who has carried the field far forward and will continue to do so.
Spain, 2014: Sten Orrenius
The International Cell Death Society is pleased to present Professor Sten Orrenius with the 2013 Pioneer Award in Cell Death for his visionary leadership and accomplishments in the field of cell stress and apoptosis.
Dr. Orrenius contributions to toxicology and cell death span over five decades. He received both scientific and medical training at the Karolinska Institute in Sweden. His early research focused on drug-induced toxicology, establishing important biochemical links between endoplasmic reticulum directed cytochrome P450 metabolism and reactive oxygen species (ROS) that depleted cellular thiols. His pioneering work on drug-induced toxicant stress also led to the realization that cytoplasmic stresses, most notably ROS and Ca2+ dysregulation, impacted mitochondria biology associated with a collapse of mitochondrial permeability and membrane potential. These discoveries brought him into the mainstream of apoptosis, where his group described in elegant details the relationships between glucocorticoid induced thymocyte apoptosis and calcium, and where he was also the first to propose activation of a calcium activated nuclear endonuclease. His curiosity about the role of the mitochondria in apoptosis has led to numerous advances in the field, particularly the complex nature of inter-organelle crosstalk in apoptosis, and its interplay between ROS, Ca2+, cytochrome C, and caspase activation.
For his work, Dr. Orrenius been presented many awards including the ECDO Career Award for Excellence in Cell Death Research in 2003, and the Distinguished Lifetime Toxicology Scholar Award by the Society of Toxicology in 2006. He is a member of the Royal Swedish Academy of Sciences and a Foreign Associate Member of the National Academy of Sciences in the US. For more than 30 years (1971 to 2002), he was a member of the Nobel Assembly at the Karolinska Institute where he served on the Nobel committee. Dr. Orrenius has contributed over 500 publications in a broad arena of biology. The society is honored to present Professor Orrenius with the first CDS Pioneer Award for work on apoptosis.
Spain, 2013: Mauro Piacentini
In the mid 1980’s Mauro Piacentini began to publish articles on the transglutaminases, and he quickly realized that they had a role to play in the then emerging field of apoptosis. He attended one of the first conferences focused on cell death and apoptosis, in Sardinia in 1989, and from then on he talked about the importance of the field and the need to recognize it formally. Since that time he has been a leader in both the research and the presentation of the field. He was a founding editor of Cell Death and Differentiation, which he has led to its current high status among journals, and is a deputy editor of Cell Death and Disease. He was an active participant and enthusiastic supporter of the first Gordon Conference on Cell Death and has subsequently served as Chair of the conference. He was one of the founders of the European Cell Death Organization, and has served as its Vice President and President. He can be found at virtually every important gathering of the field, articulating his view of current research and where it is heading.
In his research he has ranged from transglutaminase to the study of AIDS, where he was one of the first to describe the importance of cell death in AIDS and the mechanism by which HIV triggered cell death. More recently he has turned his attention to the interaction of apoptosis and autophagy, and the role of AMBRA1 in autophagy. Included among his almost 250 papers are insightful and often the first papers on many aspects of cell death and apoptosis.
He has taken his interests to the world, organizing meetings throughout Europe and elsewhere, and organizing courses in Argentina, Brazil, and Cuba, among other countries, and, in conjunction with the ICDS, in Iran, Turkey, and South Africa.
He serves as Professor and member of the Board of Directors of the University of Rome “Tor Vergata,” and ECDO, and is the Director of Basic Research at the National Institute of Infectious Diseases and has been on the Board of Directors of ICDS since its founding. For all these achievements, he has justly been honored by agencies in Italy, Belgium, Slovenia, and Japan and has won the Descartes Award of the European Commission. We are pleased to add the name of the International Cell Death Society to those recognizing the achievements of Mauro Piacentini.
Singapore, 2012: Adi Kimchi
Adi Kimchi makes you think. You might recognize her as a woman who invented a field—the death-associated protein kinases, or DAPk’s—but she is far more complex and provocative than that.
In all fields we go through several periods. In the first phase, a discovery explains everything we need to know. In the second phase, the discovery does not explain everything, as there are complications or alternatives. In the third phase, we begin to integrate the several options. For the field of cell death, the first phase would be the period in which apoptosis was considered to be the entire explanation of how cells die. The second phase would be the period in which it was recognized that autophagy might also be a major form of cell death. In the third phase, we began to understand that these pathways and others are interconnected.
A few voices have argued, somewhat inarticulately, that they were connected. After all, if a cell is very sick and you block one way to death, sooner or later the cell will die. You do not need an instruction manual to die. However, it was Dr. Kimchi who has forced us to think about how this might work. Using systems analysis and every available technique, she forces us to look at the big picture, how all the pathways interact. In essence, she is a juggler, throwing 23 balls into the air all at the same time and forcing us to watch all of them. It is a tough job, and I don’t know anyone who does it as well as she does. However, in cell biology, it probably is the only way to go. When you alter just one parameter, you necessarily force all the other parameters to adjust accordingly. For all their value, cells that have genes knocked down, knocked in, or knocked out, and cells in which one activity is poisoned, make adjustments to their new lives, and we will never truly understand them until we can observe them in their entirety. This is Adi’s gift to us. Like a very demanding teacher, she forces us to look at the entire story and thus to become better and more thoughtful researchers.
Dr. Kimchi has published well over 150 provocative and challenging papers. She has already won several prestigious awards, including the Milstein Award for Excellence in Cytokine Research, the Landau Award for Excellence in Biology and Biotechnology, the Seroussi Award for Cancer Research, and the Lombroso Prize for Cancer Research. She is the Helena Rubinstein Professor in Cancer Research at the Weizmann Institute in Israel and heads the Department of Molecular Genetics there. As she says, “My aim is to reveal the complete self-destruct network. This understanding will help us to fix problems—both those of excess cell death, as in degenerative nerve diseases, and those in which harmful cells fail to die, such as cancer.” We thank her for making us work and think, and we are delighted to add to the accolades.
Brazil, 2011: Guido Kroemer
Guido Kroemer first attracted the attention of at least the North American scientific community when, at the Banbury Conference on Apoptosis in 1990, he appeared as a very articulate (in five languages) young man he announced, to some surprise, that mitochondria depolarized and became leaky shortly before apoptosis could be recognized. Xiaodong Wang and Donald Newmeyer had reported that cytochrome c could activate caspase 3, but Guido was saying something larger—that the permeability of mitochondria to ions and to relatively small molecules could be the point at which the decision of a cell to undergo apoptosis was made, and that the mitochondria could be a therapeutic target.
From that point the Kroemer laboratories have generated an astonishing stream (over 600) of outstanding papers, using numerous unusual compounds and imaginative techniques to isolate and identify the specifics of the control of mitochondrial permeability. As this story began to solidify into an accepted part of the canon of cell death, Guido’s thoughts moved to other questions, for instance what happens to cells that do not die by apoptosis, and why some cells are more resistant to apoptosis than others. These questions led him to examine the relationship between apoptosis and autophagy, and to emphasize the importance of crosstalk between the two. In research and theoretical papers, the Kroemer group has explored how autophagy can protect a cell and how it can sometimes trigger apoptosis—in all cases provoking others with challenging questions as to how and in what circumstances it all fits together. Along the way, he has challenged others with probing questions about the evolutionary origin of apoptosis and its role in homeostasis. Today, in collaboration with his wife Laurence Zitvogel, he returns to his first interest, the role of apoptosis in the immune system, as always provoking others with challenging and deep questions.
He has been justly recognized with many awards, including the prestigious Descartes Prize of the EuropeanUnion, the Carus Medal of the German Academy of Sciences, the Grand Prix Mergier-Bourdeix of the FrenchAcademy of Sciences, the Lucien Dautrebande Prize of the Belgian Royal Academy of Medicine, the Gallet & Breton Prize of the French Academy of Medicine, the Duquesne Prize of the French National League against Cancer and the “Coup d’Elan” Prize of the Fondation Bettencourt-Schueller, among others. He is currently themost cited scientist worldwide in the field of cell death as well as in the area of mitochondrial research. TheInternational Cell Death Society belated honors one of its prolific and provocative leaders.
Turkey, 2010: Eileen White
Starting with her initial discoveries that an adenovirus homolog of Bcl-2 rendered the virus oncogenic and her elaboration of the interactions of anti-tumor factors such as p53 and these pro-cancer-favoring genes, Eileen became among the first, and the most prolific, investigator of the role of metabolism in apoptosis and oncogenesis. Following this lead, she discovered that apoptosis-resistant tumor cells acquired their resistance by activating autophagy, and that autophagy could protect cells by eliminating damaged materials or organelles and providing nutrient or other resources to challenged cells.
She applies this understanding of autophagy and metabolism to argue that cells have many options to overcome challenge, and that therapies to protect cells (in neural disease) or destroy them (in cancer) must take into account these several options. Her success in raising and defending these ideas has led to her major role as a consultant to pharmaceutical industry and to numerous awards including a MERIT award from the National Cancer Institute, the Red Smith award from the Damon Runyon Cancer Research Foundation.
South Africa, 2009: Douglas R. Green
Always colorful, provocative, and imaginative, Doug Green is a familiar and prominent figure in most meetings on cell death. His wide-ranging interests have led him to important observations and discoveries regarding the sensitivities of cells of the immune system to toxins, growth and necrosis factors, interactions with related cells, and responses to genetic changes.
His curiosity in knowing more about how mitochondria impacted apoptosis led to a series of brilliant and daring experiments to track the step-by-step progress to apoptosis; and his curiosity about why some cells were more sensitive than others to identical challenges led to a detailed and well-designed exploration of autophagy, metabolism, and receptor-ligand interactions in cell death.
South Africa, 2009: Marie-Lise Gougeon
An important factor in getting the world to recognize the medical importance of apoptosis was the recognition that most of the loss of CD4+ cells in patients with AIDS was apoptosis of uninfected bystander cells, suggesting that their suicide might be preventable. The most important contributor to this idea was Marie-Lise Gougeon. Her impeccable research, documentation, and elaboration of mechanisms built the case for the importance of cell suicide in the presence of virus, the ability of viruses to control the fate of host and bystander cells, and the necessity of providing support for cells that can be protected.
The ideas that she generated or helped to promulgate have led to HAART (Highly Active Antiretroviral Therapy) and therapies based on cell support. In addition to her outstanding research, she is active in the social ramifications of the disease, traveling throughout the world to learn about the geographic and population aspects of AIDS, and to train workers in the most effective and affordable means of treatment and prevention.
China, 2008: H. Robert Horvitz
Following the suggestion of Sidney Brenner to document all the cells inCaenorhabditis elegans, Bob Horvitz and John Sulston in 1977 published a map of the worm’s development, noting also that 111 cells were born only to die shortly thereafter. By 1990 Horvitz’s group had identified a small number of genes that controlled the deaths of these cells, when they electrified the community by announcing that the primary killer gene was not only a protease but a known protease.
This discovery burst open the entire subject of apoptosis, leading quickly to recognition of the caspase family of proteases and generating the fervent activity that we now see in research and biotechnical and pharmaceutical efforts to directly or indirectly control the activity of caspases and thereby apoptosis. For this and many subsequent discoveries, Horvitz, Sulston, and Brenner were awarded the 2002 Nobel Prize in Physiology or Medicine.
China 2008: Zahra Zakeri (Special Award)
Moving from virology to apoptosis and back again, Zahra Zakeri has been the first to spot many breakthroughs in the field of cell death, including the activation of myc and fos in apoptosis; the importance of autophagy in cell death; and the interplay in which viruses and cells compete to control apoptosis to achieve their goals. However, this award, to Dr. Zakeri as “Ambassador in Science” salutes her ability to bring people together. She has done this by bringing together many collaborators, whether with herself or introducing other scientists whose common purpose she has identified.
On a larger scale, she was a prime motivator to initiate the Gordon Conference on Cell Death, and the energy behind the foundation of the International Cell Death Society and Scientists Without Frontiers. The ICDS has grown remarkably since she founded it in 19??, and through Scientists Without Frontiers she has taken meetings and scientists to countries that otherwise have not had access to Western science; has introduced visiting and host scientists to each other; and has arranged collaborations and exchanges among them. Within this framework she has also built strong support for young scientists and women in science.
Brazil 2006: Richard A. Lockshin
In his doctoral thesis Richard Lockshin documented and stated what struck him as an obvious point, that the death of cells during development could be considered like any other developmental event to be a controlled process. In 1964 and 1965, he and his mentor, Carroll M. Williams, published the argument and the experimental evidence in a series of papers under the thesis title “Programmed Cell Death”.
In subsequent papers, Lockshin was among the first to identify the synthesis of new proteins required to activate developmental cell death; the importance of autophagy in cell death processes; and the essentially normal physiological state of the dying cell until late in its collapse. He and his wife Zahra Zakeri founded the Gordon Conference on Cell Death and the International Cell Death Society.
Brazil 2006: Junying Yuan
The International Cell Death Society presents the 2006 Scientific Award to Professor Junying Yuan for her discoveries that elucidated the genetic basic of programmed cell death and necroptosis.
Having grown up in a family of scientists and engineers in Shanghai during the Chinese cultural revolution, Junying knew the importance of science education at an early age. Majoring in biology and chemistry, Junying attended Fudan University in Shanghai, and based on her spectacular academic performance, she was accepted into the PhD program at Harvard in 1982. With a keen interest in cell death, Junying convinced the program director at Harvard to allow her to work at MIT in the laboratory of Professor Robert Horwitz.
As a graduate student, Junying’s contributions to the field of programmed cell death were nothing short of remarkable. Her research focused on unraveling genes essential for cell death in C. elegans, and demonstrated that the programmed death machinery was regulated by two preeminent genes, ced-4 and ced-3, that when mutated blocked developmental death. This pioneering work not only showed that programmed cell death was cell autonomous, and highly predictable in worm development.
After completing her PhD PhD studies at Harvard, Dr. Yuan started her own lab at the Massachusetts General Hospital from 1990 to 1993 and later returned to Harvard Medical School where she currently holds the rank as Professor of Cell Biology. As an independent scientist, she showed that the programmed cell death machinery was evolutionarily conserved, and that the worm ced-3 was the counterpart of the mammalian caspase 3. These discoveries brought Junying into the mainstay of mammalian apoptosis and neurodegeneration, where her group described in great details the relationships between trophic factor deprivation and caspase activation. Her curiosity about the role of cell death in neurodegeneration and injury also led to the identification of a new type of caspase-independent cell death, called necroptosis, which is highly relevant for ischemic death during stroke and infarction. Her laboratory has recently described in great detail the pathways involving necroptosis, and developed the first small molecule inhibitors called Nec-1.
For her work, Dr. Yuan has been presented many awards including SCBA Outstanding Young Investigator Award from MD Anderson, the 2002 Innovator Award for Breast Cancer Research, and the 2005 NIH Director’s Pioneer Award. The society is honored to present Professor Yuan with the 2006 International Cell Death Society Award.
Ireland 2004: Shigekazu Nagata
In 1991 the oncology world was startled to learn that the primary lesion in many tumors was not a lesion in cell cycle but rather one in apoptosis. One of these very important papers was “The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis.” by Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S. in Cell. 1991 66: 233-43.
With this seminal paper Shige and his team quickly moved to identifying mutations of the genes for Fas and Fas Ligand as causes of lupus-like syndromes in mice, thereby opening the question of the role of apoptosis in the immune system as a central issue in health and disease of the hematopoietic system. The Nagata laboratory has continued to make many contributions to our understanding of apoptosis in the development, physiology, and pathology of the immune and central nervous systems, and he remains a leading contributor to the field.
Ireland 2004; Peter Krammer
In 1989, Peter Krammer began to give lectures in which, using spectacular pictures, he described a molecule that could cause even huge mouse tumors of hematopoietic origin to completely disappear. Quickly recognizing how it worked, he called the molecule APO-1, which he described in a paper in Science: Monoclonal antibody-mediated tumor regression by induction of apoptosis. Trauth BC, Klas C, Peters AM, Matzku S, Möller P, Falk W, Debatin KM, Krammer PH. Science. 1989 245:301-5.
The molecule proved to be an already-known molecule, CD95, also being explored as Fas for its role in autoimmune disease, but Krammer’s results put him in the forefront of the exploration of the role of apoptosis in cancer, a vast field in which he and his laboratory have made and continue to make major contributions, at theoretical, research, and clinical levels, and his laboratory has produced a new generation of outstanding researchers.
Noosa, Australia, 2002: John F. Kerr
John Kerr had been studying liver pathology since the mid-1960’s, paying attention as were others to the activity of lysosomes in cell death. In these studies he began to notice certain consistent patterns that he could not explain. For instance, although the movement of ions and water could explain cell lysis, or necrosis, in cells that had lost energy resources, some cells shrank and became dense cells with dark, compacted nuclei. Furthermore, this type of death was found not only in liver cells but in many other types of pathology, an idea that he summarized in 1971 as shrinkage necrosis (Shrinkage necrosis: a distinct mode of cellular death. Kerr JF. J Pathol. 1971 Sep;105(1):13-20).
Shortly thereafter he departed on sabbatical to Scotland, where he met and compared notes with Andrew Wyllie and Alastair R. Currie. They concluded that the phenomenon was quite general and implied a new biology of cell death, unknown at the time but surely as important as the biology of cell division. They consulted a Classics scholar seeking a suitable parallel to “mitosis” and found a term that would excite the imagination of pathologists, developmental biologists, and cell and molecular biologists throughout the world.Their description of the phenomenon and its name was published in 1972: Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Kerr JF, Wyllie AH, Currie AR. Br J Cancer. 1972 Aug;26(4):239-57.
Two hundred thousand publications later, we can agree that this paper represented a profound insight.