Previously Recognized Leaders in Cell Death
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.

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.

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.

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.

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.

China, 2008: H. Robert Horvitz

Following the suggestion of Sidney Brenner to document all the cells in Caenorhabditis 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.

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.

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.

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.

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 European Union, the Carus Medal of the German Academy of Sciences, the Grand Prix Mergier-Bourdeix of the French Academy 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 the most cited scientist worldwide in the field of cell death as well as in the area of mitochondrial research. The International Cell Death Society belated honors one of its prolific and provocative leaders.