n this interview, Dr. Guido Kroemer talks with Special Topics about his highly cited work in apoptosis research. A recent survey by Special Topics shows that Dr. Kroemer is among the top 10 researchers in this field, with 115 papers cited a total of 8,052 times. In ISI Essential Science Indicators Web product, Dr. Kroemer’s work can be found in the fields of Clinical Medicine, Biology & Biochemistry, and Immunology. Dr. Kroemer is a Research Director at the Institut Gustave-Roussy in Villejuif, France.

Obviously, we are interested in the fine mechanisms of mitochondrial apoptosis. So, we would like to understand the detailed molecular mechanisms accounting for MMP, both in health and in disease. In particular, we are interested in how MMP contributes to cell death induced by the human immunodeficiency virus, how MMP contributes to illicit neuronal cell death, and how anti-cancer chemotherapy elicits MMP. We are also wondering how the resistance of mitochondria to MMP can explain the resistance of cancer cells to apoptosis induction, and we hope to develop strategies for overcoming chemotherapy resistance by targeting tumor mitochondria. In addition, we are intrigued by the mode of action of one particular apoptogenic factor released from mitochondria that we discovered and baptized "apoptosis inducing factor", AIF. AIF is phylogenetically conserved (which is not the case for caspases), and it is involved in the very first wave of morphogenetic cell death of the mouse embryo, as shown by knockout studies. We would like to dissect the mechanisms through which AIF translocates to the nucleus and causes chromatin condensation and degradation.

So in a way, we are attempting to follow up our initial discoveries, and to apply these findings to the comprehension of major apoptosis-related diseases including cancer and AIDS. Nonetheless, we would also like to tackle a few of the truly fundamental questions in cell death research; for instance, on the molecular links between different types of cell death such as apoptosis, autophagic cell death, senescence, and mitotic catastrophe. It is my intimate conviction that resolving fundamental issues has much higher prospects of application than research designed to be applied from the very beginning. I do hope that, in spite of the general conjecture, both the national and European funding agencies will allow me to proceed in accord with my convictions.

  What are the social implications of your work, if any?

The notion that MMP would constitute an apoptotic checkpoint proved to be operative for applied biomedical science in the sense that:

	Detection of MMP has become a surrogate marker of cell death.
	MMP is locally regulated at the level of mitochondrial membranes by several oncogene products, in particular the anti-apoptotic proteins of the Bcl-2 family.
	Several genetically determined diseases associated with cell loss, in particular neurodegenerative diseases, have been linked to mutations in mitochondrial proteins.
	Some intracellular parasites (viruses and bacteria) including several major pathogens such as human immunodeficiency virus-1, hepatitis B virus, or influenza virus, regulate MMP by producing proteins which target mitochondria.
	Several cytotoxic compounds (toxins and drugs) induce MMP in a direct fashion, that is, via a direct action on mitochondria.
	Induction of MMP by drugs specifically designed to target mitochondrial receptors (proteins or lipids) turned out to be efficient in the experimental treatment of cancers.
	Several cytoprotective drugs directly act on mitochondria to prevent MMP, and such drugs are useful for the prevention of acute cell death in several experimental paradigms of acute cell death, e.g. in ischemic reperfusion damage of the heart or of the brain.

As a result, it appears likely that pharmacological interventions on MMP will be taken advantage of to suppress unwarranted cell death and to enforce cell death in tumor cells. So research on MMP is relevant to several diseases with a major socioeconomic impact.

  What tools or technological advances have been important in your research, if any?

Technological advance has been instrumental for our research, at many levels. On the one hand, we developed a whole series of techniques in our laboratory. This applies to cytofluorometric staining protocols allowing for the monitoring of mitochondrial change at the single-cell or single-organelle level, as well as to the development of cell-free assays allowing for the direct assessment of apoptosis-related changes in isolated mitochondria and nuclei. On the other hand, we profited from the general technological advancement using, for instance, advanced proteomics approaches for our research.

  Did you expect your work to become highly cited, or is this surprising to you?

We (myself and my collaborators Dr. Zamzami and Dr. Susin, who also figure in the list of the 25 most-cited apoptosis researchers) did expect, indeed, as early as in 1995 that our work would be highly cited. We also anticipated that a large number of groups would move into the field of mitochondrial apoptosis, given the importance of the phenomenon. To paraphrase the German philosopher Schopenhauer, a truth, once discovered, is first ridiculed, then violently opposed, and finally considered as trivial. This is exactly what has been happening to the discovery that MMP controls apoptosis. Many groups on mitochondrial regulation of apoptosis do not even cite our initial work any more but instead cite more recent technological papers or general reviews.

  How rapidly has the state of our knowledge about your field evolved in the past decade, and what were the key discoveries that furthered the advancement of the field?

Advances in the field of apoptosis have been breathtaking over the last 10 years. In as little as 10 years many of the key components of the death regulatory machinery have been discovered, ranging from Fas/Apo-1/CD95-like death receptors to caspases and caspase activators. For our own studies, Xiaodong Wang's work showing that cytochrome c release from mitochondria leads to caspase activation has been most stimulating. It has also been very important that many signal transduction pathways have been connected to MMP and apoptosis control, both in health and in death. There were so many key discoveries in this vast area of research that it is impossible to enumerate them all.

Guido Kroemer, M.D., Ph.D.
Institut Gustave-Roussy
Villejuif, France