Apoptosis: a needed return to first principles

Response from SloviterI agree completely with Dr Fujikawa's reasoning and arguments [1xApoptosis: ignoring morphology and focusing on biochemical mechanisms will not eliminate confusion. Fujikawa, D.G. Trends Pharmacol. Sci. 2002; 23: 309–310Abstract | Full Text | Full Text PDF | PubMed | Scopus (7)See all References][1], but only in theory. In practice, I believe that careful morphological analysis and interpretation are beyond the expertise of most investigators who study the mechanisms of cell death and hope to be able to discuss their results within the context of ‘apoptosis’. Although apoptosis was originally described morphologically, countless articles purporting to identify apoptotic cells contain no morphological data whatsoever. Countless other studies show morphological features that have been misidentified and misclassified as ‘apoptotic’, leading to a cascade of erroneous inferences and conclusions about the etiologies of neurological disorders. Thus, my point about removing morphology as a defining characteristic of a certain kind of cell death derives primarily from the observation that the misinterpretation of morphology has produced a stream of articles that have declared virtually every example of brain cell death to be ‘apoptosis’, as if apoptosis were a real entity. However, my overall point is not about morphology, or whether we should coin more accurate morphological names for dying cells. My central argument is that the compulsive human addiction to creating names for ideas that cannot be defined precisely, and then imbuing them with cosmic significance and an independent existence, must be kicked cold turkey [2xApoptosis: a guide for the perplexed. Sloviter, R.S. Trends Pharmacol. Sci. 2002; 23: 19–24Abstract | Full Text | Full Text PDF | PubMed | Scopus (85)See all References][2].Dr Beranek argues that apoptosis is not difficult to define, and suggests that the confusion surrounding the meaning of apoptosis is a consequence of quick scientific evolution that has not paid enough attention to biological diversity and variability [3xApoptosis: coming to terms with biological diversity. Beranek, J.T. Trends Pharmacol. Sci. 2002; 23: 308Abstract | Full Text | Full Text PDF | PubMedSee all References][3]. On the contrary, I would argue that perhaps the dominant problem in modern science is the extreme reductionism that gives too much attention to the currently fashionable minutiae at the expense of the ‘big picture’. With the triumph of modern biology in the 19th and 20th centuries, the philosophical and historical foundations of science are now seen as quaintly interesting, but largely irrelevant, and we are the poorer for it. Few students appreciate how important the Greek concept of causality is to their ability to interpret experimental results logically, and few professional experimentalists understand why the Greeks felt they could not rely on the results of experiments, and why Francis Bacon came to believe that experimentation was imperative if science was to bear fruit and improve the quality of human existence. Apoptosis is hard to define partly because definition is a Greek idea no longer studied or understood by most students of science.Finally, I agree in theory with the thoughtful comments of Peter Clarke [4xApoptosis: from morphological types of cell death to interacting pathways. Clarke, P.G.H. Trends Pharmacol. Sci. 2002; 23: 308–309Abstract | Full Text | Full Text PDF | PubMedSee all References][4]. I would not want to leave the impression that we should abandon the notion of morphological types of cell death. On the contrary, morphology is one of the few real experimental endpoints, and its accurate evaluation and analysis are invaluable. My concern is with the misinterpretation of ambiguous morphological features and their forced linkage to poorly defined concepts. In artistic endeavors, ambiguity of meaning is often an intentional and fruitful device. In science, ambiguous expression is counterproductive and a bit like playing tennis with the net down: it makes the game easier, but the results are not very impressive.