Kerr's coining of 'Apoptosis' and its relevance in skin wound healing and fibrosis.

Abstract

‘Apoptosis’, a Greek word meaning ‘dropping off’ or ‘falling off’, was first used by Kerr and team to label a form of cell death (Table 1) by a controlled genetic process whose morphological features were described in their seminal paper Kerr et al. (1), commented in this article. (The full article is freely available in PubMed Central http://www.ncbi.nlm.nih.gov/pubmed/4561027). Although they were the first to coin the term, it had been observed by a handful of scientists since the mid-nineteenth century and described under names such as ‘necrobiosis’ and ‘chromatolysis’ (2). By mid-1900’s, spontaneous cell death was a concept known to developmental biologists, but the features involved were not elucidated, and it drew little interest from the wider scientific community (2). It was not until Kerr’s landmark paper that ‘apoptosis’ as we know it came to be recognized as a phenomenon distinctly different from ‘necrosis’. Kerr himself initially used the term ‘shrinkage necrosis’ to describe his observations of cell death. In his 1965 experiment, he ligated a branch of the hepatic portal vein resulting in liver atrophy. He observed classical necrosis and a different form of cell death in the surviving tissue as liver shrinkage occurred. Some hepatocytes rounded off into small bodies of cytoplasm which sometimes contained condensed chromatin, these were then engulfed by the neighbouring cells or by specialized histiocytes (3). Kerr observed that these cells were in reality dying off to probably achieve a balance between surviving cells and the remaining blood supply (4). In the following years, he began to study the morphological features of ‘shrinkage necrosis’ using the electron microscope. On a sabbatical leave to Aberdeen, he collaborated with pathologists Alastair Currie and Andrew Wyllie who had themselves observed ‘shrinkage necrosis’ in rat adrenal cortices when adrenocorticotropic hormone was suppressed (3). It was here that they coined the term ‘apoptosis’ and described its morphological features. Decades later, this has evolved into the current understanding of the morphological hallmarks of apoptosis summarized in Fig. 1. Kerr et al. studied various instances of spontaneous cell loss such as in neoplasms, types of liver and adrenal injury, and in ontogenesis. They came to the fascinating conclusion that the morphological and ultra structural features exhibited by the phenomenon of cell death in each case were the same (1). We believe this was a remarkable achievement as nobody so far had realized that the features of this process in various tissues was similar enough to propose it as a concept of programmed cell death which as Kerr put it ‘plays a complementary but opposite role to mitosis’ in maintaining tissue homoeostasis. Interestingly, Kerr’s paper on apoptosis did not lead to an immediate flurry of research on the topic. However, the invention of novel techniques to detect apoptosis in cells, the discovery of genes regulating apoptosis in Caenorhabditis elegans and their mammalian homologues such as the BCL2 gene all played crucial roles in kindling scientific interest towards elucidating the biochemical mechanisms of apoptosis and the apoptotic machinery (5). It is now a well-known fact that altered tissue homoeostasis as a result of too much or too less apoptosis leads to a number of cutaneous pathologies such as toxic epidermal necrolysis, psoriasis, forms of skin cancer and fibrosis (6). Moreover, the molecular