‘Centennial’ Nobel Conference on apoptosis and human disease

More than a hundred years ago, a sharp-eyed German anatomist described a unique form of spontaneous cell death in regressing ovarian follicles that he termed chromatolysis for the breaking up and disappearance of nuclei.¹ Reports of cell death with similar characteristics in other tissues followed, and in the middle of the last century it was clear that programmed cell death (PCD) during embryonic development was associated with the same morphological features (for review see²). In 1972, Kerr and colleagues described a form of physiological cell death based on the appearance of specific morphological criteria.³ It was given the name apoptosis and suggested to be responsible for maintenance of tissue homeostasis in the adult organism. The first biochemical evidence of apoptosis followed a few years later when the appearance of oligonucleosomal-length DNA fragments in irradiated lymphocytes was reported;⁴ this effect was subsequently linked to increased endonuclease activity and for many years to come the ‘DNA ladder’ was the prime hallmark of apoptosis.⁵ Work on the genetic regulation of cell death was initiated about the same time when it was discovered that cells of diverse origins in the nematode Caenorhabditis elegans undergo the same morphological changes at specific times in development.⁶ Following relatively few developments in the field during the early 1980s, advances over the last 15 years have been swift and a role for apoptotic cell death in embryonic development, tissue homeostasis, and the onset of different diseases, including neurodegenerative disorders and cancer, has been demonstrated. At the recent Nobel Conference, entitled ‘Apoptosis: Mechanisms and Implications for Human Disease’ held in Stockholm, October 4–7, 2001, leaders in apoptosis and cell death research met to discuss the latest developments in the field. The conference covered a veritable smörgåsbord of topics ranging from basic mechanisms of apoptosis to the role of apoptosis in human disease. What emerged was a sense that efforts to understand basic mechanisms of apoptosis are beginning to pay off in the form of novel strategies for treating disease. In this review, we summarize the meeting's major concepts and themes as well as discuss some unresolved controversies in this rapidly evolving field.

R Horvitz's (Cambridge, MA, USA) pioneering work on the genetic regulation of PCD during the development of C. elegans made him an obvious choice for the introductory lecture. There are 959 somatic cells in the adult nematode and an additional 131 cells undergo PCD during development. The function of three genes–egl-1 (egl, egg laying defective), ced-3 (ced, cell death abnormal), and ced-4 – is required for PCD to take place. Loss-of-function aberrations in these genes result in the survival of the 131 cells that are normally predetermined to die. A fourth gene, ced-9 (similar to human Bcl-2), protects cells from PCD, and loss-of-function mutations in this gene result in the death of cells that would normally survive.

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