In the past it has generally been assumed that certain cell-culture conditions, such as interactions with specific hormones and deprivation of basic nutrients and growth factors, result in physical damage or metabolic collapse of the cell, leading to a passive, or "necrotic," death. It was thought that the cell was at the complete mercy of its environment and had no control over its fate. However, it is now clear that the cell does not always respond in such a simple and passive manner. Instead, a range of factors can trigger a highly complex and genetically regulated cellular response during which specific "death proteins" are activated, a phenomenon that has been named apoptosis (1). It is these proteins that are responsible, ultimately, for the death and destruction of the cell. Indeed, in many cases, the cell may have sustained only low levels of damage. Clearly, under these conditions apoptotic death will be premature and is often referred to as cellular suicide.
Apoptosis is now acknowledged as a fundamentally important process that plays an essential role in embryogenesis and in the maintenance and functionality of the highly ordered cell populations that constitute higher organisms. Indeed, there are now few aspects of biomedical research upon which apoptosis has not had an impact. It is as a consequence of its fundamental nature that any failure in its regulatory mechanisms leads to many of the diseases that pose the greatest challenges to medical science. This has resulted in an explosion of research into the genetic basis of apoptosis, the objective of which is to develop novel therapeutics for a wide range of disorders, including cancer, AIDS, and ischemic injury. Consequently a growing number of proteins have been identified that are involved in the induction suppression and execution of the apoptotic program. It is now clear that many of the cell lines used in the biotechnology industry for the production of therapeutics undergo apoptotic death. Obviously, the advances made in the characterization of the apoptotic pathway may be applied to the suppression of the apoptotic response in industrial culture processes. This should provide the biotechnologist with a new route to the optimization ofculture performance.
We begin by describing the biochemical basis of apop-tosis, the morphological changes that accompany it, and some of the techniques that have been used to identify apoptotic cells. This is followed by a general discussion of the regulation and induction of apoptosis. We then describe studies that have investigated this phenomenon from a biotechnological perspective. Particular reference is made to the conditions that elicit an apoptotic response, the cell lines that are susceptible, and the effect of bcl-2 overexpression on cell survival and productivity in the bioreactor environment.
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