First issue statement

As we enter the twenty-first century,mankind faces enormous ecological challenges arising from alarge human population with limited energy sources,diminished supplies of many scarce resources,andwidespread environmental contamination.Technologies to meet these challenges are increasingly depen-dent on combined methods using biotechnology,chemistry and chemical engineering to achieve solutions.This unique combination of methodologies has given rise to a growing discipline that has been termed Bio-process Engineering.We now announce the publication of a journal with this title.The joumal is being     

Anecdotal,Historical and Critical Commentaries on Genetics: In the Beginning Was the Worm …

The replicative life span (RLS) of Saccharomyces cerevisiae has been established as a model for the genetic regulation of longevity despite the inherent difficulty of the RLS assay, which requires separation of mother and daughter cells by micromanipulation after every division. Here we present the mother enrichment program (MEP), an inducible genetic system in which mother cells maintain a normal RLS—a median of 36 generations in the diploid MEP strain—while the proliferative potential of daughter cells is eliminated. Thus, the viability of a population over time becomes a function of RLS, and it displays features of a survival curve such as changes in hazard rate with age. We show that viability of mother cells in liquid culture is regulated by SIR2 and FOB1, two opposing regulators of RLS in yeast. We demonstrate that viability curves of these short- and long-lived strains can be easily distinguished from wild type, using a colony formation assay. This provides a simplified screening method for identifying genetic or environmental factors that regulate RLS. Additionally, the MEP can provide a cohort of cells at any stage of their life span for the analysis of age-associated phenotypes. These capabilities effectively remove the hurdles presented by RLS analysis that have hindered S. cerevisiae aging studies since their inception 50 years ago.THE budding yeast Saccharomyces cerevisiae is a popular model system for studying fundamental processes of cellular aging (reviewed in Steinkraus et al. 2008). Analyses over the past 50 years have led to the idea that budding yeast can be used to study three types of cellular aging. Replicative aging describes the division potential of individual cells and relies on the asymmetric cell divisions of budding yeast that yield distinct mother and daughter cells. Replicative life span (RLS) is defined as the number of times an individual cell divides before it undergoes senescence (Mortimer and Johnston 1959). Chronological aging describes the capacity of cells in stationary phase (analogous to G₀ in higher eukaryotes) to maintain viability over time, which is assayed by their ability to reenter the cell cycle when nutrients are reintroduced (Longo et al. 1996). Finally, budding yeast have been used to study clonal senescence, which is analogous to the Hayflick limit imposed on mammalian tissue culture cells and characterized by a finite number of times a population of cells can divide. Although wild-type yeast populations do not senesce, this phenomenon has been observed in mutant strains such as those lacking telomerase components (Lundblad and Szostak 1989; Singer and Gottschling 1994).While genetic screens have been applied to examine clonal and chronological aging (Lundblad and Szostak 1989; Powers et al. 2006; Murakami et al. 2008), they have been limited in their application to studying replicative aging (Kaeberlein and Kennedy 2005; Kaeberlein et al. 2005b). This limitation arises from the arduous nature of isolating replicatively aged yeast cells. The current “gold standard” for isolating aged mother cells is by micromanipulation, where daughter cells are counted and removed after every division (Park et al. 2002). Although micromanipulation is currently the only method capable of accurately measuring RLS in yeast, it is severely constrained by the small number of cells that can be analyzed. Thus, genetic analysis of the regulation of RLS has been limited to a candidate gene approach (reviewed in Steinkraus et al. 2008).True genetic analysis of RLS will require large populations of aged cells. However, there are two confounding issues that make isolation of aged individuals difficult. First, single-cell pedigree analysis has shown that age-associated phenotypes, such as replicative life span potential, segregate asymmetrically between mother and daughter cells, rendering age-associated phenotypes nonheritable (Egilmez and Jazwinski 1989; Kennedy et al. 1994). Thus, daughter cells are generally “reset” to a young state with every generation. Second, when age is measured in terms of cell divisions, an unfractionated population is predominately young. The fraction of the population at an age of n cell divisions is ∼1/2ⁿ. Individual cells that reach the median RLS, which is ∼26 generations for haploid cells of the S288C strain background (Kaeberlein et al. 2005a), represent an insignificant fraction of the total population. In fact, it is unlikely that any cell reaches such an advanced age because nutrient depletion will limit the division potential of the population (Dickinson and Schweizer 1999).As an alternative to micromanipulation, methods were developed to isolate aged cells from liquid cultures (Smeal et al. 1996; Sinclair and Guarente 1997; Chen and Contreras 2007). However, due to the exponential growth of progeny cells, these populations are technically limited to 7–12 generations before nutrient depletion interferes with replicative aging. While sequential rounds of growth and purification are possible, the inability to continuously follow an undisturbed cohort of cells prevents the measurement of RLS by these methods. Instead, purification methods are primarily used for the examination of molecular changes associated with aging cells. Unfortunately, low yields and loss of viability due to purification methods diminish their utility for analyzing phenotypes that affect cells of advanced age. As an alternative to purification from natural populations, a strategy to genetically regulate the replicative capacity of daughter cells and avoid the limits imposed by exponential growth has been described (Jarolim et al. 2004). While this system effectively prevents division of daughter cells, it unintentionally decreases the median RLS of mother cells to four cell divisions, thus restricting its usefulness.Here we describe the development of a novel genetic selection against newborn daughter cells, the “mother enrichment program” (MEP), which restricts the replicative capacity of daughter cells while allowing mother cells to achieve a normal RLS. We demonstrate that upon induction of the selection, the viability of MEP strains growing in liquid culture is determined by the RLS of the initial population of mother cells. MEP cultures therefore allow the comparison of RLS between strains without the need for micromanipulation. Additionally, because MEP cultures are not subject to nutrient limitation, single-step affinity purification of aged cells can be achieved at any point during their life span. Together, these capabilities substantially resolve the technical hurdles that have made replicative aging studies in S. cerevisiae exceptionally challenging.     

A special issue on ＇Cancer＇

Cancer is a set of diseases characterized by uncontrolled or inappropriate cell growth, which is strongly associated with defects in signal-transduction proteins. Understanding the molecular details of major signaling pathways is critical for developing therapeutic strategies against cancers. In this special issue, we have invited several prominent experts in the field of cancer research to summarize the recent advances in this field. The articles in this special issue can be grouped into four major topics： （i） the molecules involved in cancer signaling pathway （Feng ZH, Hu WW, Liu BL, and Wang ZH）, （ii） metabolic reprogramming and hypoxia in cancer （Lei QY and Zhang HF）, （iii） noncoding RNA and anticancer drugs （Huang X and Xi YG）, and （iv） immuno- modulatory drugs （Chang XB）.