Biological weapons

Anthrax has been a major cause of death in grazing animals and an occasional cause of death in humans for thousands of years. Since the late 1800s there has been an exceptional international history of anthrax vaccine development. Due to animal vaccinations, the rate of infection has dropped dramatically. Anthrax vaccines have progressed from uncharacterized whole-cell vaccines in 1881, to pXO2-negative spores in the 1930s, to culture filtrates absorbed to aluminum hydroxide in 1970, and likely to recombinant protective antigen in the near future. Each of these refinements has increased safety without significant loss of efficacy. The threat of genetically engineered, antibiotic and vaccine resistant strains of Bacillus anthracis is fueling hypothesis-driven research and global techniques--including genomics, proteomics and transposon site hybridization--to facilitate the discovery of novel vaccine targets. This review highlights historical achievements and new developments in anthrax vaccine research.     

The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus

Mice carrying mutations at the W locus located on chromosome 5 are characterized by severe macrocytic anaemia, lack of hair pigmentation and sterility. Mutations at this locus appear to affect the proliferation and/or migration of cells during early embryogenesis and result in an intrinsic defect in the haematopoietic stem cell hierarchy. An understanding of the molecular basis of the complex and pleiotropic phenotype in W mutant mice would thus provide insights into the important developmental processes of gametogenesis, melanogenesis and haematopoiesis. Here we show that the mouse mutant W has a deletion of the c-kit proto-oncogene. Interspecific backcross analysis demonstrates that the W locus is very tightly linked to c-kit and that the two loci cannot be segregated at this level of analysis. c-kit is the cellular homologue of the oncogene v-kit of the HZ4 feline sarcoma virus and encodes a transmembrane protein tyrosine kinase receptor that is structurally similar to the receptors for colony-stimulating factor-1 (CSF-1) and platelet derived growth factor. The co-localization of c-kit with W provides a molecular entry into this important region of the mouse genome. In addition, these observations provide the first example of a germ-line mutation in a mammalian proto-oncogene and implicate the c-kit gene as a candidate for the W locus.     

Stochastic gene expression out-of-steady-state in the cyanobacterial circadian clock

Recent advances in measuring gene expression at the single-cell level have highlighted the stochastic nature of messenger RNA and protein synthesis. Stochastic gene expression creates a source of variability in the abundance of cellular components, even among isogenic cells exposed to an identical environment. Recent integrated experimental and modelling studies have shed light on the molecular sources of this variability. However, many of these studies focus on systems that have reached a steady state and therefore do not address a large class of dynamic phenomena including oscillatory gene expression. Here we develop a general protocol for analysing and predicting stochastic gene expression in systems that never reach steady states. We use this framework to analyse experimentally stochastic expression of genes driven by the Synechococcus elongatus circadian clock. We find that, although the average expression at two points in the circadian cycle separated by 12 hours is identical, the variability at these two time points can be different. We show that this is a general feature of out-of-steady-state systems. We demonstrate how intrinsic noise sources, owing to random births and deaths of mRNAs and proteins, or extrinsic noise sources, which introduce fluctuations in rate constants, affect the cell-to-cell variability. To distinguish experimentally between these sources, we measured how the correlation between expression fluctuations of two identical genes is modulated during the circadian cycle. This quantitative framework is generally applicable to any out-of-steady-state system and will be necessary for understanding the fidelity of dynamic cellular systems.