Tissue repair and stem cell renewal in carcinogenesis

Cancer is increasingly being viewed as a stem cell disease, both in its propagation by a minority of cells with stem-cell-like properties and in its possible derivation from normal tissue stem cells. But stem cell activity is tightly controlled, raising the question of how normal regulation might be subverted in carcinogenesis. The long-known association between cancer and chronic tissue injury, and the more recently appreciated roles of Hedgehog and Wnt signalling pathways in tissue regeneration, stem cell renewal and cancer growth together suggest that carcinogenesis proceeds by misappropriating homeostatic mechanisms that govern tissue repair and stem cell self-renewal.     

The case for a US prospective cohort study of genes and environment

Information from the Human Genome Project will be vital for defining the genetic and environmental factors that contribute to health and disease. Well-designed case-control studies of people with and without a particular disease are essential for this, but rigorous and unbiased conclusions about the causes of diseases and their population-wide impact will require a representative population to be monitored over time (a prospective cohort study). The time is right for the United States to consider such a project.     

Sustainable trophy hunting of African lions

In most species, sport hunting of male trophy animals can only reduce overall population size when the rate of removal of males is so high that females can no longer be impregnated. However, where males provide extensive paternal care, the removal of even a few individuals could harm the population as a whole. In species such as lions, excessive trophy hunting could theoretically cause male replacements (and associated infanticide) to become sufficiently common to prevent cubs reaching adulthood. Here we simulate the population consequences of lion trophy hunting using a spatially explicit, individual-based, stochastic model parameterized with 40 years of demographic data from northern Tanzania. Although our simulations confirm that infanticide increases the risk of population extinction, trophy hunting could be sustained simply by hunting males above a minimum age threshold, and this strategy maximizes both the quantity and the quality of the long-term kill. We present a simple non-invasive technique for estimating lion age in populations lacking long-term records, and suggest that quotas would be unnecessary in any male-only trophy species where age determination could be reliably implemented.     

Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox

The potential use of smallpox as a biological weapon has led to the production and stockpiling of smallpox vaccine and the immunization of some healthcare workers. Another public health goal is the licensing of a safer vaccine that could benefit the millions of people advised not to take the current one because they or their contacts have increased susceptibility to severe vaccine side effects. As vaccines can no longer be tested for their ability to prevent smallpox, licensing will necessarily include comparative immunogenicity and protection studies in non-human primates. Here we compare the highly attenuated modified vaccinia virus Ankara (MVA) with the licensed Dryvax vaccine in a monkey model. After two doses of MVA or one dose of MVA followed by Dryvax, antibody binding and neutralizing titres and T-cell responses were equivalent or higher than those induced by Dryvax alone. After challenge with monkeypox virus, unimmunized animals developed more than 500 pustular skin lesions and became gravely ill or died, whereas vaccinated animals were healthy and asymptomatic, except for a small number of transient skin lesions in animals immunized only with MVA.     

Tissue engineering: creation of long-lasting blood vessels

The construction of stable blood vessels is a fundamental challenge for tissue engineering in regenerative medicine. Although certain genes can be introduced into vascular cells to enhance their survival and proliferation, these manipulations may be oncogenic. We show here that a network of long-lasting blood vessels can be formed in mice by co-implantation of vascular endothelial cells and mesenchymal precursor cells, by-passing the need for risky genetic manipulations. These networks are stable and functional for one year in vivo.     

Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae

Whole-genome duplication followed by massive gene loss and specialization has long been postulated as a powerful mechanism of evolutionary innovation. Recently, it has become possible to test this notion by searching complete genome sequence for signs of ancient duplication. Here, we show that the yeast Saccharomyces cerevisiae arose from ancient whole-genome duplication, by sequencing and analysing Kluyveromyces waltii, a related yeast species that diverged before the duplication. The two genomes are related by a 1:2 mapping, with each region of K. waltii corresponding to two regions of S. cerevisiae, as expected for whole-genome duplication. This resolves the long-standing controversy on the ancestry of the yeast genome, and makes it possible to study the fate of duplicated genes directly. Strikingly, 95% of cases of accelerated evolution involve only one member of a gene pair, providing strong support for a specific model of evolution, and allowing us to distinguish ancestral and derived functions.     

The microscopic nature of localization in the quantum Hall effect

The quantum Hall effect arises from the interplay between localized and extended states that form when electrons, confined to two dimensions, are subject to a perpendicular magnetic field. The effect involves exact quantization of all the electronic transport properties owing to particle localization. In the conventional theory of the quantum Hall effect, strong-field localization is associated with a single-particle drift motion of electrons along contours of constant disorder potential. Transport experiments that probe the extended states in the transition regions between quantum Hall phases have been used to test both the theory and its implications for quantum Hall phase transitions. Although several experiments on highly disordered samples have affirmed the validity of the single-particle picture, other experiments and some recent theories have found deviations from the predicted universal behaviour. Here we use a scanning single-electron transistor to probe the individual localized states, which we find to be strikingly different from the predictions of single-particle theory. The states are mainly determined by Coulomb interactions, and appear only when quantization of kinetic energy limits the screening ability of electrons. We conclude that the quantum Hall effect has a greater diversity of regimes and phase transitions than predicted by the single-particle framework. Our experiments suggest a unified picture of localization in which the single-particle model is valid only in the limit of strong disorder.     

Disposable-soma senescence mediated by sexual selection in an ungulate

Senescence may result from an optimal balance between current reproductive investment and bodily repair processes required for future reproduction, a theoretical prediction difficult to prove especially in large, long-lived animals. Here we propose that teeth that have fixed dimensions early in life, but that wear during chewing, can be taken as a measure of total lifetime 'repair', and their wear rate as a measure of current expenditure in performance. Our approach also considers the sexual selection process to investigate the advance of senescence in males compared with females, when selection favouring competition over mates reduces the reproductive lifespan of males. We studied carcasses of 2,141 male and 739 female red deer (Cervus elaphus) of different ages, finding that male molariform teeth emerged at a far smaller size than expected from body size dimorphism. This led to higher workload, steeper wear rate and earlier depletion of male teeth than in females, in concordance with sex-specific patterns of lifetime performance and reproduction. These findings provide the empirical support for the disposable-soma hypothesis of senescence, which predicts that investment in bodily repair will decrease when the return from this investment may not be realized as a result of other causes that limit survival or reproduction.