Gene therapy in the clinic: whose risks?

Current experience with gene therapy for X-linked severe combined immunodeficiency disorder (X-SCID) suggests that we might now be at the point where it can be considered the 'standard of care'. This therapy carries an unquantified risk of leukaemia, raising important questions for regulators. How dangerous does a potentially curative therapy for a fatal illness need to be before we call it unsafe. How uncertain does a risk need to be for us to regard a therapy as still 'experimental'? Whose interests should prevail? Here I argue that in X-SCID it is the parents and children whom we should listen to first and foremost. How far does this patient-centred approach to licensing therapies extend? Can it be given a rational basis?     

Regulation of the AMPK-related protein kinases by ubiquitination

How can a constitutively active 'master' kinase with numerous downstream targets preferentially phosphorylate one or more of these without influencing all simultaneously? How might such a system be switched off? The characterization of the role of deubiquitination in regulating the phosphorylation and activation of AMPK (AMP-activated protein kinase)-related kinases by LKB1 suggests a novel and interesting mechanism for conferring signal transduction specificity and control at the kinase substrate level. In this issue of the Biochemical Journal, Al-Hakim et al. show that the AMPK-related kinases NUAK1 (AMPK-related kinase 5) and MARK4 (microtubule-affinity-regulating kinase 4) are polyubiquitinated in vivo and that they serve as substrates of the deubiquitinating enzyme USP9X; furthermore, the first evidence is provided for regulation of AMPK-related kinase family members mediated via unusual Lys(29)/Lys(33) polyubiquitin chains, rather than the more common Lys(48)/Lys(63) linkages.     

Epigenetics and phenotypic variation in mammals

What causes phenotypic variation? By now it is clear that phenotype is a result of the interaction between genotype and environment, in addition to variation not readily attributable to either. Epigenetic phenomena associated with phenotypic variation at the biochemical, cellular, tissue, and organism level are now well recognized and are likely to contribute to the “intangible variation” alluded to. While it is clear that epigenetic modifications are mitotically heritable, the fidelity of this process is not well understood. Inheritance through more than one generation of meioses is even less well studied. So it remains unclear to what extent epigenetic changes contribute to phenotypic variation in natural populations. How might such evidence be obtained? What are the features of phenotypes that might suggest an epigenetic component? How much of the epigenetic component is truly independent of genetic changes? The answers to such questions must come from studies designed specifically to detect subtle, stochastically determined phenotypic variation in suitable animal models.     

Choices in neuroscience careers

How do I choose a mentor? How do I decide what field of neuroscience to work in? Should I consider doing research in industry? Most students and postdoctoral researchers aiming for a successful career in neuroscience ask themselves these questions. In this article, Nature Reviews Neuroscience asks four successful neuroscientists for their thoughts on the factors one should consider when making these decisions. We hope that this Viewpoint will serve as a useful resource for junior neuroscientists who have to make important and sometimes difficult decisions that might have long-lasting consequences for their careers.     

Propensity of white women in the United States to adopt children

Demographically, adoption is a relatively rare event. In 1982, only 2.3 per cent (or about 650,000) of ever-married white women aged 15 to 44 had adopted one or more children. Adoption is an important and very relevant means of family formation for many women, particularly those for whom biological childbearing is difficult or impossible. Although there is a modest literature on adoption behavior, we have very little information about women who have shown a propensity to adopt children. How should the phenomenon of adoption propensity be conceptualized? How many women are there in the United States with such a propensity? How different is this number from the number of women who eventually adopt children? What are the characteristics of women with a propensity to adopt? The objectives of this paper are (1) to estimate the numbers of U.S. women at three different points in time (1973, 1976, and 1982) who have a propensity to adopt, according to various socioeconomic and demographic characteristics; and (2) to compare via log-linear analysis the major characteristics of these women with women who have not shown such a propensity.     

In the blood--the remarkable ancestry of Plasmodium falciparum

Discussions concerning the origin and spread of malaria are popular. Colourful and diverse players, such as early hominids, agriculturalists, conquistadors and various animals, tend to feature prominently in imagined horrible histories. So, what of recent studies on genomic diversity of Plasmodium falciparum that claim to give more precision to the subject? Have they restricted the freeform speculation or just enhanced it? Or, are they pointing to a more important understanding about the parasite that might affect its future?     

Ideas about control of skeletal and cardiac muscle blood flow (1876-2003): cycles of revision and new vision.

This perspective examines origins of some key ideas central to major issues to be addressed in five subsequent mini-reviews related to Skeletal and Cardiac Muscle Blood Flow. The questions discussed are as follows. 1). What causes vasodilation in skeletal and cardiac muscle and 2). might the mechanisms be the same in both? 3). How important is muscle's mechanical contribution (via muscle pumping) to muscle blood flow, including its effect on cardiac output? 4). Is neural (vasoconstrictor) control of muscle vascular conductance and muscle blood flow significantly blunted in exercise by muscle metabolites and what might be a dominant site of action? 5). What reflexes initiate neural control of muscle vascular conductance so as to maintain arterial pressure at its baroreflex operating point during dynamic exercise, or is muscle blood flow regulated so as to prevent accumulation of metabolites and an ensuing muscle chemoreflex or both?     

Determinants of Life-history Evolution in Nematodes

What are the determinants of parasite life-history evolution? Does life-history evolution of parasitic species differ from their free-living relatives? How and why do host and parasite life-history traits covary? Here, Serge Morand and Gabriele Sorci use recent comparative studies to investigate life-history evolution in nematodes which present both parasitic and free-living groups. Application of life-history theory to nematodes suggests that the conventional wisdom concerning the high fecundity of parasitic species could simply be the result of the larger body size of the latter when compared with free-living forms. The authors also emphasize, with the use of examples, that in most cases parasite life-history evolution depends on host features.     

How much Ascariasis is there in Africa?

What is the real burden of parasitic infections? How many people, for example, are infected with the common roundworm Ascaris lumbricoides-usually cited as'number one' in the 'league table' of human parasite prevalence? Extrapolations are often made from figures for helminth infection published in 1947 by Stoll. More recent estimates suggest almost unbelievable numbers of oscoriosis cases - about 1000 million people representing about one quarter of the world population. Such figures are important because they contribute to the perennial debate about: allocation o f scarce health resources in affected countries to infections of greatest public health importance. But where do such figures come from? In this article, David Crompton and Jim Tulley report on their appraisal of Ascaris prevalence data for Africa. Their figures were used to compile the geographic histogram on this month's cover.     

Mate choice for genetic quality when environments vary: suggestions for empirical progress

Mate choice for good-genes remains one of the most controversial evolutionary processes ever proposed. This is partly because strong directional choice should theoretically deplete the genetic variation that explains the evolution of this type of female mating preference (the so-called lek paradox). Moreover, good-genes benefits are generally assumed to be too small to outweigh opposing direct selection on females. Here, we review recent progress in the study of mate choice for genetic quality, focussing particularly on the potential for genotype by environment interactions (GEIs) to rescue additive genetic variation for quality, and thereby resolve the lek paradox. We raise five questions that we think will stimulate empirical progress in this field, and suggest directions for research in each area: (1) How is condition-dependence affected by environmental variation? (2) How important are GEIs for maintaining additive genetic variance in condition? (3) How much do GEIs reduce the signalling value of male condition? (4) How does GEI affect the multivariate version of the lek paradox? (5) Have mating biases for high-condition males evolved because of indirect benefits?     

Mosquito mortality and the evolution of malaria virulence

Abstract Several laboratory studies of malaria parasites (Plasmodium sp.) and some field observations suggest that parasite virulence, defined as the harm a parasite causes to its vertebrate host, is positively correlated with transmission. Given this advantage, what limits the continual evolution of higher parasite virulence? One possibility is that while more virulent strains are more infectious, they are also more lethal to mosquitoes. In this study, we tested whether the virulence of the rodent malaria parasite P. chabaudi in the laboratory mouse was correlated with the fitness of mosquitoes it subsequently infected. Mice were infected with one of seven genetically distinct clones of P. chabaudi that differ in virulence. Weight loss and anemia in infected mice were monitored for 16–17 days before Anopheles stephensi mosquitoes were allowed to take a blood meal from them. Infection virulence in mice was positively correlated with transmission to mosquitoes (infection rate) and weakly associated with parasite burden (number of oocysts). Mosquito survival fell with increasing oocyst burden, but there was no overall statistically significant relationship between virulence in mice and mosquito mortality. Thus, there was no evidence that more virulent strains are more lethal to mosquitoes. Both vector survival and fecundity depended on parasite clone, and contrary to expectations, mosquitoes fed on infections more virulent to mice were more fecund. The strong parasite genetic effects associated with both fecundity and survival suggests that vector fitness could be an important selective agent shaping malaria population genetics and the evolution of phenotypes such as virulence in the vector.     

Tracing the roots of ion channels.

Two sets of recent findings draw our attention to questions concerning the origin of ion channels. First, there is sequence similarity among five classes of channels: voltage-gated channels, a putative Ca(2+)-activated K+ channel, cyclic nucleotide-gated cation channels, a putative Ca2+ channel for phosphoinositide-mediated Ca2+ entry, and a plant K+ channel/transporter. Like voltage-gated K+ channels, the most recently identified members of the superfamily share the basic design of one set of six potential membrane-spanning segments plus the H5 sequence; as such, they may resemble more closely the ancestral channel, which is likely to predate the separation of the animal and plant kingdoms. Second, several members of the ABC superfamily function as ion channels, even though they were previously known as transporters or enzymes. Did some ancestral enzymes subsequently acquire channel/transporter function? Or could it be the other way around? Aside from evolutionary considerations, enzymes and ion channels can no longer be treated as separate and nonoverlapping groups of proteins. When one molecule exhibits both functions, there are interesting mechanistic questions: How might the enzyme activity such as ATP hydrolysis be coupled to activation/regulation of the intrinsic channel activity? How might interactions between the permeant ions and the channel pore in turn regulate the enzymatic function of the same molecule? It seems possible that the latter is an extension of the observed coupling between permeant ions and the gating machinery of an ion channel (Swenson and Armstrong, 1981). Finally, the potential cross-regulation between channel activity and enzyme activity within the same molecule offers many intriguing possibilities for the integration of different cellular functions.     

Worm control and anthelmintic resistance: adventures with a model

There are three common questions asked of parasitologists about anthelmintic resistance. Does it matter? How do you prevent it? Can you help me (it's here!)? In short, the respective answers are yes, read on the read on. Elizabeth Barnes, Robert Dobson and Ian Barger examine these issues in the context of nematode parasite control in grazing sheep. With the aid of a model, they examine some important factors that influence drug resistance and how farm management decisions and worm genetics modify these factors. They also explore the likely impact of new technologies on drug resistance and how efficient they need to be to sustain good worm control.     

Pronuclear injection-based mouse targeted transgenesis for reproducible and highly efficient transgene expression

Mouse transgenesis has proven invaluable for analysis of gene function and generation of human disease models. We describe here the development of a pronuclear injection-based targeted transgenesis (PITT) system, involving site-specific integration in fertilized eggs. The system was applied to two different genomic target loci to generate a series of transgenic lines including fluorescent mice, which reproducibly displayed strong, ubiquitous and stable transgene expression. We also demonstrated that knockdown mice could be readily generated by PITT by taking advantage of the reproducible and highly efficient expression system. The PITT system, which circumvents the problem of unpredictable and unstable transgene expression of conventional random-integration transgenic mice, reduces the time, cost and effort needed to generate transgenic mice, and is potentially applicable to both in vivo 'gain-of-function' and 'loss-of-function' studies.     

Developmental differentiation between tachyzoites and bradyzoites of Toxoplasma gondii

An important event in the pathogenesis of toxoplasmosis is the interconversion between the bradyzoite and the tachyzoite stage of Toxoplasma gondii within the intermediate host. The factors that influence either cyst formation (bradyzoites) or reactivation (tachyzoites) are unknown. Uwe Gross, Wolfgang Bohne, Martine Soête and Jean Fran?ois Dubremetz here describe current knowledge about the mechanisms that might lead to the induction of stage differentiation of this protozoan parasite.     

Fluorescent transgenic mice suitable for multi-color aggregation chimera studies

We recently reported a novel method of mouse transgenesis called Pronuclear Injection-based Targeted Transgenisis (PITT) using which a series of fluorescent transgenic (Tg) mice lines were generated. These lines, unlike those generated using conventional random integration methods, express the transgenes faithfully and reproducibly generation after generation. Because of this superior nature, these lines are ideal for the generation of multi-colored aggregation chimeras that can be used to study cell?Ccell interactions and lineage analyses in living embryos/organs, where the transgenes can be detected and the clonal origin of a given cell population easily traced by its distinct fluorescence. In this study, to verify if Tg fluorescent mice generated through PITT were suitable for such applications, we sought to generate chimeric blastocysts and chimeric-Tg mice by aggregating two- or three-colored 8-cell embryos. Our analyses using these models led to the following observations. First, we noticed that cell mixing was infrequent during the stages of morula to early blastocyst. Second, chimeric fetuses obtained after aggregation of the two-colored 8-cell embryos exhibited uniform cell mixing. And third, in the organs of adult chimeric mice, the mode of cell distribution could be either clonal or polyclonal, as previously pointed out by others. Implications of our novel and improved Tg-chimeric mice approach for clonal cell lineage and developmental studies are discussed.     

A “Living” Machine

Biomimetics (or bionics) is the engineering discipline that constructs artificial systems using biological principles. The ideal final result in biomimetics is to create a living machine. But what are the desirable and non-desirable properties of biomimetic product7 Where can natural prototypes be found7 How can technical solutions be transferred from nature to technology? Can we use living nature like LEC, O bricks for oonstmction our machines? How can biology help us? What is a living machine? In biomimetic practice only some “part“ (organ, part of organ, tissue) of the observed whole organism is utilized. A possible template for future super-organism extension for biornimetic methods might be drawn from experiments in holistic ecological agriculture (ecological design, permacuhure, ecological engineering, etc. ). The necessary translation of these roles to practical action can be achieved with the Russian Theory of Inventive Problem Solving (TRIZ), specifically adjusted to biology. Thus, permaculture, reinforced by a TRIZ conceptual framework, might provide the basis for Super-Organismic Bionics, which is hypothesized as necessary for effective ecological engineering. This hypothesis is supported by a case study-the design of a sustainable artificial nature reserve for wild pollinators as a living machine.     

Interoceptive basis to craving

Awareness of one's physiology is an important component of emotion. How might these processes be related to addiction? In a recent issue of Science, Naqvi et al. demonstrated that smoking addiction is disrupted by damage to the insula cortex. This suggests that brain circuits mediating interoception also contribute to craving states.