LIFE-CENTERED ETHICS, AND THE HUMAN FUTURE IN SPACE

In the future, human destiny may depend on our ethics. In particular, biotechnology and expansion in space can transform life, raising profound questions. Guidance may be found in Life‐centered ethics, as biotic ethics that value the basic patterns of organic gene/protein life, and as panbiotic ethics that always seek to expand life. These life‐centered principles can be based on scientific insights into the unique place of life in nature, and the biological unity of all life. Belonging to life then implies a human purpose: to safeguard and propagate life. Expansion in space will advance this purpose but will also raise basic questions. Should we expand all life or only intelligent life? Should we aim to create populations of trillions? Should we seed other solar systems? How far can we change but still preserve the human species, and life itself? The future of all life may be in our hands, and it can depend on our guiding ethics whether life will fulfil its full potentials. Given such profound powers, life‐centered ethics can best secure future generations. Our descendants may then understand nature more deeply, and seek to extend life indefinitely. In that future, our human existence can find a cosmic purpose.     

Guidelines,enthusiasms, uncertainty,and the limits to purchasing.

Recently government ministers have set out their vision of the future of purchasing. Ineffective treatments will be discarded and purchasing will be based on guidelines or protocols rather than activity. But have the advocates of this approach considered all the issues? This paper examines the challenges of balancing the desire for protocol based uniformity with the needs of individual patients, explores the extent to which existing purchasing structures can support this process, and questions whether such moves will actually lead to reduced costs. In each case it is concluded that oversimplistic analyses are likely to be misleading and that much of the current debate fails to recognise the complexity of health care.     

Concluding overview: looking back, looking forward

The gamma-herpesviruses are a group of related agents which share the same broad strategy for infection of and persistence within the lymphoid tissues of their hosts. Yet in evolutionary terms these agents are sufficiently diverse to display multiple different molecular mechanisms whereby that strategy can be achieved. Attempts are made to relate the different in vitro growth transforming capacities of the gamma1-herpesviruses, the T-lymphotropic gamma2-herpesviruses and the B-lymphotropic gamma2-herpesviruses to what is known about the biology of these virus infections in their natural or in experimental hosts. The review then summarizes the evidence linking gamma-herpesviruses with oncogenesis and proposes that the diverse spectrum of Epstein-Barr virus and human herpesvirus 8-associated human tumours falls into three pathogenetically distinct categories. Many questions remain unanswered in the areas of gamma-herpesvirus biology and disease pathogenesis: resolving these questions will require a broadening of our experimental approaches and a willingness to relinquish 'single-model' panaceas.     

“What’s wrong with my monkey?” Ethical perspectives on germline transgenesis in marmosets

The birth of the first transgenic primate to have inherited a transgene from its parents opens the possibility to set up transgenic marmoset colonies, as these monkeys are small and relatively easy to keep and breed in research facilities. The prospect of transgenic marmoset models of human disease, readily available in the way that transgenic laboratory mice are currently, prompts excitement in the scientific community; but the idea of monkeys being bred to carry diseases is also contentious. We structure an ethical analysis of the transgenic marmoset case around three questions: whether it is acceptable to use animals as models of human disease; whether it is acceptable to genetically modify animals; and whether these animals’ being monkeys makes a difference. The analysis considers the prospect of transgenic marmoset studies coming to replace transgenic mouse studies and lesion studies in marmosets in some areas of research. The mainstream, broadly utilitarian view of animal research suggests that such a transition will not give rise to greater ethical problems than those presently faced. It can be argued that using marmosets rather than mice will not result in more animal suffering, and that the benefits of research will improve with a move to a species more similar in phylogenetic terms to humans. The biological and social proximity of monkeys and humans may also benefit the animals by making it easier for scientists and caretakers to recognize signs of suffering and increasing the human motivation to limit it. The animal welfare and research impacts of the transition to marmoset use will depend very much on the extent to which researchers take these issues seriously and seek to minimize animal harm and optimize human benefit.     

Demography,recombination hotspot intensity,and the block structure of linkage disequilibrium

BACKGROUND: Effective gene mapping based on genetic association data will require detailed knowledge of patterns of linkage disequilibrium (LD) in human populations. It has been recently suggested that linkage disequilibrium in humans may be organized in a block-like structure, with islands of high LD separated by regions of rapid breakdown of LD due to recombination hotspots. The experimental data to date, however, are limited, and fundamental questions remain about the implications of recombination rate heterogeneity. Here, we use computer simulations to evaluate how such heterogeneity influences patterns of LD, and we develop formal criteria to assess whether the patterns are functionally block like in the context of association mapping.RESULTS: Our analyses suggest that, even in models of extreme recombination rate heterogeneity, some human populations will have a functionally block-like structure to the pattern of LD, but others will not, depending on their precise demographic histories. In fact, for many models, we find that, following an LD-generating event, populations may move through discrete phases that can be functionally described as pre-block, block, and post-block. An analysis of observed and expected patterns of LD surrounding hotspots within the MHC Class II region confirms these theoretical expectations.CONCLUSIONS: Even if highly punctuated patterns of recombination are the rule, patterns of LD are still likely to show differences among populations and among genomic regions that are of practical importance in the design of genetic association studies. The notion that the average extent of LD is a useful concept for the design of association studies must be abandoned in light of the experimental and theoretical evidence.     

The molecular biology of brain and mind development

The recent dramatic development of molecular neurobiology has focused almost entirely on biological events in individual brain cells, and it seems that many of the goals of such work will soon be attained. Yet, when we attain those goals, we will still have to ask how this information will enable us to understand the properties of brain cell collectivities and their presumptive roles in higher brain functions. Even general ideas about those functions are not yet well defined. Therefore, it seems worthwhile to start studying correlations of the molecular events to these higher functions to help delineate the molecular aspects that need study. It is readily appreciated that we cannot tell what other animal species see, hear, taste, smell and feel when touching something, though we can foresee the time when we will be able to detail the biochemical and biophysical consequences of all inputs to those senses. Thus, however deep our understanding of the biology of those species, we are unable to establish relations between their biological responses to inputs and their presumptive mental perceptions. Even though humans can use language to talk about those perceptions, we cannot even verify whether someone else's perceptions are the same as our own, as with the old question of whether two individuals see the same thing when viewing something blue. Questions about still higher mental functions of human brains are even less accessible to analysis and can be approached at best, by using correlations. In this article are a number of such questions and their current correlation-level answers.     

Molecular barcoding and phylogeography of sexual and asexual freshwater planarians of the genus Dugesia in the Western Mediterranean (Platyhelminthes, Tricladida, Dugesiidae)

Planarians of the genus Dugesia have a worldwide distribution with high species diversity in the Mediterranean area. In this area, populations with a triploid karyotype that reproduce by fissiparity are exceptionally frequent, outnumbering the sexual populations. This situation poses interesting questions, such as the age of these asexual lineages, whether they all belong to the same species or whether the triploidization event is recurrent, and what factors (climatic, geographical, historical...) explain the prevalence of these asexual forms. However, asexual populations cannot be assigned to a species due to the lack of copulatory apparatus – the main structure used in species identification. In this study, we have developed a DNA barcoding method, based on COI and ITS-1 sequences, which allows the assignment of the fissiparous forms to sexual species. At the same time, phylogenetic analysis from species of the western Mediterranean have unveiled the presence of species with highly differentiated populations alongside species with a wide distribution and almost no genetic variation. The roles of habitat instability, dispersal capacity and human activities are briefly discussed.     

Conscientious Objection to Vaccination

Vaccine refusal occurs for a variety of reasons. In this article we examine vaccine refusals that are made on conscientious grounds; that is, for religious, moral, or philosophical reasons. We focus on two questions: first, whether people should be entitled to conscientiously object to vaccination against contagious diseases (either for themselves or for their children); second, if so, to what constraints or requirements should conscientious objection (CO) to vaccination be subject. To address these questions, we consider an analogy between CO to vaccination and CO to military service. We argue that conscientious objectors to vaccination should make an appropriate contribution to society in lieu of being vaccinated. The contribution to be made will depend on the severity of the relevant disease(s), its morbidity, and also the likelihood that vaccine refusal will lead to harm. In particular, the contribution required will depend on whether the rate of CO in a given population threatens herd immunity to the disease in question: for severe or highly contagious diseases, if the population rate of CO becomes high enough to threaten herd immunity, the requirements for CO could become so onerous that CO, though in principle permissible, would be de facto impermissible.     

22nd European Workshop for Rheumatology Research,Leiden, The Netherlands, 28 February-3 March 2002

The European Workshop for Rheumatology Research met this year in Leiden, The Netherlands. The Workshop provided a platform to feast on new technologies and how they have taken research programmes forward. While there will be the inevitable delay during which mechanisms are devised for analysing the huge amount of information generated by these technologies, there is a lot already to look forward to. Highlights included genomic, reverse genomic and proteomic approaches to understanding disease pathogenesis and to identifying new therapeutic targets. Opportunities for exploring whether pharmacogenomics has a place in the clinic are now a reality, and phage display technology has been applied to in vivo arthritis models to identify human synovial microvascular 'post codes'.     

Pooling and comparing estimates from several experiments of a Michaelis constant for an enzyme

Often the Michaelis constant of an enzyme will be determined several times. This may be done for various reasons such as ensuring reproducibility, comparing different enzyme preparations, or examining the effects of variations in experimental conditions. In these circumstances, two questions arise. First, how can the various estimates of the Michaelis constant be compared to determine whether they are the same within the limits of experimental variation? Secondly, if they are all the same, how can the values be combined to give an overall estimate? These questions are addressed here and a solution proposed in which the sets of data are pooled and analyzed with a separate maximum velocity for each set but a common Michaelis constant. The pooled data are partitioned in suitable ways and reanalyzed to examine, by means of a variance ratio test, whether a single Michaelis constant gives a satisfactory fit to the data.     

Biological weapons, genetics and social analysis: emerging responses, emerging issues--I

Recent terrorist attacks in the USA have generated significant attention in many countries to the threats posed by biological weapons. In response to these events and the spectre of future attacks, bioscientists and professional organizations have begun or intensified asking questions about the possible malign applications of their research. As Part I of a two-part article, this paper surveys how genetics might contribute to the development of novel forms of weaponry. It is further argued that the dilemmas and difficulties facing bioscientists pose pressing and thorny questions for the hitherto agendas and orientations of those concerned with the social, ethical and political implications of genetics. Part II will examine the emerging responses initiated by biomedical organizations and spokespersons in the US and the UK. This will be done with a view to asking how scientific and medical research communities are defining and policing notions of professionalism, responsibility and accountability. On the basis of this, suggested lines for future social analysis will be offered.     

A case study on the choice,interpretation and checking of multilevel models for longitudinal binary outcomes

Recent advances in statistical software have led to the rapid diffusion of new methods for modelling longitudinal data. Multilevel (also known as hierarchical or random effects) models for binary outcomes have generally been based on a logistic-normal specification, by analogy with earlier work for normally distributed data. The appropriate application and interpretation of these models remains somewhat unclear, especially when compared with the computationally more straightforward semiparametric or 'marginal' modelling (GEE) approaches. In this paper we pose two interrelated questions. First, what limits should be placed on the interpretation of the coefficients and inferences derived from random-effect models involving binary outcomes? Second, what diagnostic checks are appropriate for evaluating whether such random-effect models provide adequate fits to the data? We address these questions by means of an extended case study using data on adolescent smoking from a large cohort study. Bayesian estimation methods are used to fit a discrete-mixture alternative to the standard logistic-normal model, and posterior predictive checking is used to assess model fit. Surprising parallels in the parameter estimates from the logistic-normal and mixture models are described and used to question the interpretability of the so-called 'subject-specific' regression coefficients from the standard multilevel approach. Posterior predictive checks suggest a serious lack of fit of both multilevel models. The results do not provide final answers to the two questions posed, but we expect that lessons learned from the case study will provide general guidance for further investigation of these important issues.     

Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis

Epistasis plays an important role in the genetic architecture of common human diseases and can be viewed from two perspectives, biological and statistical, each derived from and leading to different assumptions and research strategies. Biological epistasis is the result of physical interactions among biomolecules within gene regulatory networks and biochemical pathways in an individual such that the effect of a gene on a phenotype is dependent on one or more other genes. In contrast, statistical epistasis is defined as deviation from additivity in a mathematical model summarizing the relationship between multilocus genotypes and phenotypic variation in a population. The goal of this essay is to review definitions and examples of biological and statistical epistasis and to explore the relationship between the two. Specifically, we present and discuss the following two questions in the context of human health and disease. First, when does statistical evidence of epistasis in human populations imply underlying biomolecular interactions in the etiology of disease? Second, when do biomolecular interactions produce patterns of statistical epistasis in human populations?Answers to these two reciprocal questions will provide an important framework for using genetic information to improve our ability to diagnose, prevent and treat common human diseases. We propose that systems biology will provide the necessary information for addressing these questions and that model systems such as bacteria, yeast and digital organisms will be a useful place to start. BioEssays 27:637–646, 2005. © 2005 Wiley Periodicals, Inc.     

Farm background, socioeconomic status, and fertility: the two-generation hypothesis

This paper examines whether the effects of farm background on socioeconomic differentials in fertility are diminished among nonfarm couples. The data are for a sample of white ever-married women belonging to the 1901-1910 birth cohorts. The research provides another test of the 2 generation-urbanite hypothesis 1st advanced by the Goldberg studies of Detroit and Indianapolis. Unlike a number of other studies, the findings do not support the hypothesis. Thus, a number of questions arise concerning the results obtained by previous investigators in support of this hypothesis. Different types of samples measuring farm background and socioeconomic status may be plausible explanations for the differing results. It is also important to note that both the Detroit and Indianapolis samples can hardly be considered representative of US urban populations in the 1940s and 1950s. A further difficulty with the Detroit study was that Goldberg aggregated the data of a relatively large number of cohorts. The Indianapolis sample was constrained by the eligibility requirements of the original study. The difficulties of adequately testing Goldberg's hypothesis may have been compounded by the extension of the hypothesis to nationally representative samples. Moreover, The hypothesis was not supported when education was used as a measure of socioeconomic status in the Detroit study. Until other studies can be carefully replicated, definitive answers to such questions as to whether fertility differentials by socioeconomic status will disappear or have become attenuated must remain an unanswered question.     

Unanswered questions in ecology

This is very much a personal view of what I think are some of the most important unanswered questions in ecology. That is, these are the questions that I expect will be high on the research agenda over the coming century. The list is organized hierarchically, beginning with questions at the level of individual populations, and progressing through interacting populations to entire communities or ecosystems. I will try to guess both at possible advances in basic knowledge and at potential applications. The only thing that is certain about this view of the future is that much of it will surely turn out to be wrong, and many of the most interesting future developments will be quite unforeseen.     

Long-term ecological sites: musings on the future, as seen (dimly) from the past

Long-term ecological sites are 'listening places'– places where we press our ears to the earth and strain to hear its pulse. Such sites will be needed especially in coming decades, as ecosystems throughout the world face mounting stresses, mostly from human influences. My aim, in these musings, is to elicit conversation, by way of seven questions, about how best to look after the long-term sites, so that they remain intact, relevant, and enlightening for our successors, decades hence.     

Decoding dangerous death: how cytotoxic chemotherapy invokes inflammation, immunity or nothing at all

Chemotherapy and immunotherapy can be either synergistic or antagonistic modalities in the treatment of cancer. Cytotoxic chemotherapy not only affects the tumor but also targets dividing lymphocytes, the very cells that are required to develop an immune response. For this reason, chemo- and immunotherapy have been seen as antagonistic. However, cell death can be immunogenic and the way in which chemotherapeutic drug kills a tumor cell is likely to be an important determinant of how that dying cell interacts with the immune system and whether the interaction will lead to an immune response. When a cell dies as the result of infection, the immune system responds rapidly and the system of Toll-like receptors (TLR) plays a key role in this process. In this review, we will briefly summarize the intracellular signaling pathways that link TLR ligation with immune activation and we will address the questions where and how TLRs recognize their targets.     

Signs of Anger: Representation of Agonistic Behaviour in Invertebrate Cognition

In this essay I shall examine the representation of aggression and its issues in the model animal, the Fruit Fly, Drosophila melanogaster. The Fruit Fly is the model animal for genetics and more recently neuroscience. On the basis of its behaviour conclusions are being drawn that will help in the development of new treatments for clinical entities like aggression and anxiety disorders—the author questions those findings and asks whether more should be done to focus on the actual biology and behaviour—the Umwelt, instead of trying to bridge the gulf between invertebrate and human behaviours.     

Thermotaxis of human sperm cells in extraordinarily shallow temperature gradients over a wide range

On the basis of the finding that capacitated (ready to fertilize) rabbit and human spermatozoa swim towards warmer temperatures by directing their movement along a temperature gradient, sperm thermotaxis has been proposed to be one of the processes guiding these spermatozoa to the fertilization site. Although the molecular mechanism underlying sperm thermotaxis is gradually being revealed, basic questions related to this process are still open. Here, employing human spermatozoa, we addressed the questions of how wide the temperature range of thermotaxis is, whether this range includes an optimal temperature or whether spermatozoa generally prefer swimming towards warmer temperatures, whether or not they can sense and respond to descending temperature gradients, and what the minimal temperature gradient is to which they can thermotactically respond. We found that human spermatozoa can respond thermotactically within a wide temperature range (at least 29-41°C), that within this range they preferentially accumulate in warmer temperatures rather than at a single specific, preferred temperature, that they can respond to both ascending and descending temperature gradients, and that they can sense and thermotactically respond to temperature gradients as low as <0.014°C/mm. This temperature gradient is astonishingly low because it means that as a spermatozoon swims through its entire body length (46 μm) it can sense and respond to a temperature difference of <0.0006°C. The significance of this surprisingly high temperature sensitivity is discussed.