The fallacy of the Principle of Procreative Beneficence

The claim that we have a moral obligation, where a choice can be made, to bring to birth the 'best' child possible, has been highly controversial for a number of decades. More recently Savulescu has labelled this claim the Principle of Procreative Beneficence. It has been argued that this Principle is problematic in both its reasoning and its implications, most notably in that it places lower moral value on the disabled. Relentless criticism of this proposed moral obligation, however, has been unable, thus far, to discredit this Principle convincingly and as a result its influence shows no sign of abating. I will argue that while criticisms of the implications and detail of the reasoning behind it are well founded, they are unlikely to produce an argument that will ultimately discredit the obligation that the Principle of Procreative Beneficence represents. I believe that what is needed finally and convincingly to reveal the fallacy of this Principle is a critique of its ultimate theoretical foundation, the notion of impersonal harm. In this paper I argue that while the notion of impersonal harm is intuitively very appealing, its plausibility is based entirely on this intuitive appeal and not on sound moral reasoning. I show that there is another plausible explanation for our intuitive response and I believe that this, in conjunction with the other theoretical criticisms that I and others have levelled at this Principle, shows that the Principle of Procreative Beneficence should be rejected.     

Differences in Curriculum Structure between High School and University Biology: The Implications for Epistemological Access

Despite doing well in biology at high school, some students struggle with the same subject at university level. This can have implications for epistemological access - access to knowledge that allows students to remain at university. Therefore, it is important to identify factors that may be causing this problem. We propose that one such factor may be differences in the structure of knowledge between the two levels. Therefore, this paper will assess some of the differences in the structuring of knowledge that exist between a high school and a university biology curriculum. To do this, a section of a high school and a university textbook which cover the same topic will be analysed using one aspect of Legitimation Code Theory called Semantics. Our findings suggest that there is a mismatch between the semantic range students are expected to navigate at university and that demanded by high school biology, and that this may pose a stumbling block to students gaining epistemological access to first-year study at university. If this is indeed the case, then pedagogic interventions which explicitly address this may contribute to improving undergraduate student retention and throughput rates at university.     

Even if the fetus is not a person,abortion is immoral: The impairment argument

Much of the debate about the ethics of abortion has centered on whether the fetus is a person. In an attempt to sidestep this complex issue, I argue that, even if the fetus is not a person, abortion is immoral. To arrive at this conclusion, I argue that giving a fetus fetal alcohol syndrome is immoral, and that if this is so, then killing the fetus is immoral. Roughly, this is because killing the fetus impairs it more than giving it fetal alcohol syndrome. Since abortion (in most cases) amounts to killing the fetus, this means that abortion (in most cases) is immoral. I defend the premises of this argument against a plethora of objections, concluding that they either do not work, or commit their proponent to a controversial position.     

Quantifying the degree of self-nestedness of trees: application to the structural analysis of plants

In this paper, we are interested in the problem of approximating trees by trees with a particular self-nested structure. Self-nested trees are such that all their subtrees of a given height are isomorphic. We show that these trees present remarkable compression properties, with high compression rates. In order to measure how far a tree is from being a self-nested tree, we then study how to quantify the degree of self-nestedness of any tree. For this, we define a measure of the self-nestedness of a tree by constructing a self-nested tree that minimizes the distance of the original tree to the set of self-nested trees that embed the initial tree. We show that this measure can be computed in polynomial time and depict the corresponding algorithm. The distance to this nearest embedding self-nested tree (NEST) is then used to define compression coefficients that reflect the compressibility of a tree. To illustrate this approach, we then apply these notions to the analysis of plant branching structures. Based on a database of simulated theoretical plants in which different levels of noise have been introduced, we evaluate the method and show that the NESTs of such branching structures restore partly or completely the original, noiseless, branching structures. The whole approach is then applied to the analysis of a real plant (a rice panicle) whose topological structure was completely measured. We show that the NEST of this plant may be interpreted in biological terms and may be used to reveal important aspects of the plant growth.     

A step toward barcoding life: a model-based, decision-theoretic method to assign genes to preexisting species groups

A major part of the barcoding of life problem is assigning newly sequenced or sampled individuals to existing groups that are preidentified externally (by a taxonomist, for example). This problem involves evaluating the statistical evidence towards associating a sequence from a new individual with one group or another. The main concern of our current research is to perform this task in a fast and accurate manner. To accomplish this we have developed a model-based, decision-theoretic framework based on the coalescent theory. Under this framework, we utilized both distance and the posterior probability of a group, given the sequences from members of this group and the sequence from a newly sampled individual to assign this new individual. We believe that this approach makes efficient use of the available information in the data. Our preliminary results indicated that this approach is more accurate than using a simple measure of distance for assignment.     

Scientific Citizenship and good governance: implications for biotechnology

In the wake of public distrust regarding biotechnology, it has been suggested that the debate should be moved "upstream", whereby the public help to set research priorities. Although many scientists see this as an illogical reaction to a loss of faith in science, we argue that the boundaries between science and its technological applications have become blurred and this produces conflicts of interests that have led to this crisis of trust. Furthermore, this distrust is also a crisis in governance that calls for a new open and democratic approach to scientific research. We propose that the concept of Scientific Citizenship, based on good governance, will help to restore public trust and bridge the gap between science and the society that it serves. Integral to this is the suggestion that the governance of science forms part of the training for scientists.     

From single biobanks to international networks: developing e-governance

The future holds the possibility to link and network biobanks, existing biorepositories and reference databases for research purposes in ways that have not been possible before. There is the potential to develop 'research portals' that will enable researchers to access these research resources that are located around the globe with the click of a mouse. In this paper, I will argue that our current governance system for research is unable to provide all of the oversight and accountability mechanisms that are required for this new way of doing research that is based upon flows of data across international borders. For example, our current governance framework for research is nationally based, with a complex system of laws, policies and practice that can be unique to a jurisdiction. It is also evident that many of the nationally based governance bodies in this field do not have the legal powers or expertise to adjudicate on the complex issues, such as privacy and disclosure risks that are raised by cross-border data sharing. In addition, the conceptual underpinning of this research governance structure is based on the "one researcher, one project, one jurisdiction" model. In the conclusion of this paper, I lay out some preliminary ideas as to how this system has to change to accommodate research that is based on networks. I suggest that a move to digital governance mechanisms might be a start to making research governance systems more appropriate for the 21st century.     

Selection for mutants altered in the expression or export of outer membrane porin OmpF.

Strains in which the lacZ gene (which specifies beta-galactosidase) is fused to a gene encoding an envelope protein often exhibit a phenotype termed overproduction lethality. In such strains, high-level synthesis of the cognate hybrid protein interferes with the process of protein export, and this leads ultimately to cell death. A variation of this phenomenon has been discovered with lacZ fusions to the gene specifying the major outer membrane porin protein OmpF. In this case, we find that lambda transducing phage carrying an ompF-lacZ fusion will not grow on a host strain that constitutively overexpresses ompF. We have exploited this observation to develop a selection for ompF mutants. Using this protocol, we have isolated mutants altered in ompF expression and have identified mutations that block OmpF export. Our results suggest that it should be possible to adapt this selection for use with other genes specifying exported proteins.     

Coenzyme B12 riboswitches are widespread genetic control elements in prokaryotes

Recent studies have begun to reveal that numerous fundamental metabolic pathways in bacteria are regulated by riboswitches residing within certain messenger RNAs. These riboswitches selectively bind metabolites and modulate gene expression in response to changing ligand concentrations. Previously, we provided evidence that the btuB mRNAs of Escherichia coli and Salmonella typhimurium each carry a coenzyme B12-dependent riboswitch that causes repressed translation of the encoded cobalamin-transport protein at elevated coenzyme concentrations. Herein, we use a phylogenetic analysis to define a consensus sequence and secondary structure model for the ligand- binding domain of this riboswitch class. RNA structures that conform to this model are widespread in both Gram-positive and Gram-negative organisms. In addition, we find that the 5'-untranslated region (5'-UTR) of the cobalamin biosynthesis (cob) operon of S.typhimurium carries an RNA motif that matches this consensus sequence. Biochemical and genetic characterization of this motif confirms that the RNA directly binds coenzyme B12, and that it likely serves as a genetic control element for regulating expression of the 25-gene operon for cobalamin production in this pathogen.     

Endocytosis of cholera toxin by human enterocytes is developmentally regulated

Many secretory diarrheas including cholera are more prevalent and fulminant in young infants than in older children and adults. Cholera toxin (CT) elicits a cAMP-dependent chloride secretory response in intestinal epithelia, which accounts for the fundamental pathogenesis of this toxigenic diarrhea. We have previously reported that the action of this bacterial enterotoxin is excessive in immature enterocytes and under developmental regulation. In this study, we tested the hypothesis that enhanced endocytosis by immature human enterocytes may, in part, account for the excessive secretory response to CT noted in the immature intestine and that enterocyte endocytosis of CT is developmentally regulated. To test this hypothesis, we used specific inhibitors to define endocytic pathways in mature and immature cell lines. We showed that internalization of CT in adult enterocytes is less and occurs via the caveolae/raft-mediated pathway in contrast to an enhanced immature human enterocyte CT uptake that occurs via a clathrin pathway. We also present evidence that this clathrin pathway is developmentally regulated as demonstrated by its response to corticosteroids, a known maturation factor that causes a decreased CT endocytosis by this pathway.     

Plasmid pRQ7 from the hyperthermophilic bacterium Thermotoga species strain RQ7 replicates by the rolling-circle mechanism.

The hyperthermophilic bacterium Thermotoga species strain RQ7 harbors an 846-bp plasmid, pRQ7, with a single open reading frame. Previously published analyses of the DNA sequence of pRQ7 suggested that it may replicate by a rolling-circle (RC) replication mechanism, and this report provides experimental evidence supporting this hypothesis. Single-stranded pRQ7 DNA accumulates in strain RQ7, as evidenced by the facts that this DNA bound to nitrocellulose membranes under nondenaturing conditions, was sensitive to S1 nuclease digestion, and hybridized to only one of two homologous DNA probes specific for each strand of the plasmid. The DNA encoding the open reading frame was cloned and expressed in Escherichia coli and gave a protein with a molecular mass of 26 kDa, similar to that deduced by sequence analysis. This protein bound to a fragment of pRQ7 that contains a putative double-stranded replication region in a magnesium-dependent reaction and made this fragment sensitive to S1 nuclease activity. It did not cause this same S1 nuclease sensitivity in the remainder of pRQ7. This activity on pRQ7 DNA suggests that this protein plays a role in plasmid replication.     

Final words: cell age and cell cycle are unlinked

Cooper has a simple belief: that the cell cycle is connected to age and size. Furthermore, as a result of this connection in his mind he believes that there are no possible manipulations that can operate on a batch culture to synchronize cells within the cell cycle, such that those cells can undergo a semblance of a normal cell cycle. His formulation of this argument is as a 'fundamental law', the law of conservation of cell-age order (LCCAO). The first part of this law - 'there is no batch treatment of the culture that can lead to an alteration of the cell-age order' - can probably be proved true, in the mathematical sense, and certainly makes intuitive sense. Unfortunately the corollaries of this law are rather suspect, drawing inferences from cell age to cell size to the cell cycle.     

An Atg13 protein-mediated self-association of the Atg1 protein kinase is important for the induction of autophagy

Autophagy pathways in eukaryotic cells mediate the turnover of a diverse set of cytoplasmic components, including damaged organelles and abnormal protein aggregates. Autophagy-mediated degradation is highly regulated, and defects in these pathways have been linked to a number of human disorders. The Atg1 protein kinase appears to be a key site of this control and is targeted by multiple signaling pathways to ensure the appropriate autophagic response to changing environmental conditions. Despite the importance of this kinase, relatively little is known about the molecular details of Atg1 activation. In this study we show that Atg13, an evolutionarily conserved regulator of Atg1, promotes the formation of a specific Atg1 self-interaction in the budding yeast, Saccharomyces cerevisiae. The appearance of this Atg1-Atg1 complex is correlated with the induction of autophagy, and conditions that disrupt this complex result in diminished levels of both autophagy and Atg1 kinase activity. Moreover, the addition of a heterologous dimerization domain to Atg1 resulted in elevated kinase activity both in vivo and in vitro. The formation of this complex appears to be an important prerequisite for the subsequent autophosphorylation of Thr-226 in the Atg1 activation loop. Previous work indicates that this modification is necessary and perhaps sufficient for Atg1 kinase activity. Interestingly, this Atg1 self-association does not require Atg17, suggesting that this second conserved regulator might activate Atg1 in a manner mechanistically distinct from that of Atg13. In all, this work suggests a model whereby this self-association stimulates the autophosphorylation of Atg1 within its activation loop.     

Predicting prokaryotic ecological niches using genome sequence analysis

Automated DNA sequencing technology is so rapid that analysis has become the rate-limiting step. Hundreds of prokaryotic genome sequences are publicly available, with new genomes uploaded at the rate of approximately 20 per month. As a result, this growing body of genome sequences will include microorganisms not previously identified, isolated, or observed. We hypothesize that evolutionary pressure exerted by an ecological niche selects for a similar genetic repertoire in those prokaryotes that occupy the same niche, and that this is due to both vertical and horizontal transmission. To test this, we have developed a novel method to classify prokaryotes, by calculating their Pfam protein domain distributions and clustering them with all other sequenced prokaryotic species. Clusters of organisms are visualized in two dimensions as 'mountains' on a topological map. When compared to a phylogenetic map constructed using 16S rRNA, this map more accurately clusters prokaryotes according to functional and environmental attributes. We demonstrate the ability of this map, which we term a "niche map", to cluster according to ecological niche both quantitatively and qualitatively, and propose that this method be used to associate uncharacterized prokaryotes with their ecological niche as a means of predicting their functional role directly from their genome sequence.     

At the periphery of the amidohydrolase superfamily: Bh0493 from Bacillus halodurans catalyzes the isomerization of D-galacturonate to D-tagaturonate

The amidohydrolase superfamily is a functionally diverse set of enzymes that catalyzes predominantly hydrolysis reactions involving sugars, nucleic acids, amino acids, and organophosphate esters. One of the most divergent members of this superfamily, uronate isomerase from Escherichia coli, catalyzes the isomerization of d-glucuronate to d-fructuronate and d-galacturonate to d-tagaturonate and is the only uronate isomerase in this organism. A gene encoding a putative uronate isomerase in Bacillus halodurans (Bh0705) was identified based on sequence similarity to uronate isomerases from other organisms. Kinetic evidence indicates that Bh0705 is relatively specific for the isomerization of d-glucuronate to d-fructuronate, confirming this functional assignment. Despite a low sequence identity to all other characterized uronate isomerases, phylogenetic and network-based analysis suggests that a second gene in this organism, Bh0493, is also a uronate isomerase, although it is an outlier in the group, with <20% sequence identity to any other characterized uronate isomerase from another species. The elucidation of the X-ray structure at a resolution of 2.0 A confirms that Bh0493 is a member of the amidohydrolase superfamily with conserved residues common to other members of the uronate isomerase family. Functional characterization of this protein shows that unlike Bh0705, Bh0493 can utilize both d-glucuronate and d-galacturonate as substrates. In B. halodurans, Bh0705 is found in an operon for the metabolism of d-glucuronate, whereas Bh0493 is in an operon for the metabolism of d-galacturonate. These results provide the first identification of a uronate isomerase that operates in a pathway distinct from that for d-glucuronate. While most organisms that contain this pathway have only one gene for a uronate isomerase, sequence analysis and operon context show that five other organisms also appear to have two genes and one organism appears to have three genes for this activity.     

Williams's theory of the evolution of senescence: still useful at fifty

George Williams indicated that he would not expect senescence to evolve in organisms that lack a distinction between germ line and soma. Escherichia coli--long assumed to lack even a hint of this distinction--is now known to senesce, posing what would seem to be a challenge to Williams's well-known theory of the evolution of senescence. However, in this review, I will show that cell division in E. coli produces a degree of germ-soma modularity sufficient to generate age structure and antagonistic pleiotropic effects, thereby satisfying the requirements of Williams's theory. From this perspective, senescence in E. coli is supportive and points the way to a better understanding of the pleiotropies that connect adaptive complexity and senescence. Sexual reproduction is but one of the complex adaptations illuminated by this approach.     

PrlA suppressor mutations cluster in regions corresponding to three distinct topological domains.

The SecY protein of Escherichia coli and its homologues in other organisms, are integral components of the cellular protein translocation machinery. Suppressor mutations that alter SecY (the prlA alleles) broaden the specificity of this machinery and allow secretion of precursor proteins with defective signal sequences. Twenty-five prlA alleles have been characterized. These suppressor mutations were found to cluster in regions corresponding to three distinct topological domains of SecY. Based on the nature and position of the prlA mutations, we propose that transmembrane domain 7 of SecY functions in signal sequence recognition. Results suggest that this interaction may involve a right-handed supercoil of alpha-helices. Suppressor mutations that alter this domain appear to prevent signal sequence recognition, and this novel mechanism of suppression suggests a proofreading function for SecY. We propose that suppressor mutations that alter a second domain of SecY, transmembrane helix 10, also affect this proof-reading function, but indirectly. Based on the synthetic phenotypes exhibited by double mutants, we propose that these mutations strengthen the interaction with another component of the translocation machinery, SecE. Suppressor mutations were also found to cluster in a region corresponding to an amino-terminal periplasmic domain. Possible explanations for this unexpected finding are discussed.     

Induction of apoptosis by tumor cell-targeted toxins

Targeted toxins are fusion proteins that combine a targeting molecule that selectively binds to and enters tumor cells with a protein toxin that kills the target cells. These molecules represent an exciting approach to develop effective cancer-specific therapeutics that have few side effects on normal tissues and numerous such toxins are in various stages of pre-clinical and clinical development to treat a wide variety of tumors. In this review, we discuss this strategy, describe ways that the toxins activate the apoptosis machinery and discuss future developments in this field.     

On the role of uncoupling protein-2 in pancreatic beta cells

Pancreatic beta cells secrete insulin when blood glucose levels are high. Dysfunction of this glucose-stimulated insulin secretion (GSIS) is partly responsible for the manifestation of type 2 diabetes, a metabolic disorder that is rapidly becoming a global pandemic. Mitochondria play a central role in GSIS by coupling glucose oxidation to production of ATP, a signal that triggers a series of events that ultimately leads to insulin release. Beta cells express a mitochondrial uncoupling protein, UCP2, which is rather surprising as activity of such a protein is anticipated to lower the efficiency of oxidative phosphorylation, and hence to impair GSIS. The mounting evidence demonstrating that insulin secretion is indeed blunted by UCP2 agrees with this prediction, and has provoked the idea that UCP2 activity contributes to beta cell pathogenesis and development of type 2 diabetes. Although this notion may be correct, the evolved function of UCP2 remains unclear. With this paper we aim to provide a brief account of the present state of affairs in this field, suggest a physiological role for UCP2, and highlight some of our own recent results.