An evolutionary perspective on FoxP2: strictly for the birds?

FoxP2 mutations in humans are associated with a disorder that affects both the comprehension of language and its production, speech. This discovery provided the first opportunity to analyze the genetics of language with molecular and neurobiological tools. The amino acid sequence and the neural expression pattern of FoxP2 are extremely conserved, from reptile to man. This suggests an important role for FoxP2 in vertebrate brains, regardless of whether they support imitative vocal learning or not. Its expression pattern pinpoints neural circuits that might have been crucial for the evolution of speech and language, including the basal ganglia and the cerebellum. Recent studies in songbirds show that during times of song plasticity FoxP2 is upregulated in a striatal region essential for song learning. This suggests that FoxP2 plays important roles both in the development of neural circuits and in the postnatal behaviors they mediate.     

The “molecular” traveling salesman

We consider a method for optimization of NP-problems motivated by natural evolution. The basic entity is a population of individuals searching in state space defined by the problem. A message exchange mechanism between individuals enables the system to proceed fast and to avoid local optima. We introduce the concept of isolated evolution to maintain a certain degree of variance in the population. The global optimum can be approached to an arbitrary degree. The method is applied to the TSP and its behavior is shown in a couple of simulations.On leave from: Institut für Theoretische Physik und Synergetik, Universität Stuttgart, Pfaffenwaldring 57/IV, D-7000 Stuttgart 80, Federal Republic of Germany     

“Treasure your exceptions”: recent advances in molecular genetics of glomerular disease

The glomerular filtration barrier consists of endothelial cells, the glomerular basement membrane, and podocytes. The membrane is a highly crosslinked macromolecular meshwork composed of specific extracellular matrix proteins. The adjacent foot processes of podocytes are bridged along their basolateral surfaces by a slit diaphragm (a porous filter structure of nephrin molecules). Recent discoveries of mutations in the range of genes encoding proteins involved in the structure or function of the glomerular filtration barrier have provided new insights into mechanisms of glomerular diseases. In this review, we summarize recent progress in the elucidation of the genetic basis of some glomerulopathies in humans.     

The challenges for molecular nutrition research 4: the “nutritional systems biology level”

Nutritional systems biology may be defined as the ultimate goal of molecular nutrition research, where all relevant aspects of regulation of metabolism in health and disease states at all levels of its complexity are taken into account to describe the molecular physiology of nutritional processes. The complexity spans from intracellular to inter-organ dynamics, and involves iterations between mathematical modelling and analysis employing all profiling methods and other biological read-outs. On the basis of such dynamic models we should be enabled to better understand how the nutritional status and nutritional challenges affect human metabolism and health. Although the achievement of this proposition may currently sound unrealistic, many initiatives in theoretical biology and biomedical sciences work on parts of the solution. This review provides examples and some recommendations for the molecular nutrition research arena to move onto the systems level.     

Explaining the “Pulse of Protoplasm”: The search for molecular mechanisms of protoplasmic streaming

Explanations for protoplasmic streaming began with appeals to contraction in the eighteenth century and ended with appeals to contraction in the twentieth. During the intervening years, biologists prop...     

The “evolutionary argument” and the metaphilosophy of commonsense

Recently in these pages it has been argued that a relatively straightforward version of an old argument based on evolutionary biology and psychology can be employed to support the view that innate ideas are a naturalistic source of metaphysical knowledge. While sympathetic to the view that the “evolutionary argument” is pregnant with philosophical implications, I show in this paper how it needs to be developed and deployed in order to avoid serious philosophical difficulties and unnecessary complications. I sketch a revised version of the evolutionary argument, place it in a new context, and show that this version in this context is not vulnerable to the standard criticisms levelled against arguments of this general type. The philosophical import of this version of the argument lies not in any metaphysical conclusions it sanctions directly, but in the support it lends to the metaphilosophy of commonsense.     

Biosimilars 2.0: Guiding principles for a global “patients first” standard

In the European Union, biosimilar products have been approved since 2006 under an abbreviated pathway that leverages their similarity to an existing “reference” biological product. The products approved to date are based on recombinant versions of endogenous proteins with well-understood structures and pharmacology, but complicated safety and immunogenicity profiles. The period during the 2000s that included the first reviews, approvals, sale and use of biosimilars is referred to herein as “Biosimilars 1.0.” Over the next several years, a new and advanced tranche of biosimilars will be developed for complex reference products, including medicines used in the treatment of cancer and autoimmune diseases. A global market for biosimilars is developing and this may well foreshadow the beginning of the second era of product development. This Biosimilars 2.0 period will likely be characterized by the development of complex products, global harmonization of standards and the increasing demand for long-term monitoring of pharmaceuticals. The products developed in this period should exhibit high levels of fidelity to the reference products and should be rigorously evaluated in analytical, non-clinical and clinical comparisons. Additionally, Biosimilars 2.0 manufacturers should strive for transparency in their labels and take proactive strides to be accountable to providers and patients for the quality of their products. An important opportunity now exists for the healthcare community, industry and regulators to work in partnership, to outline the appropriate standards for these products and to facilitate increased access while meeting patients'' needs.Key words: biotechnology, biosimilars, generic drugs, monoclonal antibodies, pharmacodynamics, pharmacokinetics     

A meta‐analysis of isolation by distance: relic or reference standard for landscape genetics?

Isolation by distance (IBD) has been a common measure of genetic structure among populations and is based on Euclidean distances among populations. Whereas IBD does not incorporate geographic complexity (e.g. dispersal barriers, corridors) that may better predict genetic structure, a new approach (landscape genetics) joins landscape ecology with population genetics to better model genetic structure. Should IBD be set aside or should it persist as the most simple model in landscape genetics? We evaluated the status of IBD by collecting and analyzing results of 240 IBD data sets among diverse taxa and study systems. IBD typically represented a low proportion of variance in genetic structure (mean r²=0.22) in part because many studies included relatively few populations (mean=11). The number of populations studied (N) was asymptotically related to IBD significance; a study with 9 populations has only 50% probability of significance, while one with >23 populations will have 90% probability of significance. Surprisingly, ectothermic animals were significantly (p=0.0018) more likely to have significant IBD than endotherms, which suggests a metabolic basis underlying gene flow rates. We also observed marginally significant effects on IBD significance for a) taxa in general and b) dispersal modes within actively‐dispersing endotherms. Other factors analyzed (genetic markers, genetic distances, habitats, active or passive dispersal, plant growth form) did not significantly affect IBD, likely related to typical N. For multiple reasons we conclude that IBD should continue as the simplest reference standard against which all other, more complex models should be compared in landscape genetics research.     

“The tools of the discipline: Biochemists and molecular biologists”: A comment

Conclusion and Issues for Further Investigation This last result leads, rather naturally, to some concluding observations and a series of questions for further investigation. These case studies show that in all of the sites examined, the institutionalization of molecular biology as a discipline was primarily driven by the need to separate groups of practitioners with divergent but overlapping interests within the local context. Thus molecular biology was contingently separated from agricultural or medical biochemistry, virology, work on the physiology of nucleic acids, and so forth for contingent local institutional reasons. This makes it even more pressing to try to understand how molecular biology came to be delimited on a larger scale. How did it come to be a discipline with specific intellectual content (or did it?), including some problems, tools, and practices and excluding others? How did it gain authority as the forefront biological science by the mid-1960s? We need to understand the ways in which the tensions between different practices, projects, aims, understandings of the goals of molecular biology, and so on were resolved, on what scale and in what venues, so that something approximating the political character of a discipline, rather than a federation, was achieved. If these case studies provide a sound starting point, it will nevertheless prove difficult to answer the interconnected questions implicit here satisfactorily.One means of getting at such questions that should prove of considerable interest is to examine carefully the work of those who were widely cited in the papers of the late fifties through the mid-seventies by the people now considered major founders of molecular biology. By studying the contributions of those who are now omitted in the standard histories and recollections, we will gain a clearer sense of the possibilities that were open as molecular biology took shape. It is already widely recognized that the contributions of a number of biochemists have been given short shrift, but (as the example of Ernest Gale in Rheinberger's study illustrates) there are a great many more figures whose line of work were then crucial but who are now overlooked.⁶ To understand both what molecular biology was at the time of its early institutionalization and what is has become, it will be enormously helpful to understand at what point the definition or ideology hardened and the grounds for inclusion and exclusion of individuals and lines of work were reformed. Studies of this sort are appropriate in many other areas as well, of course; in general, they should different histories, political standing, and institutional bases of those disciplines in their national cultures. It is likely (but a matter for investigation!) that such differences influenced the opportunities for introducing new bench practices, if in no other way than by delimiting the niches within which certain practices could be initiated.⁷ And since new practices can fail to achieve their objectives, can transform the direction of work and disciplinary allegiances of their practitioners, can lead to only routine results, or can open up important new vistas, the character of the available niches from which to work can prove to have a strong influence on the direction that new work takes if and when it starts to flourish. A key aspect of this problematic (not yet adequately studied, I believe) is the problem of drawing boundaries between different kinds of work and determining where each should fit among established disciplines and/or within some new construct. To the extent that an international solution is ultimately achieved to such problems, it must surely be achieved in light of initially different ways of dealing with it in different countries.Underlying work of the sort we have been exploring is the thorny problem of how best to contextualize the work being studied. This, I believe, is one of the major historiographic problems that we must face in the history of science. It is by no means a new problem, of course, but a particularization of the age-old problem of the (seeming) overdetermination of historical events. If we deal with local cultures, to understand how they develop and their fate we need to understand their location within larger cultures. But it is utterly unclear how to draw appropriate boundaries on the relevant larger culture(s). As even this brief discussion has shown, institutional cultures, the cultures of sponsoring agencies, the culture of science (or of biological science, physical science, etc., as appropriate), and national cultures all can provide relevant contexts, all can occasionally determine the fate of work undertaken in a particular local context. The potentially intractable problem of delimiting the boundaries of investigation looms large here, but it is one that must be faced explicity if we are to profit fully from the enormously stimulating investigations of local cultures exemplified in the four papers published in this symposium. My own view is that we have no abstract standard available for determining which boundaries are appropriate to a given study, and, indeed, that no single contextualization is adequate to the examination of any given case, but that, nonetheless, we can (at least sometimes) distinguish useful and explanatory delimitations of the larger context from others that prove to be misleading.Against this background, I hope that the four papers published in this special issue will stimulate the readers of the JHB to carry out similar studies—that is, studies that seek to characterize and contextualize local experimental cultures —over a wide range of cases. I also hope that some of those who take up this challenge will deal with the larger questions raised by the need to find a way of balancing different, sometimes competing, contextualizations of such studies. The fact that any given case requires multiple contextualizations, resulting in multifaceted representations no one of which is alone adequate, will surely land us in fascinating, hopefully fruitful and productive, controversies.     

Pericentromeric structure of human X “isochromosomes”: evidence for molecular heterogeneity

Summary Three different long-arm X isochromosomes and an isodicentric X chromosome were examined by in situ hybridization with X-chromosome-specific -satellite probes and by quantitation of Southern blots hybridized with proximal short-arm probes. Each chromosome had a unique pericentromeric structure. The isodicentric X chromosome was clearly dicentric, showing two distinct -satellite hybridization signals and duplication of short-arm material. Two isochromosomes showed a larger than normal, bifid -satellite signal and also had duplications of different extents of short-arm material. The third X isochromosome could not be distinguished from a classical long-arm isochromosome; it did not have a short-arm duplication and it had a single -satellite signal. These data indicate that rearrangements responsible for X isochromosome formation can occur at numerous locations in the pericentromeric region and that some X isochromosomes may involve duplications of substantial portions of the short arm.     

“Missing” protists: a molecular prospective

Molecular ecology methods based on 18S rRNA amplification and sequencing have revealed an astounding diversity of microbial eukaryotes in every environment sampled so far. This is certainly true of new species and genera, as essentially every new survey discovers a wealth of novel diversity at this level. This is almost certain for taxa that are higher in taxonomic hierarchy, as many molecular surveys reported novel clades within established protistan phyla, with some of these clades repeatedly confirmed by subsequent studies. It may also be that the molecular approaches discovered several lineages of the highest taxonomic order, but this claim has not been vigorously verified as yet. Overall, the field of protistan diversity remains in its infancy. The true scale of this diversity is unknown, and so are the distribution of this diversity, its patterns, spatial and temporal dynamics, and ecological role. The sampled diversity appears to be just the tip of the iceberg, and this offers outstanding opportunities for microbial discovery for the purposes of both basic and applied research. Special Issue: Protist diversity and geographic distribution. Guest editor: W. Foissner.