Searching for the Holy Grail; protein–protein interaction analysis and modulation

The first EMBO workshop on ‘Protein–Protein Interaction Analysis & Modulation’ took place in June 2012 in Roscoff, France. It brought together researchers to discuss the growing field of protein network analysis and the modulation of protein–protein interactions, as well as outstanding related issues including the daunting challenge of integrating interactomes in systems biology and in the modelling of signalling networks.     

Clusia: Holy Grail and enigma

Clusia is the only genus with bona fide dicotyledonous trees performing Crassulacean acid metabolism (CAM). Clusia minor L. is extraordinarily flexible, being C(3)/CAM intermediate and expressing the photosynthetic modes C(3), CAM, CAM-cycling, and CAM-idling. C(3) photosynthesis and CAM can be observed simultaneously in two opposite leaves on a node and possibly even within the same leaf in the interveinal lamina and the major vein tissue, respectively. The relative activity of photosystem II (PhiPSII) indicating photosynthetic energy use, is larger under photorespiratory than under non-photorespiratory conditions due to the particular energy demand of photorespiration. The heterogeneity of PhiPSII over the leaves as visualized by chlorophyll fluorescence imaging in the C(3) mode is larger under non-photorespiratory conditions than under photorespiratory conditions. These observations indicate that photorespiration, presumably by its particular energy demand, synchronizes photosynthetic activity over the leaves. In the CAM mode, the heterogeneity of PhiPSII is more dependent on the transitions between CAM phases. Free-running circadian oscillations of photosynthesis are strongly dampened in both the C(3) and the CAM mode. Photorespiration is under circadian clock control in both the C(3) and the CAM mode. PhiPSII and the heterogeneity of PhiPSII oscillate in phase with CO(2) uptake and photorespiration only under non-photorespiratory conditions. Under photorespiratory conditions, PhiPSII does not oscillate and there is no heterogeneity, again indicating the stabilizing function of photorespiration. Plants acclimatized to perform CAM switch to C(3) photosynthesis during free-running oscillations while subjected to constant illumination.     

The quest for the Holy Grail: a disease-modifying osteoarthritis drug

The unfortunate story of the matrix metalloproteinase inhibitor PG116800, which had no effect on the osteoarthritic process but had unexpected side effects, highlights the following. First, reality does not always match the theory. Second, cell biology data must be interpreted within the context of a specific environment. Third, the specificity of an enzyme inhibitor is always relative. Finally, a critical evaluation of the benefit/risk ratio of a drug must be carefully conducted and checked before and after launch. Well designed post-marketing surveillance is mandatory.     

River macrophyte indices: not the Holy Grail!

1. Recent studies have demonstrated that there is generally no unambiguous relationship between plant species composition and specific environmental conditions in rivers. Nevertheless, indices of environmental pressures based on macrophytes are flourishing, because of the requirements of the Water Framework Directive (WFD). 2. We first reviewed nine such indices against 13 criteria for bioindicators. Then, using data from France and England, we tested whether the IBMR (Macrophyte Biological Index for Rivers) and LEAFPACS (predictions and classification system for macrophytes) methods could reliably indicate nutrient and hydromorphological pressures. Finally, we used an improved bootstrapping method to estimate accuracy. 3. Currently, most indices lack ecological meaning for a variety of reasons, including partial sampling (backwaters are excluded); reliance on list of taxa (there are identification difficulties) rather than structure and functions; correlation rather than causation; application within a limited biogeographical area; reliance on ‘expert’ judgement; high precision but poor accuracy; poorly defined reference conditions; lack of independent tests; and an inability to discriminate reliably between the target pressures of interest from confounding background variables. 4. IBMR was a far better indicator of pH (or HCO₃‐pCO₂) than it was of soluble reactive phosphorus, SRP (or SRP‐NH₄). While there was a highly significant correlation between IBMR and SRP after removing the effect of pH, the relationship was weak (r² = 0.08, n = 215, P < 0.001). 5. LEAFPACS is a multi‐metric method summing up five individual indices, each compliant with the WFD. Its individual metrics were not better correlated with nutrient and hydromorphological pressures (with r² < 0.1, n = 62, P < 0.05) than was the IBMR. The meaning of the overall metric is questionable. 6. There are problems in determining the precision of the indices, owing to uncertainties in recording, but they are less than the uncertainties in determining accuracy (because species optima and tolerances are sometimes poorly known). 7. Reliable information is needed to improve the state of our rivers. Macrophyte indices are able to detect statistically significant pressures from a large population of sites but cannot be applied at specific sites, as required by the WFD, owing to large uncertainties and low explanatory power. Typically, more than 90% of the variability in macrophyte indices is attributed to factors other than human pressure. The WFD would be better served by a simpler, holistic approach based on our current mechanistic understanding of river processes. These findings are likely to apply also to other taxonomic groups (macroinvertebrates, diatoms, fish) used in the assessment of purported ecological quality and to palaeolimnological measures of reference status.     

Animal models of human anthrax: The Quest for the Holy Grail

Anthrax is rare among humans, few data can be collected from infected individuals and they provide a fragmentary view of the dynamics of infection and human host–pathogen interactions. Therefore, the development of animal models is necessary. Anthrax has the particularity of being a toxi-infection, a combination of infection and toxemia. The ideal animal model would explore these two different facets and mimic human disease as much as possible. In the past decades, the main effort has been focused on modelling of inhalational anthrax and the perception of specific aspects of the infection has evolved in recent years. In this review, we consider criteria which can lead to the most appropriate choice of a given animal species for modelling human anthrax. We will highlight the positive input and limitations of different models and show that they are not mutually exclusive. On the contrary, their contribution to anthrax research can be more rewarding when taken in synergy. We will also present a reappraisal of inhalational anthrax and propose reflections on key points, such as portal of entry, connections between mediastinal lymph nodes, pleura and lymphatic drainage.     

The evo‐devo comet

Where is ‘evo-devo'' going and how will it get there? Denis Duboule analyses the fields of evolution and development and argues that their current marriage is likely a transitory affair.In his inspiring book Ontogeny and Phylogeny (1977), the late Stephen J. Gould explained why developmental biology and evolution, two essential domains of the life sciences, had diverged during the course of the twentieth century; both disciplines had to reach independently a platform of mutual understanding, a theoretical framework wherein concepts are understood and accepted by both parties. A step towards this goal was achieved in the 1980s with the discovery that animals not only share similar ‘developmental genes'', but also more integrated structural and functional aspects of their ontogenies (McGinnis et al, 1984; Akam, 1989). While these advances opened the door towards a molecular understanding of development, the analyses of gene expression in various species also allowed for the establishment of correlations between genetic activities and evolving forms.This comparative approach triggered the emergence of novel animal models and generated a portfolio of concepts, which now-a-days form the basis of a discipline sometimes referred to as ‘evo-devo'' (Wallace, 2002; Carroll, 2005; de Robertis, 2008). The frontiers of this field, however, are not clearly defined. Evo-devo research extends from simply ‘PCRing'' a trendy gene from a weird animal, up to the most sophisticated molecular genetic approaches dealing with the evolution of gene function and regulation. Yet the experiments are always within the general context of homology, as understood by using either morphological, functional or regulatory criteria, indiscriminately.With our improved knowledge of the mechanisms underlying animal development, we can now address the question of natural variation; we have learnt, for instance, that rather limited sets of genes and signalling pathways are used over and over again, hence the development of most organs or structures relies on comparable rules. This, in turn, implies that developing systems have highly constrained roadmaps, the modifications of which lead generally to pleiotropic effects (Duboule & Wilkins 1998; Kirschner & Gerhart, 2005). This natural parsimony in the use of genetic tools makes it sometimes difficult to infer a conservation in function from the mere conservation of gene expression patterns—for instance, between two evolutionary distant animals—and thus calls for a deeper level of conservation to ascertain such phylogenetic relationships.This issue can be addressed either by a thorough understanding of those regulations at work, assuming that a conservation of regulatory circuits demonstrates a common phylogenetic history, or by a large survey of various species, should we accept that a robust association between gene expression and a particular trait bears an evolutionary meaning. The latter point raises the paradox of model systems: that is, whether general conclusions can be extracted from given biological items, which themselves were often chosen for study owing to particularly well-adapted features, rather than for their elusive paradigmatic value. In other words, will we ever understand the full set of core principles by working exclusively with adaptive traits that intrinsically tend to distract from these rules? While this issue is somewhat theoretical, the popular idea that some species can display advantages over others, in terms of experimental benefit, indicates clearly that such questions have not yet been discussed in sufficient depth.The lack of a clear definition of what evo-devo covers as a discipline is echoed by the difficulty to elaborate a commonly accepted set of guidelines, mostly owing to the conflicting ménage between developmental geneticists on the one hand, with their mindset inherited from T. Morgan and H. Spemann, and population (evolutionary) geneticists on the other hand, the direct descents of the new synthesis. In fact, we face a modern version of the classical dichotomy between variation—the ‘how'' question—and selection—the ‘why'' question—and we may wonder how long this productive relationship will last. While it might consolidate itself and lead to an integrated theory of evolution that includes the emerging mechanistic side, it could well split again into divergent trajectories, like a comet that returns closer to a planet every hundred years to fill itself with concepts and energy before leaving again for yet another journey.Evo-devo is arguably a transitory discipline. We are witnessing the emergence of a new developmental biology, relying on high-throughput approaches, systems analyses and modelling to use gene (information) clusters, or even full genomes, as we currently use single genes. The accompanying shift in the required competencies—for example, bioinformatics, physics and maths—although of great interest mechanistically speaking, does not necessarily strengthen the link with the genetic framework of evolution. Also, we should remember that evolution and development are disciplines built on different epistemological grounds, which bring to their fusion an unstable equilibrium. Development is a science of recurrence; based on the assumption that the same process will happen again, in each generation, leading to results that we can predict. As such, it has a fixed timeframe. Evolution relies on the exact opposite premises; it is by definition a linear process, wherefrom recurrence is impossible. It has no clear timeframe and (so far) no predictable result. The former discipline explains how things happen, the latter how things most likely happened.This theoretical antagonism might nevertheless become obsolete once the mechanisms of development are fully understood and once the computation of various ontogenetic roadmaps will discriminate the possible from the impossible, thus telling us which form could evolve out of a given species. This will primarily concern macro-evolution, as micro-evolutionary phenomena are probably less constrained and, as such, more difficult to anticipate. If this were true, one should be able to predict with some accuracy the few alternative solutions offered to one particular species for the next million years, especially if environmental conditions can also be predicted. In such a scenario, the next rendezvous with the comet will turn evolution into a predictive science. This may indeed take another century.     

Functional evolutionary developmental biology (evo‐devo) of morphological novelties in plants

Abstract The origin of morphological and ecological novelties is a long‐standing problem in evolutionary biology. Understanding these processes requires investigation from both the development and evolution standpoints, which promotes a new research field called “evolutionary developmental biology” (evo‐devo). The fundamental mechanism for the origin of a novel structure may involve heterotopy, heterochrony, ectopic expression, or loss of an existing regulatory factor. Accordingly, the morphological and ecological traits controlled by the regulatory genes may be gained, lost, or regained during evolution. Floral morphological novelties, for example, include homeotic alterations (related to organ identity), symmetric diversity, and changes in the size and morphology of the floral organs. These gains and losses can potentially arise through modification of the existing regulatory networks. Here, we review current knowledge concerning the origin of novel floral structures, such as “evolutionary homeotic mutated flowers”, floral symmetry in various plant species, and inflated calyx syndrome (ICS) within Solanaceae. Functional evo‐devo of the morphological novelties is a central theme of plant evolutionary biology. In addition, the discussion is extended to consider agronomic or domestication‐related traits, including the type, size, and morphology of fruits (berries), within Solanaceae.     

In Search of the Holy Grail of Heliocobacter pylori Remedies

In this issue, Gisbert et al. (pp. 157–62) present the results of a noncomparative study evaluating a twice daily, 5‐day regimen of ranitidine bismuth citrate, amoxicillin, clarithromycin and metronidazole twice daily for Helicobacter pylori cure. This study is one of a few stuides that evaluate a 5‐day triple antimicrobial regimen in combination with a antisecretory agent. Although the study design precludes making any definite conclusion, it does encourage additional investigation of these types of regimens. Randomized controlled trials (RCTs) using regimens containing multiple agents should consider both standard‐of‐care comparator regimens and comparator regimens that will provide a better understanding of why regimens are more effective or better tolerated. The goal of treatment should be to maintain a lower bound 95% confidence interval (CI) of the point estimate of greater than 80% and a ‘delta’ (lower bound 95% CI of the difference in rates) of less than 10%. All RCTs should conduct susceptibility testing to evaluate the impact of resistance on efficacy and explain eradication failures. Finally, consideration should be given to the inclusion of patients with functional dyspepsia in H. pylori studies evaluating H. pylori cure since patients with peptic ulcer disease are becoming harder to find.     

In search of the Holy Grail: Media discourse and the new human genetics

It has widely been recognized that the media play a key role in framing debates about genetic issues. This paper provides an overview of the major areas of debate within the social scientific literature on media, public understanding of science and human genetics. It evaluates current approaches to assessing the role of the media in influencing public policy debates. It argues that an analysis of the strategies of news sources should occupy a central role in furthering understanding about the ways in which various social actors seek to influence public policy agendas. At present, within the field of human genetics, only a handful of researchers have systematically examined the strategies of news sources from the perspective of the sources themselves. While recent research has focused upon identifying the major sources and how they are used in science reporting, there remains much to be done in uncovering the processes of negotiation and contestation among social actors prior to issues gaining media coverage.     

Revisiting the Holy Grail: using plant functional traits to understand ecological processes

One of ecology's grand challenges is developing general rules to explain and predict highly complex systems. Understanding and predicting ecological processes from species' traits has been considered a ‘Holy Grail’ in ecology. Plant functional traits are increasingly being used to develop mechanistic models that can predict how ecological communities will respond to abiotic and biotic perturbations and how species will affect ecosystem function and services in a rapidly changing world; however, significant challenges remain. In this review, we highlight recent work and outstanding questions in three areas: (i) selecting relevant traits; (ii) describing intraspecific trait variation and incorporating this variation into models; and (iii) scaling trait data to community‐ and ecosystem‐level processes. Over the past decade, there have been significant advances in the characterization of plant strategies based on traits and trait relationships, and the integration of traits into multivariate indices and models of community and ecosystem function. However, the utility of trait‐based approaches in ecology will benefit from efforts that demonstrate how these traits and indices influence organismal, community, and ecosystem processes across vegetation types, which may be achieved through meta‐analysis and enhancement of trait databases. Additionally, intraspecific trait variation and species interactions need to be incorporated into predictive models using tools such as Bayesian hierarchical modelling. Finally, existing models linking traits to community and ecosystem processes need to be empirically tested for their applicability to be realized.     

Clinical examination or whole-body magnetic resonance imaging: the Holy Grail of spondyloarthritis imaging

Whole-body magnetic resonance imaging allows acquisition of diagnostic images in the shortest scan time, leading to better patient compliance and artifact-free images. Methods of clinical examination of the anterior chest wall joints vary between physician groups and consideration of the rules of rib motion is suggested. The type of joint and its synovial lining may also aid imaging/clinical correlation. This well-written study by experts in the field with a standardized design and methodology allows good scientific analysis and suggests the advantages of whole-body magnetic resonance imaging in anterior chest wall imaging. Selection of clinical examination criteria and specific joints may have had an influence on the study results and the lack of association reported.