Chitosomes: past, present and future

José Ruiz-Herrera's discovery that chitin microfibrils could be made by a fungal extract paved the way for elucidating the intracellular location of chitin synthetase. In collaboration with Charles Bracker, chitosomes were identified as the major reservoir of chitin synthetase in fungi. Unique in size, buoyant density, and membrane thickness, chitosomes were found in a wide range of fungi. Their reversible dissociation into 16S subunits is another unique property of chitosomes. These 16S subunits are the smallest molecular entities known to retain chitin synthetase activity. Further dissociation leads to complete loss of activity. From studies with secretory mutants, yeast researchers concluded that chitosomes were components of the endocytosis pathway. However, key structural and enzymatic characteristics argue in favor of the chitosome being poised for exocytotic delivery rather than endocytotic recycling. The chitosome represents the main vehicle for delivering chitin synthetase to the cell surface. An immediate challenge is to elucidate chitosome ontogeny and the role of proteins encoded by the reported chitin synthetase genes in the structure or function of chitosomes. The ultimate challenge would be to understand how the chitosome integrates with the cell surface to construct the organized microfibrillar skeleton of the fungal cell wall.     

Life: past, present and future

Molecular methods of taxonomy and phylogeny have changed the way in which life on earth is viewed; they have allowed us to transition from a eukaryote-centric (five-kingdoms) view of the planet to one that is peculiarly prokarote-centric, containing three kingdoms, two of which are prokaryotic unicells. These prokaryotes are distinguished from their eukaryotic counterparts by their toughness, tenacity and metabolic diversity. Realization of these features has, in many ways, changed the way we feel about life on earth, about the nature of life past and about the possibility of finding life elsewhere. In essence, the limits of life on this planet have expanded to such a degree that our thoughts of both past and future life have been altered. The abilities of prokaryotes to withstand many extreme conditions has led to the term extremophiles, used to describe the organisms that thrive under conditions thought just a few years ago, to be inconsistent with life. Perhaps the most extensive adaptation to extreme conditions, however, is represented by the ability of many bacteria to survive nutrient conditions not compatible with eukaryotic life. Prokaryotes have evolved to use nearly every redox couple that is in abundance on earth, filling the metabolic niches left behind by the oxygen-using, carbon-eating eukaryotes. This metabolic plasticity leads to a common feature in physically stratified environments of layered microbial communities, chemical indicators of the metabolic diversity of the prokaryotes. Such 'metabolic extremophily' forms a backdrop by which we can view the energy flow of life on this planet, think about what the evolutionary past of the planet might have been, and plan ways to look for life elsewhere, using the knowledge of energy flow on earth.     

Biodiversity: past, present and future

On 12-15 May 2011, a diverse group of students, researchers and practitioners from across Canada and around the world met in Banff, Alberta, to discuss the many facets of biodiversity science at the 6th Annual Meeting of the Canadian Society for Ecology and Evolution.     

Ranavirus: past, present and future

Emerging infectious diseases are a significant threat to global biodiversity. While historically overlooked, a group of iridoviruses in the genus Ranavirus has been responsible for die-offs in captive and wild amphibian, reptile and fish populations around the globe over the past two decades. In order to share contemporary information on ranaviruses and identify critical research directions, the First International Symposium on Ranaviruses was held in July 2011 in Minneapolis, MN, USA. Twenty-three scientists and veterinarians from nine countries examined the ecology and evolution of ranavirus-host interactions, potential reservoirs, transmission dynamics, as well as immunological and histopathological responses to infection. In addition, speakers discussed possible mechanisms for die-offs, and conservation strategies to control outbreaks.     

Biodiversity: past, present, and future

Data from the fossil record are used to illustrate biodiversity in the past and estimate modern biodiversity and loss. This data is used to compare current rates of extinction with past extinction events. Paleontologists are encouraged to use this data to understand the course and consequences of current losses and to share this knowledge with researchers interested in conservation and ecology.     

Anti-obesity drugs: past,present and future

The ideal anti-obesity drug would produce sustained weight loss with minimal side effects. The mechanisms that regulate energy balance have substantial built-in redundancy, overlap considerably with other physiological functions, and are influenced by social, hedonic and psychological factors that limit the effectiveness of pharmacological interventions. It is therefore unsurprising that anti-obesity drug discovery programmes have been littered with false starts, failures in clinical development, and withdrawals due to adverse effects that were not fully appreciated at the time of launch. Drugs that target pathways in metabolic tissues, such as adipocytes, liver and skeletal muscle, have shown potential in preclinical studies but none has yet reached clinical development. Recent improvements in the understanding of peptidergic signalling of hunger and satiety from the gastrointestinal tract mediated by ghrelin, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, have opened up new possibilities. Although some have now reached clinical development, it is uncertain whether they will meet the strict regulatory hurdles required for licensing of an anti-obesity drug. However, GLP-1 receptor agonists have already succeeded in diabetes treatment and, owing to their attractive body-weight-lowering effects in humans, will perhaps also pave the way for other anti-obesity agents. To succeed in developing drugs that control body weight to the extent seen following surgical intervention, it seems obvious that a new paradigm is needed. In other therapeutic arenas, such as diabetes and hypertension, lower doses of multiple agents targeting different pathways often yield better results than strategies that modify one pathway alone. Some combination approaches using peptides and small molecules have now reached clinical trials, although recent regulatory experience suggests that large challenges lie ahead. In future, this polytherapeutic strategy could possibly rival surgery in terms of efficacy, safety and sustainability of weight loss.     

Pain genetics: past, present and future

Chronic pain is a classic example of gene × environment interaction: inflammatory and/or nerve injuries are known or suspected to be the etiology of most chronic pain syndromes, but only a small minority of those subjected to such injuries actually develop chronic pain. Once chronic pain has developed, pain severity and analgesic response are also highly variable among individuals. Although animal genetics studies have been ongoing for over two decades, only recently have comprehensive human twin studies and large-scale association studies been performed. Here, I review recent and accelerating progress in, and continuing challenges to, the identification of genes contributing to such variability. Success in this endeavor will hopefully lead to both better management of pain using currently available therapies and the development and/or prioritizing of new ones.     

Gene duplication: past, present and future

Gene duplication is of central interest to evolutionary developmental biology, having been implicated in evolutionary increases in complexity. These ideas stem principally from the Lewis model for the evolution of the BX-C and Ohno's proposal for genome duplications during chordate evolution. Here I revisit these models and show how recent data have confirmed their essential features, but forced some important revisions. These include revised dates for homeotic gene duplications and for widespread gene duplication in vertebrate evolution. I also outline the major unresolved questions in the study of gene duplication, and its relevance to evolution and development.     

RAMPs: The past, present and future

The discovery of receptor-activity-modifying proteins (RAMPs) as accessory proteins required for the appropriate localization and function of certain G-protein coupled receptors (GPCRs) produced a paradigm shift in our understanding of GPCR regulation. Three RAMPs have now been demonstrated to be crucial for various aspects of the life cycle of calcitonin-like receptor (CLR) including endoplasmic reticulum-to-Golgi translocation, internalization and recycling. Although the RAMP-CLR interaction was the first to be identified, other GPCRs belonging to both the class B and C families of GPCRs also seem to be regulated by RAMPs. The recent advances in our knowledge of the cellular and biochemical regulation of RAMPs and how they in turn regulate the life cycle of GPCRs could lead to therapeutic advances in several diseases.     

CellML: its future, present and past

Advances in biotechnology and experimental techniques have lead to the elucidation of vast amounts of biological data. Mathematical models provide a method of analysing this data; however, there are two issues that need to be addressed: (1) the need for standards for defining cell models so they can, for example, be exchanged across the World Wide Web, and also read into simulation software in a consistent format and (2) eliminating the errors which arise with the current method of model publication. CellML has evolved to meet these needs of the modelling community. CellML is a free, open-source, eXtensible markup language based standard for defining mathematical models of cellular function. In this paper we summarise the structure of CellML, its current applications (including biological pathway and electrophysiological models), and its future development—in particular, the development of toolsets and the integration of ontologies.     

ACMC: past,present and future.

In this article, the president of the Association of Canadian Medical Colleges (ACMC) and its director of research review the issues that have confronted ACMC since its inception: the founding of ACMC; development of the clinical teaching unit; creation of the Medical Research Council and expansion of the research mission; the Royal Commission on Health Services and the founding of new faculties of medicine; ACMC''s in-house research program; accreditation and ACMC''s links with medical education in the United States; and French-language medical education in Canada. The review points out the perennial nature of many of these issues, and how often perceived solutions to the problems later become problems themselves. It ends on the optimistic note that ACMC can successfully meet the challenges of the future.     

Calcium signalling: past, present and future

Ca2+ is a universal second messenger controlling a wide variety of cellular reactions and adaptive responses. The initial appreciation of Ca2+ as a universal signalling molecule was based on the work of Sydney Ringer and Lewis Heilbrunn. More recent developments in this field were critically influenced by the invention of the patch clamp technique and the generation of fluorescent Ca2+ indicators. Currently the molecular Ca2+ signalling mechanisms are being worked out and we are beginning to assemble a reasonably complete picture of overall Ca2+ homeostasis. Furthermore, investigations of organellar Ca2+ homeostasis have added complexity to our understanding of Ca2+ signalling. The future of the Ca2+ signalling field lies with detailed investigations of the integrative function in vivo and clarification of the pathology associated with malfunctions of Ca2+ signalling cascades.