High-throughput screening assay for the identification of compounds regulating self-renewal and differentiation in human embryonic stem cells

High-throughput screening (HTS) of chemical libraries has become a critical tool in basic biology and drug discovery. However, its implementation and the adaptation of high-content assays to human embryonic stem cells (hESCs) have been hampered by multiple technical challenges. Here we present a strategy to adapt hESCs to HTS conditions, resulting in an assay suitable for the discovery of small molecules that drive hESC self-renewal or differentiation. Use of this new assay has led to the identification of several marketed drugs and natural compounds promoting short-term hESC maintenance and compounds directing early lineage choice during differentiation. Global gene expression analysis upon drug treatment defines known and novel pathways correlated to hESC self-renewal and differentiation. Our results demonstrate feasibility of hESC-based HTS and enhance the repertoire of chemical compounds for manipulating hESC fate. The availability of high-content assays should accelerate progress in basic and translational hESC biology.     

Cell biology, chemogenomics and chemoproteomics

The scientific techniques used in molecular biological research and drug discovery have changed dramatically over the past 10 years due to the influence of genomics, proteomics and bioinformatics. Furthermore, genomics and functional genomics are now merging into a new scientific approach called chemogenomics. Advancements in the study of molecular cell biology are dependent upon "omics" researchers realizing the importance of and using the experimental tools currently available to cell biologists. For example, novel microscopic techniques utilizing advanced computer imaging allow for the examination of live specimens in a fourth dimension, viz., time. Yet, molecular biologists have not taken full advantage of these and other traditional and novel cell biology techniques for the further advancement of genomic and proteomic-oriented research. The application of traditional and novel cellular biological techniques will enhance the science of genomics. The authors hypothesize that a stronger interdisciplinary approach must be taken between cell biology (and its closely related fields) and genomics, proteomics and bio-chemoinformatics. Since there is a lot of confusion regarding many of the "omics" definitions, this article also clarifies some of the basic terminology used in genomics, and related fields. It also reviews the current status and future potential of chemogenomics and its relationship to cell biology. The authors also discuss and expand upon the differences between chemogenomics and the relatively new term--chemoproteomics. We conclude that the advances in cell biology methods and approaches and their adoption by "omics" researchers will allow scientists to maximize our knowledge about life.     

2004 ASM Conference on the New Phage Biology: the 'Phage Summit'

In August, more than 350 conferees from 24 countries attended the ASM Conference on the New Phage Biology, in Key Biscayne, Florida. This meeting, also called the Phage Summit, was the first major international gathering in decades devoted exclusively to phage biology. What emerged from the 5 days of the Summit was a clear perspective on the explosive resurgence of interest in all aspects of bacteriophage biology. The classic phage systems like lambda and T4, reinvigorated by structural biology, bioinformatics and new molecular and cell biology tools, remain model systems of unequalled power and facility for studying fundamental biological issues. In addition, the New Phage Biology is also populated by basic and applied scientists focused on ecology, evolution, nanotechnology, bacterial pathogenesis and phage-based immunologics, therapeutics and diagnostics, resulting in a heightened interest in bacteriophages per se, rather than as a model system. Besides constituting another landmark in the long history of a field begun by d'Herelle and Twort during the early 20th century, the Summit provided a unique venue for establishment of new interactive networks for collaborative efforts between scientists of many different backgrounds, interests and expertise.     

Metabolomics for phytomedicine research and drug development

Metabolomics, including both targeted and global metabolite profiling strategies, is fast becoming the approach of choice across a broad range of sciences including systems biology, drug discovery, molecular and cell biology, and other medical and agricultural sciences. New analytical and bioinformatics technologies and techniques are continually being created or optimized, significantly increasing the crossdisciplinary capabilities of this new biology. The metabolomes of medicinal plants are particularly a valuable natural resource for the evidence-based development of new phytotherapeutics and nutraceuticals. Comparative metabolomics platforms are evolving into novel technologies for monitoring disease development, drug metabolism, and chemical toxicology. An efficient multidisciplinary marriage of these emerging metabolomics techniques with agricultural biotechnology will greatly benefit both basic and applied medical research.     

Fundamental issues in systems biology

In the context of scientists' reflections on genomics, we examine some fundamental issues in the emerging postgenomic discipline of systems biology. Systems biology is best understood as consisting of two streams. One, which we shall call 'pragmatic systems biology', emphasises large-scale molecular interactions; the other, which we shall refer to as 'systems-theoretic biology', emphasises system principles. Both are committed to mathematical modelling, and both lack a clear account of what biological systems are. We discuss the underlying issues in identifying systems and how causality operates at different levels of organisation. We suggest that resolving such basic problems is a key task for successful systems biology, and that philosophers could contribute to its realisation. We conclude with an argument for more sociologically informed collaboration between scientists and philosophers.     

Bacterial conjugation-based antimicrobial agents

A clear imperative exists to generate radically different antibacterial technologies that will reduce the usage of conventional chemical antibiotics. Here we trace one route into this new frontier of drug discovery, a concept that we call the bacterial conjugation-based technologies (BCBT). One of the objectives of the BCBT is to exploit plasmid biology for combating the rising tide of antibiotic-resistant bacteria. Specifically, the concept utilizes conjugationally delivered plasmids as antimicrobial agents, and it builds on the accumulated work of many scientists dating back to the discoveries of conjugation and plasmids themselves. Each of the individual components that comprise the approach has been demonstrated to be feasible. We discuss the properties of bacterial plasmids to be employed in BCBT.     

Hot springs and cool natural products

Natural products have played a unique role in providing new tools and insights in chemical biology. The tremendous value of natural products was highlighted by scientists from Korea and Japan at the 4(th) Korea-Japan Chemical Biology symposium.     

Global challenges in stem cell research and the many roads ahead

The field of stem cell research has grown to include a vibrant international community of scientists and clinicians who come from both academia and industry and who strive to shed light on the biology of these remarkable cells and find applications in drug discovery, disease modeling, and regenerative medicine.     

Interface Biology of Implants

Implants are widely used in various clinical disciplines to replace or stabilize organs. The challenge for the future is to apply implant materials to specifically control the biology of the surrounding tissue for repair and regeneration. This field of research is highly interdisciplinary and combines scientists from technical and life sciences disciplines. To successfully apply materials for regenerative processes in the body, the understanding of the mechanisms at the interface between cells or tissues and the artificial material is of critical importance. The research focuses on stem cells, design of material surfaces, and mechanisms of cell adhesion. For the third time around 200 scientists met in Rostock, Germany for the international symposium “Interface Biology of Implants.” The aim of the symposium is to promote the interdisciplinary dialogue between the scientists from the different disciplines to develop smart implants for medical use. In addition, researchers from basic sciences, notably cell biology presented new findings concerning mechanisms of cell adhesion to stimulate research in the applied field of implant technology.Key words: interface, implant, stem cells, adhesion, mechanics, surface, biomaterialMedical implants play a growing role in routine clinical practice. In addition to replace or stabilize injured tissue permanently or transiently, the application of implant materials to stimulate the regeneration of tissue is becoming a challenge in the field of regenerative medicine. The use of implant materials is based on the idea that biomaterials function not only as mechanical support for cells and tissue but also provide a matrix to induce signal transduction in the cells that control complex molecular mechanisms responsible for proliferation und differentiation. In this context, the interface between artificial materials and living cells or tissue is an exciting field of great scientific interest and constitutes one of the most dynamic and expanding field in science and technology. Progress in this field is mainly driven by the fundamental importance for clinical applications. The research is characterized by a multidisciplinary collaboration between physics, engineers, biologists and clinicians.In May 2009, for the third time after 2003 and 2006 around 200 scientists met in Rostock-Warnemünde for the symposium “Interface Biology of Implants” to discuss biointerface processes at a fundamental level. The main goals of this symposium are to simulate the interdisciplinary dialogue between scientists of the different disciplines and to introduce current knowledge of basic research in cell biology and material science into the applied field of implant technology. The programme was organized in invited presentations of 20 internationally renowned scientists and complemented by short talks of mostly young scientists selected from the submitted abstracts. In addition, 80 posters presented latest results in this multidisciplinary field.The symposium was opened with a keynote lecture presented by Hartmut Hildebrand (Lille). He gave an overview about the 7,000 years old history of application of implant materials. Rare photographs were shown which demonstrated that in these early times prostheses mainly made from metallic materials were used to restore teeth, extremities and the skull of the human body. These old documents stressed the historical relevance of medical application of implant materials.The symposium on two days was composed of four sessions covering the interdisciplinary research in the field. The session “Stem cells and biomaterials” discussed the biological response and signalling mechanism of stem cells in the interaction with a material surface. The session “Bioactivation of implant surfaces” focussed on the tailoring of surfaces to control the cell physiology. To stimulate the field by recent data in basic cell biology, talks were presented in the third session, dealing with molecular mechanisms involved in cell adhesion. A special session dealt with the role and mechanism of controlling cells by mechanics.     

International Society of Chronobiology: Membership Information

The International Society for Chronobiology has as its aims, furthering the study of temporal changes in living matter, including biological rhythms in development and ageing in individuals and populations; studying and defining the mechanisms of temporal changes; fostering practical applications for chronobiological findings to mankind in basic and applied biology, physiology, work hygiene and the medical sciences; promoting education in and wide understanding of chronobiology; and furthering contact between scientists in the field and providing a forum for practitioners of chronobiology.     

International Society of Chronobiology: Membership Information

The International Society for Chronobiology has as its aims, furthering the study of temporal changes in living matter, including biological rhythms in development and ageing in individuals and populations; studying and defining the mechanisms of temporal changes; fostering practical applications for chronobiological findings to mankind in basic and applied biology, physiology, work hygiene and the medical sciences; promoting education in and wide understanding of chronobiology; and furthering contact between scientists in the field and providing a forum for practitioners of chronobiology.     

pLoc_bal-mHum: Predict subcellular localization of human proteins by PseAAC and quasi-balancing training dataset

A cell contains numerous protein molecules. One of the fundamental goals in molecular cell biology is to determine their subcellular locations since this information is extremely important to both basic research and drug development. In this paper, we report a novel and very powerful predictor called “pLoc_bal-mHum” for predicting the subcellular localization of human proteins based on their sequence information alone. Cross-validation tests on exactly the same experiment-confirmed dataset have indicated that the new predictor is remarkably superior to the existing state-of-the-art predictor in identifying the subcellular localization of human proteins. To maximize the convenience for the majority of experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc_bal-mHum/, by which users can easily get their desired results without the need to go through the detailed mathematics.     

Recent advances in target identification of bioactive natural products

Natural products are a tremendous source of tool discovery for basic science and drug discovery for clinical uses. In contrast to the large number of compounds isolated from nature, however, the number of compounds whose target molecules have been identified so far is fairly limited. Elucidation of the mechanism of how bioactive small molecules act in cells to induce biological activity (mode of action) is an attractive but challenging field of basic biology. At the same time, this is the major bottleneck for drug development of compounds identified in cell-based and phenotype-based screening. Although researchers’ experience and inspiration have been crucial for successful target identification, recent advancements in genomics, proteomics, and chemical genomics have made this challenging task possible in a systematic fashion.     

Bugs, drugs and chemical genomics

The serendipitous discovery of penicillin inspired intensive research into how small molecules affect basic cellular processes and their potential to treat disease. Biochemical and genetic approaches have been fundamental for clarifying small-molecule modes of action. Genomic technologies have permitted the use of chemical-genetic strategies that comprehensively study compound-target relationships in the context of a living cell, providing a systems biology view of both the cellular targets and the interdependent networks that respond to chemical stress. These studies highlight the fact that in vitro determinations of mechanism rarely translate into a complete understanding of drug behavior in the cell. Here, we review key discoveries that gave rise to the field of chemical genetics, with particular attention to chemical-genetic strategies developed for bakers' yeast, their extension to clinically relevant microbial pathogens, and the potential of these approaches to affect antimicrobial drug discovery.     

The Making of the Women in Biology Forum (WiB) at Bioclues

The Women in Biology forum (WiB) of Bioclues (India) began in 2009 to promote and support women pursuing careers in bioinformatics and computational biology. WiB was formed in order to help women scientists deprived of basic research, boost the prominence of women scientists particularly from developing countries, and bridge the gender gap to innovation. WiB has also served as a platform to highlight the work of established female scientists in these fields. Several award-winning women researchers have shared their experiences and provided valuable suggestions to WiB. Headed by Mohanalatha Chandrasekharan and supported by Dr. Reeta Rani Singhania and Renuka Suravajhala, WiB has seen major progress in the last couple of years particularly in the two avenues Mentoring and Research, off the four avenues in Bioclues: Mentoring, Outreach, Research and Entrepreneurship (MORE).In line with the Bioclues vision for bioinformatics in India, the WiB Journal Club (JoC) recognizes women scientists working on functional genomics and bioinformatics, and provides scientific mentorship and support for project design and hypothesis formulation. As a part of Bioclues, WiB members practice the group''s open-desk policy and its belief that all members are free to express their own thoughts and opinions. The WiB forum appreciates suggestions and welcomes scientists from around the world to be a part of their mission to encourage women to pursue computational biology and bioinformatics.     

Cell-PLoc: a package of Web servers for predicting subcellular localization of proteins in various organisms

Information on subcellular localization of proteins is important to molecular cell biology, proteomics, system biology and drug discovery. To provide the vast majority of experimental scientists with a user-friendly tool in these areas, we present a package of Web servers developed recently by hybridizing the 'higher level' approach with the ab initio approach. The package is called Cell-PLoc and contains the following six predictors: Euk-mPLoc, Hum-mPLoc, Plant-PLoc, Gpos-PLoc, Gneg-PLoc and Virus-PLoc, specialized for eukaryotic, human, plant, Gram-positive bacterial, Gram-negative bacterial and viral proteins, respectively. Using these Web servers, one can easily get the desired prediction results with a high expected accuracy, as demonstrated by a series of cross-validation tests on the benchmark data sets that covered up to 22 subcellular location sites and in which none of the proteins included had > or =25% sequence identity to any other protein in the same subcellular-location subset. Some of these Web servers can be particularly used to deal with multiplex proteins as well, which may simultaneously exist at, or move between, two or more different subcellular locations. Proteins with multiple locations or dynamic features of this kind are particularly interesting, because they may have some special biological functions intriguing to investigators in both basic research and drug discovery. This protocol is a step-by-step guide on how to use the Web-server predictors in the Cell-PLoc package. The computational time for each prediction is less than 5 s in most cases. The Cell-PLoc package is freely accessible at http://chou.med.harvard.edu/bioinf/Cell-PLoc.     

Interface Biology of Implants

Implants are widely used in various clinical disciplines to replace or stabilize organs. The challenge for the future is to apply implant materials to specifically control the biology of the surrounding tissue for repair and regeneration. This field of research is highly interdisciplinary and combines scientists from technical and life sciences disciplines. To successfully apply materials for regenerative processes in the body, the understanding of the mechanisms at the interface between cells or tissues and the artificial material is of critical importance. The research focuses on stem cells, design of material surfaces, and mechanisms of cell adhesion. For the third time around 200 scientists met in Rostock, Germany for the international symposium “Interface Biology of Implants”. The aim of the symposium is to promote the interdisciplinary dialogue between the scientists from the different disciplines to develop smart implants for medical use. In addition, researchers from basic sciences, notably cell biology presented new findings concerning mechanisms of cell adhesion to stimulate research in the applied field of implant technology.     

Learning from Gobind Khorana: “The difficult we do today,the impossible tomorrow”

Prof. Har Gobind Khorana was one of the greatest scientists of the twentieth century. Drawing on his strong roots in organic chemistry, he had a remarkable ability to select and focus his intellect on successfully addressing some of the most important challenges in modern biology in a career spanning nearly 6 decades. His pioneering contributions in gene synthesis and protein structure–function studies, and more broadly in what he termed “chemical biology,” continue to have a major impact on modern biomedical science.     

Mass spectrometry imaging: Facts and perspectives from a non-mass spectrometrist point of view

Mass Spectrometry Imaging (MSI, also called Imaging Mass Spectrometry) can be used to map molecules according to their chemical abundance and spatial distribution. This technique is not widely used in mass spectrometry circles and is barely known by other scientists. In this review, a brief overview of the mass spectrometer hardware used in MSI and some of the possible applications of this powerful technique are discussed. I intend to call attention to MSI uses from cell biology to histopathology for biological scientists who have little background in mass spectrometry. MSI facts and perspectives are presented from a non-mass spectrometrist point of view.     

Cognitive empathy in inter-disciplinary research: The contrasting attitudes of plant breeders and molecular biologists towards rice

I draw attention to the perceptions of and interactions between molecular biologists and scientists engaged in plant breeding in India, who have been attempting to employ molecular biology tools to understand and intervene to improve the rice crop. The present essay suggests that the concept of cognitive empathy is crucial for enabling basic scientists and applied scientists to begin to understand phenomena from the point of view of the other and from the point of view of society at large, and in arriving at solutions that are scientifically feasible and socially acceptable. Socialization into disciplinary cultures, organizational factors and individual anxieties seem to inhibit inter-disciplinary collaboration. The majority of rice breeders and a small group of molecular biologists emphasize the relative merits of marker-assisted selection (MAS) in the near term vis-à-vis the currently controversial transgenic approach for rice crop improvement in India. An earlier version was presented at the International Transdisciplinarity Conference held at the Swiss Federal Institute of Technology, Zürich, Switzerland, February 27–March 1, 2000.