Despite the unexpected cold summer weather (20°C/68°F), morning began early here in the city of Yokohama with a familiar breakfast at McDonald’s.  The second day of the conference began with the third plenary entitled, “Lost in translation: the difficult path for stem cells to the clinic.” Although recent advances in stem cell research reduced a gap between bench and bed and brought a great deal of hope from patients seeking curative treatments, challenges we the investigators face remained still and it was both necessary and obligatory for the members of ISSCR to recognize them.

From an industrial point of view, Ann Tsukamoto (StemCells Inc, USA) introduced highly purified expandable and bankable human neural stem cells (HuCNS-SC) and HuCNS-SC derived functional myelin producing oligodendrocytes which showed enhanced conduction velocity and up to 20 wraps of myelin sheaths in vivo. While Tsukamoto focused on the shiny path of clinical applications of stem cells closing her talk with promising pre-clinical trial data consisted of four Pelizaeus-Merzbacher Disease (PMD) patients, Masayo Takahshi (Riken CDB, Japan) emphasized reproducibility and safety of “donor cells” and the importance of “environmental conditions” of host where the cells would be transplanted into. In order to achieve reproducibility, Takahashi established a culture method which allowed to differentiate hES/iPS cells into mature retinal cells such as retinal pigment epithelial cells (RPE) and adapted autologous iPS cells to prevent host rejections. With her “reproducible and safe” iPS cell-derived RPE, Takahashi targeted a disease called, wet-type age-related macular degeneration (AMD) for which the cure remains unavailable and observed structural recoveries from RPE sheet transplanted monkeys.  Furthermore, to define the environmental conditions, Takahashi transplanted various cell lines into the subretinal space and observed rare incidents of tumorigenesis characterizing that the macular region was a “tumor suppressive environment”.

Near the end of the third plenary, the final talk was given by Jan Helge Solbakk, ethics and public policy committee chair of ISSCR.  Dr. Solbakk spoke for the “tragedy of translation”; he reminded us the investigators that millions of people have been watching a play called stem cell research: not in a sense of horseplay but in a sense of tragedy.  Solbakk pointed out that some have been played the tragedy of “moral superiority” and practiced “inferior science.”  Moral errors should be avoided, he said, but should play a tragedy of robustness, commitment, and fidelity, he added.  As we the investigators develop a “sociality” within the watching public including the patients, Solbakk asked us to share not only the successes of research but the failures as well.

Dongjin R. Lee

(3 votes)

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“In a world of total darkness, a glimmer of light emboldens human spirit”. A view on the work of stem cell scientists among the closing remarks from a moving talk by the NBC journalist Charles Sabine, recently diagnosed with Huntington’s disease. It brought into sharp focus one of the many reasons why this field of research holds so much potential for the future of medicine and therapeutics, and also reflected the overall message from previous talks by heavy-hitters in stem cell science; we are on the cusp of discoveries which could make regenerative medicine a reality.

The conference began mid-afternoon, once we had claimed our passes and purple tote bags filled to the brim with leaflets from companies extoling the virtues of their newest products-I was especially drawn to the claim that I could “Have a weekend off! Change media less often!”…ah but if only my supervisor agreed!

In the huge National Conference Centre at the Pacific Yokohama hotel, Fred Gage, the outgoing president of the ISSCR welcomed the 3,150 registered attendees of the conference and outlined the future aims of the organisation: to educate, investigate and influence public policy, and to increase focus on translational science. This meeting, the first to take place in Asia, was an opportunity to allow basic and clinical researchers to collaborate and facilitate the development of safe, science-based applications of discoveries in the field of stem cell research. This call for cooperation was echoed by the president of the Japan Science and Technology Agency, Michiharu Nakamura, who encouraged “global collaboration”…considering these are the guys who support Shinya Yamanaka and have committed ￥35 billion to research in the 18 years, I think it’s a prudent message!

The keynote talks began with Rudolf Jaenisch, recipient of this year’s ISSCR Public Service Award presented by Rob and Cheryl McEwen, Canadian philanthropists and supporters of stem cell research and innovation. He described his lab’s most recent work in the area of reprogramming and their quest to understand if this process is deterministic or stocastic. He showed how their detailed analysis of cells could lead to greater control of the generation of induced pluripotent stem cells (iPSCs) and finished his talk describing how these cellsmay be used to model human disease and provided an insight into an issue in all scientific experiments: how to generate a proper control!

More fundamental in vitro research was presented by Austin Smith, a key figure in establishing our understanding of the mechanism of pluripotantcy. His talk focused on the mechanism of 2i media and in detail how it functions to maintain stem cells in a “ground state” of pluripotantcy. He also discussed it’s use in other contexts and most interestingly, widened the potential perspective on the definition of what might be considered a stem cell. Mechanisms preventing the aquisition of this pluripotent, self-renewing state were described by the legend that is Prof. John Gurdon-he of two-headed Xenopus fame! Describing his investigation of the “resistance to reprogramming”, it was fantastic to discover that older techniques such as nuclear transfer (which he had been crucial in developing) could provide insight into the questions posed by the modern field of Reprogramming. The use of iPSCs for patients was again addressed by Kazutoshi Takahashi, one half of the famous reprogramming duo. He outlined a system by which stem cells and iPSCs could be screened for their suitability for use in therapeutic applications based on highly detailed transcriptional and epigenetic investigation of multiple cell lines.

The importance of epigenetics was again touched upon by Jane Visvader, who discussed molecular regulation of mammary stem cells at the beginning of the second Planary Session. Elaine Fuchs described their investigation of the role of sweat glands and recent discovery of a stem cell population contained within-more than just a cooling system it seems! An eyeball staring back at you in a dish might sound like something from a horror film, but for Dr. Yoshiki Sasai, the spontaneous generation of optic cups from mouse and human ES cells provided an opportunity to investigate the mechanism of development and formation of this important part of the body. His films showing the folding and curving of cell-layers into 3D structures were breathtaking, and highlighted how small observations can lead to bigger stories.

Finally, the Ernest Mcculloch Memorial Lecture was given by Prof. Irving Weissman, instrumental in identifying and enumerating hematopoietic stem cells in mouse models and humans. His talk encompassed the huge number of breakthroughs in the area of haematopoietic stem cell research from it’s early beginnings will little understood lineages to it’s modern-day potential use for cancers such as lymphoma.

While the topic of the day’s talks varied widely, the singular mood was one of forward-facing hope for the future of stem cells and their use in regenerative medicine. Looking up into the neon-tinged night sky, I felt the potential for our research was as high as the towering skyscrapers of Yokohama Bay.

James

#ISSCR2012 #Japan #StemCells #Conference #iPS

(7 votes)

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We all love the beauty of fluorescence, as neatly highlighted by the prevalence of fluorescent images in the Node’s recent Development cover competition.

Such aesthetic data comes at a price however; expensive mercury vapour lamps, or lasers are integral components of the fluorescent microscope. These powerful light sources provide energy which is absorbed by the fluorophore, and subsequently re-emitted as fluorescence. It was believed that the cheaper halogen lamps found on standard bright field microscopes simply lacked the power to do this effectively.

A recent PLoS one article has shown this to be untrue, potentially broadening the availability of fluorescent microscopy by lowering costs, and narrowing the “scientific gap” between developing and developed nations.

The Wakayama lab, from RIKEN CDB, fitted excitation and emission filters to both inverted and upright halogen lamp microscopes, these were then used to examine specimens labelled using fluorescently tagged secondary antibodies. The results are impressive: the presented images are almost as good as those obtained using a mercury vapour lamp.

Cdx2 (green) and Oct3/4 (red) antibody labelled mouse blastocyst- imaged using a halogen-lamp microscope

Halogen lamp microscopes typically have a single light source, and inserting a filter in this way would normally disable standard bright field illumination, a major limitation preventing effective manipulation of fluorescent samples. This technical obstacle was overcome by clever design. The excitation filter is of smaller diameter than the condenser, thus unfiltered light can pass around its periphery under the control of a movable diaphragm.  In this way the single halogen lamp source can simultaneously provide fluorescent and bright field illumination. Practical applications of the apparatus were demonstrated in the article by the removal of fluorescently tagged chromosomes from mouse and bovine oocytes.

The pages of the Node itself are testament to the power of fluorescent imaging to inspire and delight. Wakayama’s team are hoping that inexpensive modification of existing halogen microscopes in schools and teaching labs will help bring science to life for the next generation of budding researchers.

Yamagata K, Iwamoto D, Terashita Y, Li C, Wakayama S, Hayashi-Takanaka Y, Kimura H, Saeki K, & Wakayama T (2012). Fluorescence cell imaging and manipulation using conventional halogen lamp microscopy. PloS one, 7 (2) PMID: 22347500

(7 votes)

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FREE EVENT: Growing a human body part: exploring the frontiers of regenerative medicine

Wednesday 27th June, 7pm to 8.30pm at The Royal Institution, London, UK.

Lecturers: Dr. Helen Blau and Sir John Gurdon

Two experts in regenerative medicine present their latest research, exploring how healthcare will be revolutionised by the ability to grow new body parts.

This event will be followed by a free drinks reception, supported by The Company of Biologists.

Sir John Gurdon – Immortality: Stem cells, nuclear transfer and regenerative medicine
Specialized cells are remarkably stable; we do not have skin cells in our brain, nor heart cells in our liver.  However, the nucleus of any adult cell can be transplanted to an egg from which all kinds of different specialized cells can be grown.  This results from “reprogramming” molecules present in an egg. As these molecules come to be identified, we can envisage a time when it may be possible to create replacement cells for eyes and other organs without the need for immunosuppression.  There is therefore the prospect of giving humans rejuvenated cells to replace those worn out by age or disease.

Dr Helen Blau
Can we live forever? Is immortality possible? Can we regenerate all our tissues?  Helen Blau (Baxter Professor and Director of the Baxter Laboratory for Stem Cell Biology at Stanford University) will discuss ways by which newts regenerate their hearts and limbs and ways we might exploit such natural mechanisms in humans. Moreover, we have stem cells in our tissues now.  Dr Blau will describe approaches to making them function better in order to build brain and brawn and defer aging.

Please note tickets are free, but should be booked in advance.

See here for further details

(2 votes)

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I would have thought that all organisms heal a broken heart the same way humans do (bad movies and cheap wine), but I was wrong.  Some organisms, such as zebrafish and newts, are able to regenerate heart tissue where injury, such as myocardial infarction, occurs.  Understanding tissue regeneration is a necessary leap in generating successful stem cell therapies.  A recent paper in the Development describes the role of TGFβ signaling in zebrafish heart regeneration.

Mammals respond to myocardial infarctions by forming scar tissue at the site of the injury.  Zebrafish form scar tissue at the site of an infarction, but simultaneously begin a complex regenerative process to replace the scar tissue with healthy cardiac muscle.  This regeneration process involves the temporal and spatial coordination of both cardiac and non-cardiac cells, but the molecular players that regulate this process were unknown.  A recent paper by Chablais and Jaźwińska shows that TGFβ signaling is active during heart regeneration.  By timing and reversing inhibition of the pathway using a type I receptor inhibitor, Chablais and Jaźwińska found that TGFβ signaling is key for several steps throughout regeneration—scar deposition, tissue remodeling, and cardiomyocyte proliferation.

The images above show zebrafish heart sections after cryoinjury, which mimics myocardial infarction (left column: injured area in yellow, healthy tissue in blue).  In control sections (top row), cells both within and at the boundary of (arrowheads in zoomed image, seen in cardiomyocytes) the injured area show staining for phospho-Smad3 (green), a direct downstream TGFβ signal transducer.  New myocardium can be seen at the boundary of the injury (arrow in top left).  Treatment with the type I receptor inhibitor (bottom row) successfully suppressed pSmad3 staining and the invasion of cardiomyocytes, and eventually caused ventricular deformation.

For a more general description of this image, see my imaging blog within EuroStemCell, the European stem cell portal.

Chablais, F., & Jazwinska, A. (2012). The regenerative capacity of the zebrafish heart is dependent on TGF signaling Development, 139 (11), 1921-1930 DOI: 10.1242/dev.078543

(3 votes)

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The Page laboratory at The Scripps Research Institute in Jupiter, Florida has a postdoctoral position available to investigate the role of genetic risk factors for autism in brain development, using mouse or Drosophila as a model system. This project will investigate brain growth, patterning and connectivity at a mechanistic level using genetic models as well advanced imaging techniques to characterize phenotypes in the developing brain. 

Requirements: In addition to a PhD in a related discipline, highly motivated candidates should have expertise in developmental biology, genetics and imaging. Interested candidates should send a cover letter, CV and contact details for three references to Damon Page, Ph.D., email: paged@scripps.edu.

TSRI embraces diversity & recognizes it as being a key to our success. EOE/M/F/V/D

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The Physics of Living Matter symposium is coming to London this year . This event, first popularised in Cambridge, is a forum for interdisciplinary research in cell and developmental biology.

For all the details and to register go to:

Physics of Living Matter 7

This year’s themes include:

Dynamic cell organisation

Emergent properties of cellular assemblies

Information processing at a molecular and cellular level.

Speakers

Chris Barnes (London, UK), Tariq Enver (London, UK), U. Gaul (Munich, Germany), C. Guet (Vienna, Austria), Martin Howard (Norwich, UK), Tony Hyman (Dresden, Germany), B. Lehner (Barcelona, Spain), P. Martin (Paris, France). J. Molloy (London, UK), B. Novak (Oxford, UK), T. Risler (Paris, France), R. Rodriguez Daga (Sevilla, Spain), E. Siggia (New York, USA), V. Sourjik (Heidelberg, Germany), JP Vincent (London, UK)

Featured Bragg lecturer

Professor Roger Brent, Seattle

(2 votes)

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Here are the highlights from the current issue of Development:

Two-step loss of pluripotency

During early development, embryonic cells can form derivatives of all three embryonic layers. This pluripotency, which is regulated by a gene regulatory network that includes the transcription factors Oct4 and Nanog, is lost in mouse embryos between about E7.5 and E8.5. Here (p. 2288), Rodrigo Osorno, Anestis Tsakiridis and colleagues investigate the precise timing and mechanism of pluripotency loss in the mouse embryo. Pluripotency, they report, is extinguished at the onset of somitogenesis, and the loss of pluripotency coincides with reduced chromatin accessibility of the regulatory regions of Oct4 and Nanog, and decreased expression of these genes. Notably, pluripotency correlates with threshold levels of Oct4 and, consistent with this observation, the researchers identify a novel non-pluripotent state during which an increase in Oct4 expression can rapidly reverse chromatin closure and restore pluripotency. Finally, the researchers show that this temporary state is followed by permanent methylation-based epigenetic stabilization of the non-pluripotent state. Thus, two mechanistically separate events are responsible for the elimination of pluripotent cells during development.

Lateral inhibition at neurogenic wavefronts

During neurogenesis, lateral inhibition controls the final number of neurons. Neuronal precursors that express high levels of Delta prevent the neuronal differentiation of neighbouring cells by inducing Notch-dependent inhibitory signals in these neighbours. However, neurogenic wavefronts spread through non-neurogenic areas during development, so why isn’t lateral inhibition disrupted where these wavefronts contact non-neurogenic tissue? José María Frade, Saúl Ares and colleagues investigate this puzzle on p. 2321. The researchers show that Delta-like 1 (Dll1) is widely expressed by non-neurogenic precursors at the periphery of the developing chick retina. Using a mathematical model of lateral inhibition, they show that the absence of Dll1 ahead of the neurogenic wavefront reduces the robustness of lateral inhibition, enhances neurogenesis and alters the shape of the neurogenic wavefront, predictions that are consistent with previous observations in the retina of mice in which Dll1 was conditionally mutated. The researchers propose, therefore, that Notch-independent Delta expression ahead of the neurogenic wavefront optimizes neurogenesis by preventing perturbations in lateral inhibition and wavefront progression.

Hedgehog signals modular bone growth

The vertebrate skeleton provides structural support and protection for vital organs but how its component bones acquire their unique shapes is unknown. Here (p. 2371), Charles Kimmel and colleagues investigate the genetic regulation of morphogenesis in dermal bones, which are formed by direct differentiation of mesenchymal cells into osteoblasts, by analyzing the development of the zebrafish opercle. The researchers report that the Hedgehog (Hh) family ligand Indian hedgehog a (Ihha) is specifically expressed in a population of osteoblasts localized along the growing edge of this craniofacial bone. Loss of ihha function reduces pre-osteoblast proliferation and bone growth, whereas hyperactive Hh signalling in mutants for the Hh receptor ptch1 has opposite effects. Time-lapse and live-imaging experiments show that ihha-dependent bone growth is region specific and begins at the start of a second phase of morphogenesis, during which the opercle acquires a more-complex form. These results suggest that dermal bone development is modular, with different genes functioning at specific times and locations to pattern growth.

Lymphangiogenesis goes lyve1

The lymphatic system regulates tissue fluid homeostasis, aids immunity and helps absorb dietary fat. Because aberrant lymphatic growth is associated with cancer metastasis and chronic inflammation, a better understanding of lymphangiogenesis could identify therapeutic targets for these and other lymphatic abnormalities. The major trunk lymphatic vessel in the zebrafish embryo is a well-established model of lymphangiogenesis but the rest of the zebrafish’s lymphatic system is poorly described. On p. 2381, Phil Crosier and colleagues remedy this situation by generating transgenic lines in which the promoter of lyve1 (which encodes lymphatic vessel endothelial hyaluronan receptor 1) drives lymphatic vessel expression of fluorescent reporters. The researchers generate a map of zebrafish lymphatic development and characterize facial, intestinal and lateral lymphatic vessel networks for the first time. They also describe a novel mechanism that underlies the development of the lateral facial lymphatic. These results show that lymphatic vessel formation in zebrafish is more complex than previously thought, thereby increasing the versatility of zebrafish as a model of lymphangiogenesis.

Making dopamine neurons: less Nurr1 later is more

In vitro differentiation of stem cells has the potential to generate specific cell types for clinical use but, to date, this approach has mainly created cells with unsatisfactory phenotypes. Now, Sang-Hun Lee and colleagues generate mature dopamine (DA) neurons from rat neural progenitor cells (NPCs; see p. 2447). Midbrain DA neurons, which are the main source of dopamine in the mammalian nervous system, are lost in Parkinson’s disease. Previous attempts to induce NPC differentiation into DA neurons through the forced expression of Nurr1, a transcription factor that is expressed during midbrain development, induced DA-specific marker expression but failed to generate mature DA neurons. Here, by using an inducible retroviral vector system to express less exogenous Nurr1, and at a later time point than used previously, the researchers generate morphologically and phenotypically mature DA neurons from NPCs. Adjustment of the levels and timings of the expression of cell type-specific transcription factors to match physiological conditions, suggest the researchers, could facilitate the in vitro generation of other useful cell types.

Endoderm conduit for LR signals

Establishment of the left-right (LR) body axis is a crucial step in embryogenesis. In mouse embryos, a leftward flow of fluid in the node establishes an initial LR signal, which is transferred to the lateral plate mesoderm (LPM) where it triggers the gene expression program responsible for LR asymmetry. But how is the LR signal transferred to the LPM? On p. 2426, Yukio Saijoh and co-workers test the hypothesis that endoderm (which lies next to the node and covers the LPM) is involved in this process. The researchers report that expression of LR asymmetric genes in the left LPM is greatly reduced or absent in most mouse embryos null for the Sox17 transcription factor, which exhibit endoderm-specific defects. Interestingly, membrane localization of gap junction connexin proteins is impaired and intercellular transport between endoderm cells is disrupted in Sox17^–/– endoderm. Together, these results suggest that endoderm cells, possibly via gap junction communication, play an essential role in the transfer of LR signals during mouse LR axis establishment.

Plus…

Tudor domain proteins in development

Toshie Kai and colleagues discuss the emerging roles of Tudor domain proteins during development, most notably in the Piwi-interacting RNA pathway, but also in other aspects of RNA metabolism, the DNA damage response and chromatin modification. See the Primer article on p. 2255

The Prdm family: expanding roles in stem cells and development

Prdm factors either act as direct histone methyltransferases or recruit a suite of histone-modifying enzymes to target promoters. In their review, Hohenauer and Moore discuss the roles played by these proteins in stem cells and throughout development. See the Review article on p. 2267

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This (last…) month, several posts on the Node were about publishing issues.

Ivan Oransky wrote a guest post to tell the story of why he and Adam Marcus started the blog “Retraction Watch“, which tracks retractions across the literature.

“There are 44% more papers published every year than a decade ago, but at least 10 times the number of retractions per year.
Why the rise? (…) a few trends have manifest themselves. Some of the increase is due to more visibility for papers thanks to online publishing, and to the advent of plagiarism detection software. But journal editors Ferric Fang and Arturo Casadevall have made convincing arguments that the harsh competitive environment in which scientists work today has tempted more researchers to cut corners and commit fraud.”

Another publishing trend was picked up right here in the Development offices, where Executive Editor Katherine Brown noticed that several authors painstakingly removed “dirt” from images.

“[T]he aim of the authors was to ensure that the images were easily interpreted, and that readers weren’t diverted from the data by the extraneous bits of stuff. This may seem innocent, but it could be the first step on a dangerous slope, at the bottom of which lie the clearly fraudulent activities of deleting the bits of data that don’t fit our hypothesis, or making up data that do.”

Alfonso Martinez-Arias also considers the pressure of publication in his review of the book “Wetware” by Dennis Bray. He recommends the book, and ends by stating that “Wetware is a gust of wind that should encourage you to sail into the current of the unknown, without fear, with the imagination that is denied by the current interest in publications rather than Discovery.”

But before we end this publication-focused section of the monthly summary, I do want to point you to the three editorials written by the former and current Editors in Chief of Development, to mark the journal’s 25th birthday. It’s a great overview of the history of Development, and reflects the rapid progression of the field of developmental biology.

Competitions
There are a few competitions currently ongoing on the Node. First of all, there’s our essay competition. It’s open to anyone with research experience in developmental biology. The winner will be published in Development, and all nominees will receive a £50 Amazon gift certificate. See the announcement for full details. There is still time to start writing, so if you know someone who might be interested (a colleague or student) who may not have seen this yet, please spread the word!

Then there is another voting round for Woods Hole course images. Which of these colourful images would make a good journal cover?

You also voted for images from another course, the International Course on Developmental Biology from Quintay in Chile. Of the eight images, you selected this arrangement of zebrafish embryos as winner:

Also on the Node
–Smart signalling in the developing brain
-Updates from the BSDB meeting (part 1, part 2) and an interview with poster winner Stephen Fleenor.
-Several new job postings.

(No Ratings Yet)

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The winner of the previous round of images from the 2011 Woods Hole embryology course appeared on the cover of Development a few weeks ago. But which of the following will receive the same honour? It’s up to you to decide: vote in the poll below the images for the one you would like to see on the cover of Development. (Click any of the images to see a bigger version.) Poll closes on June 19, noon GMT.

1. Widefield image of a pilidium larvae of the Nemertean ribbon worm, Cerebratulus lacteus, stained for F-actin (green; phalloidin), Acetylated tubulin (red) and DAPI (blue; nuclei). This image was taken by Joseph Campanale, Aracely Lutes, and Stephanie Majkut.

2. Confocal image of Crepidula fornicata (slipper limpet) embryo stained for FMRF (yellow), Acetylated tubulin (green) F-actin (purple; phalloidin) and DAPI (blue; nuclei). This image was taken by Juliette Petersen and Rachel K. Miller.

3. Confocal image of squid, Loligo pealei, embryo stained for for F-actin (green; phalloidin), Acetylated tubulin (red), anti-HRP (yellow), and DAPI (blue; nuclei). This image was taken by Juliana Roscito.

4. Confocal image of squid, Loligo pealei, embryo stained for for F-actin (red; phalloidin), Acetylated tubulin (green), and DAPI (blue; nuclei). This image was taken by Lynn Kee.

(10 votes)

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