Welcome to my report from the 9th Annual ISSCR Meeting in Toronto, 2011. This is  the final part, covering the events of day four of the conference (Saturday); Follow these links to read my account of day one, day two, and day three.

Day 4 – Saturday 18th June

There is a great amount of interest in therapies involving the use of stem cells, but unfortunately it would seem that the case has been overstated, as was suggested by Irving Weissman on the first day of the conference. Nevertheless, it was very great to see some fantastic talks during the ‘Therapeutic Approaches to Stem Cells’ plenary, where the research behind already promising therapies was revealed.

To start off, Leonard Zon (Children’s Hospital and Dana-Farber Cancer Institute at Harvard) presented work studying haematopoiesis in zebrafish, which are used for screening drugs to increase HSC numbers (for exmaple pGE2). Ken Chien (Massachusetts General Hospital) showed his work directing in vivo heart cell fate using modified RNAs, a treatment shown in mice to repair infarcted heart muscle and increase coronary vasculature.

Chris Breuer from Yale School of Medicine described his work with engineering vascular grafts for use in reconstructive surgery. The main problem with using non-living vasculature for repairing congenital heart defects is that once implanted shortly after birth, they don’t grow, and so need to be replaced. Chris and his colleagues have managed to engineer large blood vessel grafts that contain living endothelium (generated from bone marrow derived mononuclear cells) that integrate seamlessly into the recipient’s existing blood vessels. The most interesting part of this reconstruction is that the cells that make up the new vessel, once the biodegradable polymer scaffold has disappeared, are not those bone-marrow derived cells that were originally implanted, but cells that have migrated from the neighbouring blood vessels, akin to how skin wounds heal.  One problem that they have encounted when using this in human patients has been the narrowing of the vessel. Whilst macrophage infiltration is essential for the forming of new vessel tissue (in addition to removing the scaffold), it appears that excessive infiltration is the cause of this narrowing. As such, current work which aims to design a ‘cell-free’ graft will have to take this balance into account.

Next, Michele De Luca (University of Modena and Reggio Emelia, Italy) presented amazing work repairing corneal injuries by using stem cells derived from the limbus, a region of the between the sclera and the cornea – video demonstrations of the delicate sugery already being performed on patients was not for the squeamish! Sheng Ding (Gladstone Institute of Cardiovascular Disease) gave a talk outling his work identifying small molecules that replace reprogramming factors and increase reprogramming efficiency, with a view to generating functional cardiomyocytes. Finally, renowned journalist Charles Sabine, addressing the ISSCR as a patient’s advocate of Huntington’s Disease, talked frankly about his life dealing with the consequences of his family’s history and his subsequent diagnosis of this condition – an incredibly moving speech which aimed to inspire stem cell researchers to strive for future cures.

For the final concurrent sessions, I attended the ‘Epigenetic Programming of Stem Cells’ track, which Yi Zhang (University of North Carolina) opened by talking about Tet proteins and the control of DNA methylation in ESCs. Next, Andrew Xiao (Yale) discussed the role of the histone variant protein H2A.X in ESCs, and Kevin Huang (UCLA) discussed his bioinformatics-based research into the regulation of the mESC transcriptome by DNA methylation.

Alessandra Giorgetti from Centre of Regenerative Medicine in Barcelona described her work involving the transdifferentiation of cord-blood derived CD133+ cells towards the neural lineage. This transdifferentiation process, which did not go through a pluripotent stem cell state, required only one transcription factor, Sox2, could be enhanced by using cMyc. The resultant neural progenitor cells gave rise to functional mature motor neurones in vitro and in vivo. Finally, Suneet Agarwal (Boston’s Children’s Hospital) returned to Tet proteins, this time focussing on the role of Tet2 in mESCs and myeloid tumourigenesis.

The final session of the meeting began with the presenation of the first McEwan Centre Award for Innovation to Shinya Yamanaka and Kazutoshi Takahashi, for their pioneering work to generate iPS cells from somatic cells using various combinations of pluripotency related transcription factors. Upon acceptance of the award (which names both senior and junior researchers of discoveries), Shinya described himself as a less than enthuastic physician before resorting to work as a scientist, and also recounted the early days of Kazutoshi’s PhD in his lab, where he consistently made mistakes that I’m sure most members of the audience are very familiar with! Kazutoshi, for his part, self-depricatingly played down his own contribution towards the innovation –  “all I did was transfection”. Shinya closed their acceptance speech by expressing gratitude for international support during the aftermath of the earthquake that hit Japan earlier in the year, and extending a warm invitation to next year’s ISSCR meeting in Yokohama.

In the closing plenary, ‘Regulatory Networks of Stem Cells’, Rick Young (Whitehead Institute, MIT) presented his lab’s work on the role of Oct4, Sox2, and Nanog in the transcriptional control circuitry of ESCs. Stuart Orkin (Harvard) presented work identifying the components of the Polycomb Repressive Complex-2 (PRC2)  and its role in controlling pluripotency in ESCs and cancer. Judi Lieberman (CBR Institute for Biomedical Research) described a genome-wide siRNA screen to identify selective inhibitors of triple negative breast cancer, which unexpected came up with proteosome components. Finally, in the Anne McLaren Memorial Lecture, Nicole Le Douarin (Academie Des Science, France) described her extensive research in the field of neural crest development, identifying the neural crest as a pluripotent organ which contributes cells to every tissue in the body.

And so ends four days of brilliant science. This year’s ISSCR meeting was my first, and it was a great experience, not least for the sense of community that the ISSCR has strived to create. I’d highly recommend anyone involved in stem cell research to head to Yokohama next year (or Boston the year after) for it.

~Richard Berks

PS. As a small cheeky plug, I’d like to point you towards a blog I write (on a regrettably infrequent basis), Coffee & Cake, Pizza & Beer, which has so far concerned itself with life as a PhD student in biological sciences. I hope to have an article about my experience from the ISSCR meeting up soon.

(3 votes)

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Welcome to my report from the 9th Annual ISSCR Meeting in Toronto, 2011. This is  part three, covering the events of day three of the conference (Friday); you can read the coverage from day one here and day two here.

Day 3 – Friday 17th June

Starting off the day and the ‘Reprogramming and Fate Conversion’ plenary session, Shinya Yamanaka (Center for IPS Cell Research & Application, Japan), somewhat of a celebrity at the conference for his work to generate the first human iPSCs, talked about his lab’s ongoing work in this field, on the comparison between iPSCs and ESCs, and the use of Glis1 as a reprogramming factor. John Gurdon (from the eponymous Gurdon Institute in Cambridge) presented his work studying the reprogramming of a somatic cell nuclei by nuclear transfer into Xenopus oocytes, a reprogramming event that occurs, unlike iPSC reprogramming, at a 100% efficiency. Eric Kallin stepped in for Thomas Graf (both from Center for Genomic Research, Spain) to talk about the role of Tet2 in the transdifferentiation of B cells to macrophages. From Mount Sinai Hospital in our host city, Andras Nagy described his lab’s work using transposons to reprogram somatic cells towards induced pluripotency, and also unveiled a multi-centre project to comprehensibly map the time course for changes in protein, RNA, and DNA during reprogramming, appropriately named “Project Grandiose” – the results of which are due at next year’s conference. Finally, Rudolf Jaenisch (Whitehead Institute for Biomedical Research) discussed his work investigating the efficiency of reprogramming.

In the ‘Haematopoietic Stem Cells’ concurrent session, host Tannishtha Reya (UCSD) presented work concerning Numb & Mushashi in control of asymmetrical division in CML, and Momoko Yoshimoto (Indiana University School of Medicine) gave a talk entitled ”Multipotent haematopoietic progenitors arise at the extra-embryonic yolk sac prior to hematopoietic stem cell emergence in the mouse embryo’. Next, Trista North (Harvard) talked about the control of HSCs in Zebrafish by reactive oxygen species and HIFα, and Rong Lu (Stanford) described her work using genetic ‘barcodes’ to track single murine HSC differentiation in vivo – multiple short DNA sequences are integrated using lentiviruses into HSCs, and after transplantation, the differentiated progeny are harvested and sequenced for the presence of these ‘barcodes’.

To finish, the other host of the session, Andreas Trumpp from DKFZ in Germany, battled through technical difficulties to give a talk that roughly divided into two parts. Firstly, he discussed the discovery of a particular subset of HSCs which divided extremely slowly (estimated at 5 divisions in a lifetime). This dormant HSC population sheds light onto how leukaemic stem cells evade damage by chemotherapy. Application of IFNα or LPS could ‘wake-up’ dormant HSCs and LSCs, indicating a potential mechanism with which to improve chemotherapy. To finish off his talk, Andreas switched to looking at breast cancer, and whether Metastatis Initiating Cells (MICs) could be identified in tumour cells circulating in the blood (called Circulating Tumour Cells, or CTCs). The key was to find CTCs of a breast cancer stem cell phenotype that had hallmarks of Mesenchymal-to-Endothelial Transition.

Back in the main lecture hall for the ‘Stem Cell Metabolism and Ageing’ plenary, Sean Morrison (University of Michigan Centre for Stem Cell Biology) derscribed his work attempting to characterise the haematopoietic stem cell niche. Irina Conboy (UCBerkley) presented work on the regulation of the Muscle Stem Cells and niche during ageing. Amy Wagers (Harvard) later on in the session gave a talk on a similar topic, including the identification of small molecules involved in muscle repair and the role of calorie intake in muscle damage.

Margaret Goodell from Baylow College of Medicine talked about her lab’s work investigating the role of DNA methylation by Dmnt3a in the regulation of haematopoietic stem cells. A conditional mutant mouse that deletes Dmnt3a in haemtopoietic cells (Mx1-Cre) showed an unexpected phenotype upon serial reconstitution of irradiated recipients; the recovery of the numbers of stem cells increased dramatically with each subsequent graft, with their differentiation capacity decreasing. This indicated that Dmnt3a is involved in the control of self-renewal and differentiation of HSCs. When global DNA methylation was analysed, both hypomethylated and hypermethylation was observed; these differentially methylated regions corresponded to genes upregulated and downregulated in leukemias, respectively. However, gene expression data did not strongly correlated with the DNA methylation patterns, and it was still unclear why, despite a variety of haematological disorders commonly showing mutations in Dmnt3a, these mice didn’t succumb to such diseases.

Read on for my report from final day of the ISSCR meeting here.

(3 votes)

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Welcome to my report from the 9th Annual ISSCR Meeting in Toronto, 2011. This is  part two, covering the events of day two (Thursday) of the conference, you can see part one here.

Day 2 – Thursday 16th June

Arriving late at the first plenary of the day, “Tissue Stem Cell Origins”, I managed to catch Michael Rudnicki (Ottawa Health Research Institute) talk about his work on role of Carm1 in muscle stem cell function. Next, in a talk entitled ‘Endothelial Origins of Haematopoietic Precursors’, Elaine Dzierzak of the Erasmus Stem Cell Institute in the Netherlands present her lab’s work identifying the emergence of haematopoietic progenitors from the aortic endothelium during early mouse development. The visualisation of these ‘haematopoietic clusters’ has been made possible by making the embryo transparent and using multi-colour confocal imaging, giving a 3D map of vasculature and the establishment of early haematopoiesis, starting at E9.5 and peaking a day later. Finishing off the plenary session was Hans Clevers from Hubrecht Institute, and his lab’s fascinating work identifying intestinal stem cells in vivo, involving some ingenius imaging work,  and their role in cancer, involving self-replicating and self-organising ‘miniguts’ (see the recent Nature paper from his lab for work on Wnt signalling in regulating instestinal crypt stem cells).

The concurrent sessions of the conference started today (five parallel sessions each day), and so I took the opportunity to dart between seminar rooms to see a variety of talks. First up, in the ‘Stem Cells & Tissue Engineering’ session, was Peter Zandstra (University of Toronto), speaking about his group’s work with the integration of reprogramming, pluripotency maintenance, and differentiation into a suspension-culture bioreactor, in particular for differentiation towards pancreatic and cardiac lineages. I found it fascinating, and timely – if regenerative medicine is ever going to be available to large numbers of people, it will have to be at an industrial scale, and Peter’s talk outlined some of the first steps towards these goals.

I then went to the ‘Human iPSCs and ESCs’ session. Amy Wong (Hospital for Sick Children, Toronto) talked about generating lung airway epithelium from Cystic Fibrosis patient-derived iPSCs in liquid-air interfaces, which would be useful for modelling the disease. Shannon Buckley (NYU School of Medicine) gave a talk on Ubiquitination, an often forgotten mechanism of regulation of ESC self-renewal and differentiation. Natalia Ivanova (Yale) gave an overview of the interactions between Nanog, Sox2, and Oct4 as a regulatory module in hESCs, and Duanqing Pei (GIBH, China) discussed his lab’s methods to increase the efficiency of inducing pluripotency, something that, again, will be critical if ‘personalised medicine’ using patient derived iPSCs is ever to become a realistic prospect for the majority.

The final plenary session of the day was concerned with the biology of Cancer Stem Cells. To start off, Thea Tlsty, from University of California in San Francisco, described the discovery of a new population of cells derived from triple negative breast cancers.  They have the ability to form mammospheres, which have all the normal breast tissue structures and can produce milk under hormonal stimulation, both in vitro and upon xenograft in vivo. However, the real intrigue begins as she described how these cells will also produce cells of all three germ-layer lineages when implanted in various locations, and can also form teratomas, properties normally reserved to desribe human pluripotent stem cells. These cells, though mortal, can even be cultured as hESCs, and bear their normal pluripotency markers of Nanog, Sox2, and Oct4. Thea concedes that more investigation is needed, and has cautiously named these cells ePPSCs – endogenous, provisionally pluripotent, somatic cells (perhaps to avoid any wrath from Irv Weissman!?)

Pier Paolo Di Fiore (University of Milan) talked about the role of Numb regulation of Notch signalling in breast cancer stem cells, using ex vivo self organising organs called ‘mammospheres’, echoing Hans Clever’s talk from earlier in the day. Stanford’s Michael Clarke presented his group’s work in the haematopoietic system, specifically looking at Bmi1 and cancer stem cell self-renewal.

In the Ernest McCulloch Memorial Lecture, John Dick from the University Health Network in Toronto, reflected on the necessity of functional assays to describe the differentiation capacity of haematopoietic stem and progenitor cells, thus underlining the importance of McCulloch’s contributions to the field. He then went on to talk about the concept of ‘clonal evolution’ in human leukaemias, the phenomenon where the major disease causing leukemic population is in fact one of many competing clones. When treatment kills off the major clone sending the patient into remission, previously hidden clones are now free to proliferate and cause a relapse. John stated that consolidating this model with that of the ‘cancer stem cell’ is the current challenge, and finished with describing some recent papers that start to bridge the gap between genetic and functional diversity of cell populations in a variety of leukaemias.

The second day of the ISSCR meeting ended with a reception, whilst half of the poster presenters stood faithfully by their offering of from the 1,500 posters. Later that evening, 1,000 people (allegedly) crammed into a club in downtown Toronto for a “social evening”, which I’m sure resulted in many sore heads the next morning! (mine included…). Read on for the report from day three here.

(2 votes)

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Attendence from over 3,800 delegates, around 140 speakers, and 1,500 posters on display over four days, in the wonderful city of Toronto:  the 9th Annual Meeting of the International Society For Stem Cell Research (ISSCR) was always going to be a great conference, and we certainly weren’t disappointed.

The quality of the research presented was high, and there were far too many talks to easily summarise in one article, so I’ve decided to split up my report into four parts, one for each day. In each, I’ve summarised the talks I saw from that day, and written a bit more about two or three of my favourite talks, from the big names in the field to some of the lesser-known (but equally engaging) researchers. If you’ve anything you’d like to add, please feel free to comment at the bottom of any of the articles.

Day 1 – Wednesday 15th June

Attracted by the promise of an interesting set of talks at the interface of academia and industry (not to mention a free breakfast!), to start off my conference I headed along to the Lonza-sponsored symposium entitled “Novel Stem Cell Tools – applications in Research, Drug Discovery, and Cell Therapy”.

Linzhao Cheng, from John Hopkins University in Baltimore, discussed his group’s work generating induced pluripotent stem cells (iPSCs) from blood cells. Using a plasmid delivered by electroporation, they have found that mononuclear CD34+ cells from the peripheral blood are more ammenable to reprogramming than the traditional fibroblast (increasing speed and efficiency of iPSC generation), as well as being a more easily accessable source of human cells. He also discussed work involving zinc finger nuclease-mediated gene targetting to correct Chronic Granulomatous Disease, which was used to insert a functional copy of the gene gp91 into a ‘safe harbour locus’ AAVS1.

We also heard talks concerning the derivation of neurones from pluripotent stem cells: from Xianmin Zeng (Buck Institute, California) about promising work in the generation of dopaminergic neurons from hPSCs for cell therapy and drug screening to treat Parkinson’s Disease, and from Alexa Poole of California Stem Cell Inc. about their new products involved motor neuron progenitor cells from in-house derived xeno-free cGMP-grade hESCs.

After the break, I headed over to a packed seminar room to see the Symposium to honor Ernest ‘Bun’ McCulloch, whose work developing Colony Forming Unit (CFU) assays paved the way for further functional assays to test stem cell pluripotency. Talking were Valerie Wallace (Ottawa Hospital Research Institute) about her work concerning the role of Hedgehog signalling in the development of the neural retina, Mickie Bhatia (McMaster Stem Cell and Cancer Research Institute) discussing heterogeneity amongst hESCs and it’s implications, and Bing Lim (Genome Institute of Singapore and Harvard Medical School) giving a fresh perspective on pluripotency factors as factors essential for differentiation.

The conference proper began with the Presidential Symposium, chaired by exiting ISSCR President Elaine Fuchs. After an address Robert McEwan from McEwan Centre for Regenerative Medicine, and a presentation of the ISSCR Public Service Award to  Robert Klein (Chairman of Independent Citizen’s Oversight Committee at CIRM), four speakers were invited to give a talk from a historical perspective of stem cell biology and regenerative medicine. Firstly, Janet Rossant from the Hospital for Sick Children in Toronto gave lecture on the importance and limitations of functional assays for pluripotency. George Daley from Children’s Hospital Boston gave his historical account of the origins of stem cell research, nuclear transfer, reprogramming, and cell therapy.

This year’s Keynote Lecture was delivered by Robert Langer from MIT. Author on over 1,100 papers and holder of over 760 patents, he gave a certainly non-exhaustive (but nonetheless exhausting!) whistlestop tour of his lab’s research, focussed on the development of materials designed to improve cell and gene therapy and solve particular problems in surgery. For example, a thermoresponsive material, changing its properties when going from room temperature to body temperature, had been developed for use in minimally invasive surgery, resulting in a thread which when knotted would tighten itself – amazing to watch on video! In addition, by dropping tiny quantities of polymers onto a microscope slide, a polymer microarray was developed, allowing for high-throughput screening of polymers which would support feeder-free growth of human hESCs. Similar screening methods were used to find chemicals that increase the efficiency of gene delivery into hESCs.

Finally, to round up the Presidential Symposium, former ISSCR president Irving Weissman (Stanford) gave a deliberately confrontational yet entertaining speech concerning who is to blame for the rise of unregulated stem cell treatments – in short, part of the blame was from scientists who over-hyped their work, giving stem cell status to cells that aren’t, and claiming major advances without appropriate function assays. His talk also included an assessment of the ISSCR public information program ‘A Closer Look at Stem Cell Treatments’.

The first plenary session of the conference – “Totipotency and Germline Development “ was the last session of the day, and I managed to catch a talk by Azim Surani (Gurdon Institute, Cambridge) on the role of epigenetic reprogramming in germ cell lineage, and Max Plank Institute’s Hans Schoeler‘s talk comparing the induction of pluripotency in somatic cells with that in germ line cells.

The conference had gotten off to a fine start, but I knew once the concurrent sessions started it’d only get more frantic! Follow this link to see the second part of my report..

(3 votes)

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Last May the Instituto Gulbenkian de Ciência (Oeiras, Portugal) hosted the EMBO Workshop on Biophysical Mechanisms of Development (EMBO BMD 2011). As one of the organizers my main mission was to put together a Science and Art contest and exhibition, related with the workshop theme, which we entitled “The Physics of Life”. We were particularly interested in work reflecting the topic of the workshop but we also accepted images related with the broader area of Biophysics or “The Physics of Life”.

The exhibition was aimed at highlighting not only the beauty and art that can be found in research images, but also the artists translations of a scientific theme. Thus, both scientists and artists were invited to apply.

We received a total of 52 images from scientists and artists from six different countries (Portugal, Spain, UK, Holland, Brazil and USA), including renowned science artists like Rob Kesseler and Andrew Carnie.

The submitted images were available for online voting at the workshop Facebook page, and the 20 images with the highest number of votes (or “likes”) were selected for display at “The Physics of Life” exhibition.

Picture types ranged from digital compositions, paintings, graphic art, macro- and microphotographs, and featured several different organisms, such as fungi, animal cells, embryos, flowers and trees. You can see the submitted images in the Facebook photo album “SciArt images in contest” and the selected ones in “The Physics of Life” exhibition.

The 20 selected images were printed and exhibited during the EMBO BMD 2011 workshop, and they remain on display at Instituto Gulbenkian de Ciência.

The winner of the contest, elected by a jury composed of members of the Organizing and Scientific Committees of the workshop, was Elsa Abranches, a post-doctoral researcher working in neural differentiation at Instituto de Medicina Molecular (Lisbon, Portugal), with the image “The Heart of a Brain“.

At the end of the workshop, we received very positive feedback on the exhibition. If you are planning on organizing such an event, I can tell you that it is very rewarding, specially thanks to all the beautiful images we received. For details on organization layouts, check our SciArt exhibition webpage here.

(8 votes)

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Sperm stem cells have a lot riding on their success.  Not only must they produce the actual sperm, but they must maintain a life-long supply.  So, the self-renewal of spermatogonial stem cells is a finely-tuned talent of these stem cells.  A recent paper in the Journal of Cell Science describes the role of Wnt signaling in spermatogonial stem cell maintenance.

Stem cells possess two key properties that make them so special – the ability to produce different types of specialized cells, and the ability for self-renewal.  As spermatogonial stem cells (SSCs) must provide a life-long supply of sperm, their self-renewal is very important.  Recently, a group looked at SSC maintenance and found a role for Wnt signaling in the process.  Yeh and colleagues used clusters of SSCs in vitro to show that Wnt5a promotes the maintenance of SSCs as a cell-extrinsic factor, and functions independently of B-catenin signaling.  Although Wnt5a does work independently of B-catenin in many diverse examples, this paper is the first to show this non-canonical pathway functioning in stem cell maintenance.  Yeh and colleagues also found that Wnt5a is expressed in vivo in cells of the testes in newborn mice.  Finally, SSC clusters expressed the Wnt5a receptors Fzd5, Fzd7 and Ror2.  In the images above, Wnt5a gene expression (red) is found in Sertoli cells (green), which serve as “nurse” cells in the testes.

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

Yeh JR, Zhang X, & Nagano MC (2011). Wnt5a is a cell-extrinsic factor that supports self-renewal of mouse spermatogonial stem cells. Journal of cell science, 124 (Pt 14), 2357-66 PMID: 21693582

(4 votes)

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We’d like to draw your attention to one of the current job postings, even if you don’t normally look at the job ads page.

After 8 very successful years with Development, Dr. Jane Alfred has decided to leave her position as Executive Editor. If you have editorial experience and are looking for a challenging role on a prestigious journal this position may be of interest to you.

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(Based in Cambridge, UK)

After 8 very successful years with Development, Dr. Jane Alfred has decided to leave her position as Executive Editor. If you have editorial experience and are looking for a challenging role on a prestigious journal this position may be of interest to you.

Applications are sought for the role of Executive Editor for Development, our flagship journal serving the developmental biology community.

Joining an experienced and successful team, including Academic Editor-in-Chief Olivier Pourquie, this is an exciting opportunity for a talented scientific editor to make a significant contribution to one of the major journals in the field. Development publishes primary research articles, reviews and topical comment, and reaches out to the wider community through its innovative blog, the Node.

Applicants will have a broad knowledge of developmental biology and stem cells, significant editorial experience and will ideally have already held an influential editorial role.

Core responsibilities include:
• Editorial management of the journal in collaboration with the Editor-in-Chief
• Working with the full team of academic editors on journal initiatives
• Management of in-house editorial and administrative teams
• Commissioning, handling peer review and developmental editing of material for the front section of the journal
• Training and support of editorial staff working on the front section
• Overseeing manuscript submission and dealing with any ethical issues that arise during the handling of primary research papers by the academic editors
• Editorial management of the Node
• Representation of the journal at international conferences and within the wider scientific community
• Creative involvement with marketing activities

Essential requirements for the job are a broad knowledge of and interest in science and the scientific community, willingness to travel, enthusiasm, commitment and excellent interpersonal skills.

This is a senior position, with an attractive salary and benefits, and represents a unique career opportunity on a prominent and highly successful journal.

The Company of Biologists (www.biologists.com) is a not-for-profit organisation, publishing four distinguished journals in the biological sciences: Development, Disease Models & Mechanisms, Journal of Cell Science and The Journal of Experimental Biology – and a new journal, Biology Open, will be launching in Autumn 2011. The organisation has an active programme of charitable giving for the further advancement of biological research, including travelling fellowships for junior scientists, contributions to academic societies and conferences, and the company runs a series of exclusive scientific workshops.

Applicants should send a CV by email to miriam@thecob.co.uk along with a covering letter that states their salary expectations and summarises their relevant experience and why they are enthusiastic about this opportunity.

Applications should be made as soon as possible and by 29th July.

(1 votes)

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The massive cow femur I keep on a shelf right in front of me in my office clearly demonstrates that the shaft of a long bone is anything but a straight, smooth, symmetric tube. It is unevenly flattened and covered with ridges and grooves, bulges and depressions. This extremely intricate topography matches perfectly with adjacent organs and tissues, tendons and joints, thereby enabling the musculoskeletal system to perform its vital functions. Oddly enough, the mechanisms that sculpt the unique and elaborate surface of each bone have been largely overlooked by the study of bone development.

My lab has studied musculoskeletal development for quite a few years, focusing on aspects such as the contribution of muscle contraction to joint formation (Kahn et al., 2009) and the involvement of tendons and muscles in the development of bone protrusions (Blitz et al., 2009). Fascinated by the morphogenetic riddle of the circumferential shape of bones, I have assembled a multidisciplinary team of scientists and students to tackle it. I first approached Prof. Ron Shahar from the Hebrew University, a scientist, veterinarian and engineer, who is an expert in bone orthopedics and mechanobiology. Together, we brought in the then Ph.D. student Amnon Sharir, also a vet, who took upon himself to integrate the developmental and biomechanical aspects of the work. I also recruited specifically for this project Tomer Stern, then an M.Sc. student with a background in mathematics and informatics.

We began by developing scanning protocols and data processing algorithms for the analysis of bone development using micro-CT images. Soon enough, we discovered that the minute dimensions of embryonic mouse bones at the onset of ossification, the low and varying mineral levels and the complex and diverse morphology all presented major obstacles to our efforts. When we finally obtained the first lucid images of how a long bone is formed, our frustration turned into excitement. We could clearly see how a ring of mineral is formed around the developing cortex, followed by construction of perpendicular struts on which the next layer of mineral is laid. The bone shaft gradually became wider and the cortex thicker, until the latter was eroded from within to reach its final thickness.

A prominent and fascinating observation was that this process turned the circumference of the bone shaft from an almost perfect circle in the cartilage anlage, to the typical uneven outline of each fully ossified bone. Using a technique we had designed to visualize and quantify three-dimensional bone features by two-dimensional color maps, we realized that this shaping process involved nonuniform distribution of mineral deposition. We therefore termed this developmental program preferential periosteal growth.

Our next challenge was to uncover the regulatory mechanisms that underlie this morphogenetic process. Using muscular dysgenesis (mdg) mice, which lack muscle contractility, we showed that muscle-induced force is required for the mineralization patterns observed in wild type embryos and for the emergence of the resulting circumferential shape. Mechanical testing revealed that the properly shaped wild type bones had a larger load-bearing capacity. Finally, analysis of the distribution of osteoblasts showed that in bones that experience muscle loads, differential distribution of these bone-forming cells is responsible for preferential bone growth.

Our study expands the prevailing model of bone development by incorporating the contribution of periosteal bone formation, under regulation of muscle forces, to the shaping of the specific three-dimensional design of each long bone. Further study is required to uncover the entire molecular and cellular regulatory pathway that transduces mechanical signals into specific patterns of mineral deposition and bone formation.

Amnon Sharir, Tomer Stern, Chagai Rot, Ron Shahar, & Elazar Zelzer (2011). Muscle force regulates bone shaping for optimal load-bearing capacity during embryogenesis Development, 138 (15), 3247-3259 : 10.1242/dev.063768

Kahn, J., Shwartz, Y., Blitz, E., Krief, S., Sharir, A., Breitel, D., Rattenbach, R., Relaix, F., Maire, P., & Rountree, R. (2009). Muscle Contraction Is Necessary to Maintain Joint Progenitor Cell Fate Developmental Cell, 16 (5), 734-743 DOI: 10.1016/j.devcel.2009.04.013

Blitz E, Viukov S, Sharir A, Shwartz Y, Galloway JL, Pryce BA, Johnson RL, Tabin CJ, Schweitzer R, & Zelzer E (2009). Bone ridge patterning during musculoskeletal assembly is mediated through SCX regulation of Bmp4 at the tendon-skeleton junction. Developmental cell, 17 (6), 861-73 PMID: 20059955

(1 votes)

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Here are the research highlights from the current issue of Development:

BMP signalling rolls up in the neural tube

During neurulation, polarised cell-shape changes at hinge points – specialised regions of the neural plate – help convert the neural plate into a tube. But how are these cell-shape changes regulated? To answer this question, Seema Agarwala and co-workers have been studying neural tube closure in the chick midbrain (see p. 3179). They identify a cell cycle-dependent bone morphogenetic protein (BMP) activity gradient in the anterior neural plate and show that it is required for ventral midline hinge point formation and neural tube closure. BMP signalling, they report, regulates the polarised cell behaviours associated with neural tube closure by modulating epithelial apicobasal polarity in tandem with the cell cycle. Because cell-cycle progression in the neural plate is asynchronous, BMP-mediated polarity modulation induces shape changes in only some neural plate cells, whereas their neighbours retain apicobasal polarity. This mosaic and dynamic modulation of polarity, the researchers propose, provides the neural plate with the flexibility to allow folding while retaining its epithelial integrity.

Tetraspanin-like protein regulates islet cell differentiation

The pancreas is a complex organ that contains ductal, exocrine and endocrine tissues. Here (p. 3213), Kristin Artinger, Lori Sussel and co-workers identify a role for Tm4sf4, a tetraspanin-like protein, during pancreatic endocrine differentiation. Tm4sf4 expression in mice is downregulated by the transcription factor Nkx2.2, which is known to be essential for islet cell differentiation. The researchers show that, in mice, Tm4sf4 is expressed in the pancreatic ductal epithelial compartment and is abundant in islet progenitor cells. Pancreatic tm4sf4 expression and its regulation by Nkx2.2 is conserved in zebrafish, and loss-of-function studies in zebrafish reveal that, in contrast to Nkx2.2, tm4sf4 inhibits α and β cell specification but promotes ε cell fate. Finally, in vitro experiments indicate that Tm4sf4 inhibits Rho-activated cell migration. The researchers propose that the primary role of Nkx2.2 during pancreatic development is to inhibit Tm4sf4 in endocrine progenitor cells, thereby allowing their delamination, migration and differentiation. Targeting Tm4sf4 could, therefore, provide a way to activate quiescent pancreas progenitors for the treatment of diabetes.

Feel the force: embryonic bone shaping

The vertebrate skeleton contains more than 200 bones, each with its own unique shape, size and function. Postnatally, bones remodel in response to the muscle forces they encounter. So bed rest, for example, causes bone thinning. Now, on p. 3247, Amnon Sharir, Elazar Zelzer and colleagues report that muscle force also regulates bone shaping during embryogenesis in mice. Using micro-computed tomography scans of embryonic long bones, the researchers identify a novel developmental programme that, through asymmetric mineral deposition and transient cortical thickening, regulates the specific circumferential shape of each bone. This programme of preferential bone growth, they report, ensures that each bone acquires an optimal load-bearing capacity. Moreover, the programme is regulated by intrauterine muscle contractions; in a mouse strain that lacks such contractions, the bones lose their stereotypical circumferential outline and are mechanically inferior. Thus, the researchers suggest, a reciprocal relationship between structure and mechanical load in utero determines the 3D morphology of developing bones.

Endoderm specification in sea urchins

In sea urchin embryos, endomesoderm specification involves β-catenin entry into the nuclei of the vegetal cells of the developing embryo. Now, on p. 3297, David McClay and colleagues reveal how the embryo uses maternal information to initiate this specification by showing that maternal Wnt6 is necessary for activation of endodermal genes. They report that the addition of Wnt6 or ectopic activation of the Wnt pathway rescues endoderm specification in eggs that lack the small region of the vegetal cortex that is normally needed for the activation of the endomesoderm gene regulatory network. This part of the vegetal cortex, they report, contains a high level of Dishevelled (Dsh), a transducer of the canonical Wnt pathway. They also report that morpholino knockdown of Wnt6 in the whole embryos of two sea urchin species prevents endoderm specification but not the expression of mesoderm markers. The researchers suggest, therefore, that maternal Wnt6 plus a localised vegetal cortex molecule, possibly Dsh, are necessary for endoderm specification in sea urchin embryos.

Gata-way to a cardiac progenitor fate

During gastrulation, cardiovascular progenitor cells (CPCs) migrate to the future heart-forming region of the embryo, where they produce the major cardiac lineages. But what regulates CPC fate and behaviour? On p. 3113, Ian Scott and colleagues report that Smarcd3b (Swi/Snf-related matrix-associated actin-dependent regulator of chromatin subfamily d member 3b) and the transcription factor Gata5 can induce a CPC-like state in zebrafish embryos. In mice, SMARCD3, GATA4 and TBX5 form a cardiac BAF (cBAF) chromatin remodelling complex that promotes myocardial differentiation in the embryonic mesoderm. The researchers now show that smarcd3b and gata5 overexpression in zebrafish embryos leads to the formation of an enlarged heart, whereas combined loss of smarcd3b, gata5 and tbx5 inhibits cardiac differentiation. Most notably, transplantation experiments show that cells overexpressing cBAF components migrate to the developing heart and differentiate into cardiac cells, even if initially placed in non-cardiogenic regions of the embryo. These results show that cBAF has a conserved role in cardiac differentiation and can promote a CPC-like state in vivo.

Aired out: FGF9 in lung development

During lung development, the secreted signalling molecule fibroblast growth factor 9 (FGF9) is expressed in both the mesothelium (the single layer of cells that envelopes the lungs) and the pulmonary epithelium (which gives rise to the proximal airways and terminal epithelial buds). Mesenchymal proliferation and epithelial branching are both reduced in Fgf9^–/– embryos, which die at birth because of impaired lung development. Intriguingly, David Ornitz and colleagues now show that mesothelial- and epithelial-derived FGF9 have distinct functions during lung development in mouse (see p. 3169). Mesothelial-derived FGF9 and mesenchymal WNT2A, they report, are required to maintain the mesenchymal FGF-WNT/β-catenin signalling pathway that is responsible for mesenchymal growth. By contrast, epithelial-derived FGF9 primarily affects epithelial branching, probably through regulation of BMP4 signalling. The researchers also show that epithelial and mesothelial FGF9 and mesenchymal β-catenin suppress the expression of the BMP4 antagonist Noggin in lung mesenchyme, thereby providing a mechanism for coupling mesenchymal and epithelial proliferation during lung development.

Plus…

In cycling tissues, stem cells coordinate tissue maintenance and repair. Here, Klein and Simons review the results of recent lineage-tracing studies and challenge the concept of the stem cell as an immortal, slow-cycling, asymmetrically dividing cell.
See the Hypothesis article on p. 3103.

The tenth annual Keystone Symposium on the Mechanism and Biology of Silencing convened in Monterey, California, in March 2011. Olivia Rissland and Eric Lai summarize the results presented at the meeting, which inspire and push this expanding field into new territories.
See the Meeting Review on p. 3093

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