I am Serena Ding, a third year PhD student, and I work at the University of Oxford’s Biochemistry Department in the United Kingdom. I am interested in the control of cell divisions, specifically in stem cells. In Dr Alison Woollard’s lab, we use a microscopic nematode called Caenorhabditis elegans as a stem cell model.

C. elegans as a model organism

C. elegans are non-pathogenic nematode worms and a truly brilliant model organism. They are found in soil and rotten fruits all over the world. Our wild type worms came from a mushroom patch in Bristol, UK. The worms are small so you can keep ~1000 on a small Nematode Growth Media (NGM) plate like this. 

Hayley Lees, PhD student, holding a 55mm NGM plate

C. elegans naturally exist as hermaphrodites (99.99%) and males (0.01%). Hermaphrodites can self-fertilize and generate a clonal population, as well as mate with males for endless possibilities of genetics. Each worm can produce over 200 offspring in a few days so you will not have to wait very long to have lots of material to work with. C. elegans live for 20-30 days, with all the somatic cell divisions taking place over a 36 hour period, so from a developmental biology point of view, C. elegans presents an excellent opportunity to study complex developmental processes over a relatively short time window. Each worm has just under 1000 cells; the cell lineage is invariant and completely described, so it is possible to pinpoint exactly when and where things go wrong for whatever reason. This means you can study development at single-cell resolution within a whole organism. Last but not least, the genome has been completely sequenced and annotated, and there are many mutants available for various genes.

For these reasons, C. elegans is widely popular as a model organism. The biennial International C. elegans meeting is the biggest worm conference, attracting over 2000 scientists from all over the world working in areas such as aging, neurobiology, and regenerative science. There are various other worm conferences focusing on particular topics or on certain geographical regions. The C. elegans community is friendly and cooperative when it comes to sharing resources. The Center for Caenorhabditis Genetics (funded by National Institutes of Health) keeps a stock of strains that can be easily requested. WormBase is a fantastic online resource for C. elegans and other worms, which contains whole genome sequence, information on all mapped genes, upcoming meetings, forums to discuss topics such as “How many worms will fit into a Mini Cooper?” and so on.

Animal maintenance

In the laboratory we typically grow C. elegans on small NGM plates. We seed the plates with E. coli bacteria OP50 – we call this a “lawn” of bacteria – on which the worms feed. C. elegans happily lives at room temperature just on the lab bench, but depending on the experiment and other staging necessities, we grow worms at 12-26.5 °C in incubators.

Equipment room with incubators set to various temperatures

Below is a picture of what a worm lab bench looks like: lots of plates indeed to maintain different strains. Some people like to stack up their plates very high without tying them together with rubber bands (see the tower of plates on the right hand side), making their bench neighbors quite nervous about using a vortex mixer in case the tower collapses…

A typical worm lab bench

The plates do get contaminated at times, usually by bacteria or fungus and sometimes by mites. In this case we clean the worms either by frequent passaging to new plates or by bleach treatment. We can transfer worms using a worm pick, which is essentially a glass pipette with a piece of platinum wire sticking out of the top. We use a flame to sterilize the metal part before picking up a worm. Because platinum wires cool very quickly, we don’t have to worry about burning the worm. We make our own worm picks and everyone has different preferences – however, when the glass picks get dropped they do break, so it’s best not to develop strong attachment to a particular pick! Bleach treatment, on the other hand, works by killing the contaminants and bursting gravid worms open so they release bleach-resistant eggs, which are then retrieved and hatched. In addition to decontaminating, bleaching is also a handy way to synchronize a worm population, which is often necessary in order to study a particular developmental stage.

The worms self-fertilize and produce lots of offspring, so the plates get crowded quickly and run out of food. Therefore we “chunk” the worms once or twice a week by cutting out a small square of the agar with a few worms using a scalpel, and transferring it to a fresh new seeded NGM plate. If chunking wasn’t done in time and worms do starve, don’t worry, they go into a developmental arrest and can still live without food for months! As long as they have access to food later, they quickly recover and are happy again. Hence the worms are fairly low maintenance. We can also freeze strains in glycerol and store them in liquid nitrogen or at -80 °C for years.

Common techniques

RNA interference (RNAi) is a popular technique in C. elegans. RNAi libraries are commercially available and consist of bacteria containing clones that are designed to silence particular genes. It is easily performed in the worms: you select the feeding clone containing your gene of interest, grow it up in media and induce the expression of double-stranded RNA by IPTG, and let the worms feed on that bacteria – the rest is magic. However RNAi is inherently variable and behaves differently for different genes, so when mutants are available, people tend to prefer those instead. It is also not uncommon to using a combination of RNAi and mutants to study gene functions.

We regularly make transgenic worms using microinjection. We inject the DNA along with a selective marker into the gonad of young adults, and then look at the progeny for transformants and stable transgenic lines. A typical injection marker is unc-119. We inject unc-119 mutants, which are essentially paralyzed, with our desired plasmid plus the unc-119 rescuing plasmid. Then we look for progeny with rescued wild-type movement, which are the transformants. Some of the transformants will yield transgenic lines. This way, we can generate various transgenic worms, such as the one with fluorescent reporters below.

Transgenic worm with fluorescent reporters, generated by microinjection

We sometimes integrate the transgenes into the worm genome afterwards to achieve stable expression. This is done by giving the worms large doses of gamma irradiation. Recently, new techniques such as MosSCI and CRISPR/Cas had been developed to allow for single copy insertion of transgenes into a precise locations of the worm genome, thus allowing for genome editing.

Microscopy is a common feature of developmental biology research, and C. elegans provides a myriad of opportunities for fascinating microscopic work given its transparency and the relative ease of generating mutants and transgenic animals. The worms are transparent so you can see right through the cuticle into whichever cells or organ you are interested in, and additional resources such as Worm Atlas provide great guidance to the worm’s anatomy.

A typical day

No two days are the same, but as I arrive in the morning I generally chunk my worms and do some molecular cloning. After coffee and crosswords I may do some microinjections or set up some genetic crosses if I need to make new strains. Otherwise I spend lots of time on the microscope looking at various markers of cell divisions, both in the wild-type situation and in mutants/RNAi-treated worms to see what goes wrong. I leave work at the end of the day feeling tired but fulfilled, looking forward to return to my lovely little worms the next day!

This post is part of a series on a day in the life of developmental biology labs working on different model organisms. You can read the introduction to the series here and read other posts in this series here.

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Organisation: Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute

Studentship starting: 01 October 2014

Application Deadline: 1st April 2014

Interview Date: 29th April 2014

Programme Overview

This studentship is targeted to applicants with a Physical Sciences, Mathematical or Computational Sciences background, who are interested in applying their training to aspects of stem cell biology.

This programme provides students with an opportunity to spend time in three different labs during their first ‘rotation’ year, before deciding where to undertake their thesis work for years 2-4.

Physical Biology of Stem Cells

Stem cells are defined by their dual capacity to self-renew and differentiate into somatic cells. Great inroads have been made towards understanding how stem cells generate tissue and sustain cell turnover in tissue. At this time most of the inroads have been made by studying the individual biochemistry of the stem cell; much less progress has been made in understanding their function across scales – from molecules to tissue – or how they interact with their physical environment.

In studying the physical biology of stem cells, the aim is to identify and characterise the importance of physical, chemical, mathematical, and engineering considerations in the function of stem cells. This could include mathematical modelling of homeostasis in tissues, engineering controlled environments to control stem cell function, imaging and biotechnology, using single molecule approaches to study molecular interactions, systems biology, or investigating the importance of the stem cell’s response to forces in its environment.

The research generated by the MRC studentships should provide new foundations for biomedical discovery, biotechnological and biopharmaceutical exploitation, and clinical applications in regenerative medicine.

Qualification Eligibility

We welcome applications from those who hold (or expect to be awarded) a relevant first degree at the highest level. You should have a passion for scientific research, specifically with a Physical Sciences, Mathematical or Computational Sciences background.

Financial Support

All applicants must meet the MRC funding eligibility requirements outlined at http://www.mrc.ac.uk/Fundingopportunities/Applicanthandbook/Studentships/Eligibility/index.htm

To Apply

Please visit http://www.stemcells.cam.ac.uk/studentships/phy-biol/ for full details. Please note you will be required to complete and submit a departmental application form, a copy of current CV, provide two references and upload a copy of your transcripts as part of the application process.

Visit http://www.physbio.group.cam.ac.uk/ for details of the current Cambridge Physical Biology network.

Questions? Email: cscr-phd@cscr.cam.ac.uk

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Supervisor: Dr. Brian Hendrich, Cambridge Stem Cell Institute, University of Cambridge

Microsoft Research Supervisor: Prof. Stephen Emmott

Application Deadline: 30 March 2014

PhD Start Date: 01 October 2014

Project Summary

Embryonic stem (ES) cells are a unique type of cell derived from the inner cell mass of the developing blastocyst, which possess the ability to self-renew indefinitely, and to differentiate into all somatic lineages; a characteristic known as pluripotency. Harnessing this potential makes them an attractive prospect for regenerative medicine, while understanding the decision-making procedures that determine differentiation is vital to our overall understanding of development. We aim to combine both state-of-the-art experimental and computational methods to uncover the processes that underlie cell fate determination. We are seeking an outstanding individual for award of a fully funded three year Microsoft PhD Scholarship. The candidate should have a strong background in biochemistry/developmental biology, knowledge of computational/mathematical methods, and the ability to contribute to both experimental work in the Hendrich lab and in computational development at Microsoft Research.

To Apply

Please visit http://www.stemcells.cam.ac.uk/studentships/microsoft/ for full details. Please note you will be required to complete and submit a departmental application form, a copy of current CV, provide two references and upload a copy of your transcripts as part of the application process.

Any questions? Email: cscr-phd@cscr.cam.ac.uk

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DEVELOPMENTAL PATTERNING OF THE VERTEBRATE NERVOUS SYSTEM

NIMR project supervisor: James Briscoe (Developmental Biology)

The complex tissues and organs of every multicellular organism develop in a precise and reproducible manner from initially indistinguishable cells. A fundamental question is how such equipotent cells acquire the appropriate identity for their location. One example of this is the vertebrate central nervous system where the generation of an extraordinary array of neurons with distinct properties and functions is required for the assembly of neuronal circuits. In many developing tissues, including the CNS, naïve cells interpret graded signals, termed morphogens, as positional cues that organize the pattern of cellular differentiation. Our goal is to understand the molecular mechanisms controlling this process.

In ventral regions of the CNS, the secreted protein Sonic Hedgehog (Shh) acts as a morphogen to induce five progenitor domains in precise spatial order in the neural tube. Each progenitor domain is distinguished by the expression of different combinations of transcription factors and each domain generates a distinct neuronal subtype. The mechanism that produces this pattern remains poorly understood. To address this, we will use a combination of in vivo experimental manipulation and in silico analysis that will systematically decipher and model the neural tube network. The function of factors identified by these approaches will be examined and used to build, challenge and refine a model of neural tube development. The identification of the players and their functions within the network will offer insight into the mechanisms and principles controlling neural tube development. Moreover, since the operations of gene regulatory programmes underpin the development of all tissues we anticipate that our analysis will have broad implications for the development of many tissues. Collaborations with physicists and computational biologists have been established to support data analysis. This proposal offers interdisciplinary training in cutting edge techniques that will provide novel insight into transcriptional networks that control cell identity.

To apply: Please download and complete the Application Form and send it to studentships@nimr.mrc.ac.uk. The deadline for applications is on Sunday 23rd March 2014. On receipt of your application your two referees will be contacted. The deadline for submission of references is 12:00 noon (GMT) on Friday 28th March 2014. Your application may not be considered until your references are in place.

References

• Balaskas, N; Ribeiro, A; Panovska, J; Dessaud, E; Sasai, N; Page, Karen M; Briscoe, J and Ribes, V (2012)
  Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the vertebrate neural tube.
  Cell 148, 273-284 
  
• Jacob, J; Kong, J; Moore, S; Milton, C; Sasai, N; Gonzalez-Quevedo, R; Terriente, J; Imayoshi, I; Kageyama, R; Wilkinson, David G; Novitch, Bennett G and Briscoe, J (2013)
  Retinoid acid specifies neuronal identity through graded expression of Ascl1.
  Current Biology 23, 412-418 
  
• Cohen, M; Briscoe, J and Blassberg, R (2013)
  Morphogen interpretation: the transcriptional logic of neural tube patterning.
  Current Opinion in Genetics & Development 23, 423-428 
  

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The first ever World Dicty Race  will require cells to navigate a complex microfluidic maze to reach a pool of chemoattractant at the finish line.  Diffusion of the chemoattractant will create a spatial gradient to guide cells along the shortest path to the finish line. The challenge is to engineer Dicty or HL60 cells to be both smart and fast!   As you know, where Dicty cells shine in precision, they lack in speed, and where HL60 are good sprinters,

they lack in precision. Thus, we are asking laboratories around the world to prepare and send us their fastest and smartest Dicty and HL60 cells.  Cells will compete against each other and against human neutrophils.  The race will take place in Boston, May 16 and winning Dicty team will get $5,000 and 15 minutes of fame at the Annual Dicty Conference.

Image: world racing dicty _thanks to Jonny Chang @ ASCB

You can get involved with the World Dicty Race in any of these three ways:

– Sign up as a participant on our website by March 14.  We only accept only one Dicty cell line from each team, but will send you devices to run the “qualifying race” in your lab.

– Share the news  about the race and our plain English project description site for the general public.

– Send us a note about the type of races that would be of interest for your area of research and will build together the microfluidic tools to make these race happen next year (email us at : dirimia@gmail.com).

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The Node was full of activity in February. Here are some of the highlights!

Research:
 
– Jennifer Fish and Richard Schneider wrote about their recent paper studying jaw size evolution using quail and duck.

– Groups at the MPI-CBG in Dresden and Fritz Lipmann Institute in Jena showed that integrin and thyroid hormones promote expansion of progenitors in the developing neocortex.

– And a recent Cell paper uncovered the structural basis of why different auxin response factors are able to activate only specific gene subsets.

Model organism series:

Great additions to our ongoing series this month!

– A day in the life of an Arabidopsis lab, by Narender Kumar (Louisiana State University).

– A day in the life of an ascidian lab, by Alicia Madgwick and Marion Gueroult-Bellone (CNRS, Montpellier).

– A day in the life of a sea urchin lab, by Tanvi Shashikant (Carnegie Mellon University).

– A day in the life of a butterfly lab, by Leila Shirai (IGC Lisbon).

Outreach:

– Alison Woollard considered her experience presenting this year’s Royal Institution Christmas Lectures.

– Simon Bishop wrote about his internship at the Naked Scientists, bringing developmental biology to the radio.

Also on the Node:

– We reposted an article by SDB president Martin Chalfie, with his advice on getting the postdoc you want.

– Mirana wrote about how a travel fellowship to visit a collaborating lab helped her establish her own lab.

– Development made a short movie about the history of their covers and the beauty of developmental biology.

– and the Node will be at the Cold Spring Harbor Laboratory conference on Avian Model Systems.

Happy Reading!

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When it comes to stem cell biology, there have been very few topics as fascinating and popular as cell reprogramming, the most famous reprogramming experiment being the one of Dolly the sheep. In stem cell biology, reprogramming refers to the concept of taking a fully specialized cell in the body and manipulating it in order to make it become another type of cell. One of the most popular approaches used by scientists to reprogram cells consists in taking a specialized cell and turn it into a pluripotent stem cell first. By definition, pluripotent stem cells can then be made to become any cell type of the body (differentiation) and kept indefinitely in the lab (self renewal).

One of the techniques used to reprogram cells into pluripotent stem cells is called somatic cell nuclear transfer (SCNT). It was used to create Dolly the sheep and consists in taking a specialized cell, extracting its nucleus (containing the genetic material), and transferring it into an empty egg (ie: the egg’s own nucleus was removed beforehand). It results in a viable embryo from which pluripotent stem cells (called embryonic stem cells) can then be isolated. Another approach, for which Prof. Yamanaka was awarded the Nobel Prize in 2012, consists in taking a specialized cell and introducing a few genes into it in order to force the production of a few key factors that induce pluripotency in the cell, producing what we call induced pluripotent stem cell (iPS).

When discovered, iPS-based reprogramming raised a lot of hope since it bypasses the need for an egg and the destruction of an embryo in order to obtain pluripotent stem cells, thus resolving one of the main ethical issues associated with stem cells. However, being so recently discovered, iPS cells are still under intensive scientific scrutiny to assess whether they are reliable and safe for clinical use.

In a recent report published in Cell Stem Cell, Le and colleagues compared mouse pluripotent stem cells obtained by SCNT versus ones obtained by iPS-based reprogramming. In the left panel of this picture, you can observe compact colonies of embryonic stem cells (ES cells) obtained from SCNT. On the right panel, you can observe similar compact shiny colonies of iPS cells. This shows that pluripotent stem cells obtained from both techniques have similar morphology; a morphology that is typical of “classically” obtained ES cells (ie: from a regular embryo). However, further down in their study, authors show that iPS cells have more genetic dysfunctions than SCNT pluripotent stem cells, demonstrating that SCNT is still superior to iPS-based reprogramming.

As a result, more studies are needed to understand which mystery factors in the egg are key to enhance the quality of iPS cells. So the decoding continues…

Picture credit:

Le, R., Kou, Z., Jiang, Y., Li, M., Huang, B., Liu, W., Li, H., Kou, X., He, W., Rudolph, K. L. et al. (2014) ‘Enhanced telomere rejuvenation in pluripotent cells reprogrammed via nuclear transfer relative to induced pluripotent stem cells’, Cell Stem Cell 14(1): 27-39. doi: 10.1016/j.stem.2013.11.005

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On receiving an e-mail from the Royal Institution back in March 2013 inviting me to submit a proposal for the delivery of the CHRISTMAS LECTURES, my first reaction was to delete it! My rough mental calculations, taking into account my usual day jobs of Principal Investigator, University Lecturer, College Tutor, Dean and Mother of two young children, didn’t seem to leave much wriggle room for anything – let alone the vision, working-up and execution of 3 lectures for teenagers on a broad biological topic (“what is life” or “where do I come from” were suggestions from the Ri) that would be televised on BBC4 over Christmas!

Over the next few days I found thoughts of the Lectures creeping in, though.  It was an honour to have been nominated – someone must think I could do a good job.  What an opportunity to share my own passion for Developmental Biology, my own flavor of what counts in biology.  What a venerable institution is the Royal Institution, with its iconic lecture theatre and rich history of science and engagement, from Michael Faraday introducing the public to electricity in 1829 to Carl Sagan’s brilliant exploration of space in 1977 to Chris Bishop’s ‘Hi-Tech Trek’ into the world of Computer Science in 2008.  What a weight of expectation! Could I really do it well? Could I make enough time to do it the justice it would deserve? Would I want to?

A follow up e-mail prodded me into action.  I needed to put together a short proposal for the delivery of the lectures – a kind of narrative arc – and this I did over a couple of snatched afternoons at the British Society for Developmental Biology Spring symposium at the University of Warwick – an auspicious setting for my deliberations. My idea was to start the lectures off talking about development – how we all start off as a single cell, the fertilized egg, and to describe the remarkable process by which this single cell is transformed into trillions of cells, all doing the right thing in the right place at the right time; being liver, for example, or brain. The second lecture would extend the mechanisms I described in the first lecture (what makes cells different from one another) by discussing what makes organisms different from one another during evolution. The third and final lecture would have the emphasis on the future – our future – and consider how our detailed knowledge of genetics and developmental biology provides opportunities for great medical advances as well as intellectual nourishment.

I envisaged two important themes running through all the lectures: firstly, an emphasis on molecular mechanisms, and secondly some insights into how we know all this – both of which I think are absolutely crucial to the engagement process.  The sorts of questions posed by developmental biology involve an awful lot of “how” – how do cells know where they are in the body?  How do they know what they should be? How do cells acquire new functions over evolution? One question always leads to another. It is impossible to answer all these questions in three lectures aimed at teenagers, but it is important to start – to get people thinking, to whet the appetite, and most importantly to give people the confidence to know that understanding the answers is within their reach.  So I very deliberately chose to spend some time on the concept of gene expression, as an important molecular explanation in developmental biology and evolution.  First of all to show the audience that genes can be switched on and off, to give them some insights into how the switching is controlled, and finally to let them know what can happen when the switches change…  The other important theme, how do we know all this? is an important way of getting people to engage and identify with the scientific process, and I wanted to go about this with something very close to my scientific heart – model organisms.  The lessons that a huge variety of model organisms, from yeast to zebrafish, can teach us about biological mechanisms are immense.  This would also allow the introduction of a whole menagerie of entertaining animals throughout the lectures, and in addition allow me to show off my favourite model organism, the nematode C. elegans, as a star of the show, my “hero organism”.

Investigating lungs, lecture 1 (“worm-cam” running in the background) . NB: Assistant Hayley Lees is a current Hertford Graduate Student

Demonstrating DNA replication, lecture 2 

I sent off my proposal and thought that would be that, then was surprised and delighted to hear that the Ri liked my ideas and wanted to come to Oxford and film an audition in my lab.  An audition!! This boiled down to one lovely friendly chap and a camera, and me just sitting by a microscope describing some worms which we had engineered to contain GFP (green fluorescent protein) fused to one of our genes of interest – a brilliant way of finding out where particular proteins are produced in multicellular animals.  After that was a period of waiting while the selection panel deliberated, and it wasn’t until early June that I got the official go-ahead. Rather fittingly, I was at Darwin’s home, Down House, that day, on our annual outing for biologists and biochemists from Hertford, to celebrate the end of their finals.  The phone call came through on the sand walk – the promenade Darwin took each evening to reflect on his days work and think through ideas.  That certainly seemed to augur well for the lectures!!

Over the summer the full gravity of what I had let myself in for became apparent.  Firstly, there was the press release, my first exposure to a new breed – journalists.  Then came a professional photoshoot and PR meetings.  The concept of the whole “package” associated with the CHRISTMAS LECTURES – commissioned press articles, interviews, BBC Radio 4 appearances, previews, social media, had never crossed my mind.  Just as well folks at the Ri (most notably the ever-resourceful and cheerful Olympia Brown) had the good sense not to apprise me of the whole deal before I said yes….

Up close and personal with lobster, lecture 3 

Meetings with the production company, Windfall, started in late September, and were fun, creative and productive.  The series title “Life Fantastic” was the inspired suggestion of Windfall chairman, David Dugan, and put an immediate end to a lot of to-ing and fro-ing between myself, the Ri, BBC and Windfall – it was the obvious and perfect choice.  So with title and outlines in place the task of fully working up the lecture content began in earnest, as the outstanding series producer Johanna Gibbon came onboard, along with my brilliant assistant at the Ri, Andrew Beale, a recent PhD graduate in circadian biology from UCL.  Content development took up most of my waking hours (and some of my sleeping ones) from the latter half of October onwards as we whipped the content into what felt like the right shape and order, with entertaining and informative demos thrown in.  The demos, of course, are the very essence of the CHRISTMAS LECTURES, and took up the most development time, from sourcing exotic animals (and cells!) to perfecting DNA extraction, to building models, to formulating fool-proof games to demonstrate key ideas in evolution, genetics and cancer biology, not to mention engineering a meeting with Charles Darwin!

Meeting Darwin, lecture 2 

I moved to London, abandoning the family, at the beginning of December when the theatre rehearsals started – long exhausting days with no realistic possibility of commuting.  Rehearsal is a very odd experience for a seasoned seminar-giver; I had never really rehearsed anything before, and also had never worked with a script – scientists usually prefer to ad lib around a powerpoint presentation, but this can’t work when you are dealing with a large crew, split second timing for demos and the general “TV thing”.  I adapted quickly, though, and it became great fun as the crew grew with the addition of the Director, David Coleman – an enthusiastic cracker of terrible jokes. We worked from early in the morning until late into the evening, either in theatre or up in the Ri “penthouse”, which doubled as the production office.  We were quite hysterical at times, very intense at others, ate a lot of pizza and drank a lot of wine. The memories of working with such a dedicated team of clever, knowledgeable, funny people (mainly women as it happened – we were dubbed “the coven” up in the penthouse) will stay with me for a long time, and the “can do” attitude was absolutely inspiring. By the time the first “record date” came along, I felt well-prepared, confident and pretty calm (mostly).  The crew grew massively the day before each record, with the addition of several cameramen, sound, lighting, script supervisor, floor supervisors (unbelievably essential for choreographing all the demos on and off), and various other technicians. I was really lucky to be able to share the whole experience with my research group, who all appeared in one or other of the lectures as “assistants” – the “Oxford Glams” – as they were known in the production office!  It was also fantastic to be able to share the experience with some other scientists, not least Paul Nurse, my old PhD supervisor, who joined me in lecture 1 to talk about his Nobel Prize-winning work on cell division.

Paul Nurse and the “mutant bicycle”, lecture 1 

Guest appearance from Robert Winston, lecture 3

By the end of lecture 3 (filmed on 19 December) I was beyond exhausted, although it took a surprising amount of time to “come down” from the adrenaline trip.  I looked forward to the TV transmission dates between Christmas and New Year with a mixture of excitement and trepidation. I knew the lectures went down well in the theatre with the wonderful audience, but how would they translate to TV? I needn’t have worried, and was totally overwhelmed by the positive response on e-mail, Twitter and even good old-fashioned letters.  Although life is now more or less back to normal (although doesn’t seem much less busy as I catch up on everything I neglected!), my involvement with the Ri, and Science Communication in general, continues.  I’ve just done a “gig” at the Ri Family Fun Day and have quite a few public lectures coming up – a new experience I have found to be extremely enjoyable and rewarding. I’m also planning some involvement with the Cheltenham Science Festival and am looking forward to the summer when the Ri Lectures go “on tour” to Singapore and Japan (and luckily the family will be able to come with me this time…!).  I can really feel the vital importance of effective and engaging science communication – particularly biological science – at a time when Government demands “impact” and some have issues with the potential implications of research in genetics and molecular biology. And if six-year olds are inspired to send me beautiful pictures of green-fluorescent worms then, job done – the next generation of scientists might just be inspired to study developmental biology….

Discovering Mendelian genetics, lecture 2 

“Life Fantastic” can be seen at http://www.rigb.org/christmas-lectures

Lectures profiled in the Independent http://www.independent.co.uk/news/people/profiles/dr-alison-woollard-ive-got-the-performing-bug-9020180.html

Photo credits:
Image 1,2 and 6- Paul Wilkinson
Image 3, 4, 5, 7 and 8- Tim Mitchell

This post is part of a series on science outreach. You can read the introduction to the series here and read other posts in this series here.

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The 1st joint meeting between the French Society of Developmental Biology (SFBD) and the network of functional studies in model organisms (EFOR) took place in Paris between the 10th and the 13th of February 2014. Over the first two days, topics discussed mainly dealt with the molecular and cellular mechanisms underlying the spatio-temporal control of homeostasis and fate decisions of progenitor/stem cells in embryonic and adult tissues. Subsequently, parallel EFOR sessions dealing with specific model organisms and imaging were offered, as well as a series of talks by researchers tackling the question of how laterality is established during embryonic development in a variety of models.

Many of the talks approached the mechanisms underlying the intrinsic control of cell fate decisions. Thomas Graf (CRG, Barcelona) challenged the idea that reprogramming of B lymphocytes into pluripotent stem (iPS) is a hard task. Imposing a transient expression of the CCAAT/enhancer binding protein C/EBPa  to these cells followed by activation of Yamanaka’s transcription factors Oct4, Sox2, Klf4, and Myc (OSKM) dramatically enhanced the reprogramming efficiency into iPS cells. Notably, he showed that the C/EBPa activity pulse makes chromatin accessible to Oct4 binding through the induction of Tet2 expression, leading to the demethylation of the regulatory regions of pluripotency genes. He raised the intriguing possibility that the competence mediated by the transient activity of C/EBPa could operate during the early phases of embryogenesis. Indeed, C/EBPa is co-expressed with Oct4 from the 2-cell stage to the morula stage before becoming downregulated in the inner cell mass of the blastocyst. Along the same line of thought, Pierluigi Scerbo’s work on Xenopus in the laboratory of Laurent Kodjabachian (IBDM, France) unraveled that the MAPK pathway controls the competence of early embryonic cells to exit pluripotency and enter differentiation in response to morphogens. Pierre Cattenoz, from the laboratory of Angela Giangrande (IGBMC, France) showed that the Glide/Gcm glial determinant needs to be degraded to insure proper glial differentiation in Drosophila neural stem cells. This is promoted by interconnected loops involving its direct target and homeobox factor Repo and the lysine acetylase CBP.

The puzzling question of how a single Transcription Factor (TF) specifies discrete cell fates within a given lineage was beautifully addressed by Sonia Stefanovic from Christoffels’ laboratory (Academic Medical Center, Amsterdam, The Netherlands). She showed that Gata4 mediates both activation of Atrio Ventricular Canal (AVC) genes in the AVC and repression of these genes in myocardium. Interestingly, this dual Gata4 function relies on cell specific cooperation between Gata4 and other TFs acting downstream to regionalized signals.

The issue of how cell fate decision is temporally controlled was also addressed. Cathy Danesin from the laboratory of Cathie Soula (CBD, France) highlighted the function of Sulf1 in temporally modulating Shh activity, hence controlling the spatial arrangement of gene expression in zebrafish ventral neural progenitors. Anne Ramat from Michel Gho’s laboratory (Developmental Biology Laboratory, France) used the mechano-sensory bristle cell lineage in adult Drosophila as a model to understand how neuronal identity is temporally implemented during cell generations. She explained that early on the two Snail-related transcription factors, Escargot and Scratch, act redundantly to maintain the binary fate decision between secondary precursor cells, whereas Escargot alone is involved cell autonomously in axon patterning. Finally, the winner of the 2013 SFBD PhD’s Prize Alicia Mayeuf-Louchart from the laboratory of Margaret Buckingham (Pasteur Institute, France) gave an overview of how mouse multipotent Pax3+ dermomyotome  progenitor cells can differentiate into various cell types, including skeletal muscle, endothelial and brown adipose cells. She showed that Notch signaling directs the endothelial choice by controlling the balance between Pax3 and Foxc2. Interestingly, manipulating endothelial cell number affects myogenic progenitor migration, and FoxC1/2 also appears to be involved in brown adipose tissue differentiation.

Another axis developed in this meeting dealt with the regulation of stem cell quiescence and potential by their environment. Strikingly, the levels of Notch signaling in many stem/progenitor cells emerged as a key point within this process. Katarzyna Siudeja in the laboratory of Allison Bardin (Curie Institute, France) revealed that spontaneous somatic mutations frequently occur in aging Drosophila intestinal stem cells that result in the appearance of tumors. High rates of loss of heterogeneity are likely due to frequent mitotic recombination events. Markedly, this genetic reshuffling often impacts on the Notch signaling pathway. Shahragim Tajbakhsh’s group (Pasteur Institute, France) is interested in understanding how muscle stem/progenitors are maintained during ontogeny and regeneration. Their data indicate that constitutive Notch signaling autonomously maintains Pax7+ stem muscle cells and controls their temporal specification. Interestingly, while the Notch effector RBPJk was initially thought to influence gene expression in absence of active signaling, the Tajbakhsh group showed that RBPJk binding to the genome was actually highly dependent on the availability of the intracellular domain of Notch. Lara Dirian in Laure Bally-Cuif‘s laboratory (NeD, INAF, France) is interested in tracing the embryonic origin of the zebrafish adult pallial neural stem cells (NSC). She found that there is heterochrony in the formation of the dorso-medial and lateral domains of these adult NSC and that their embryonic progenitors differ in their sensitivity to Notch signaling. Marion Coolen, from the same laboratory, uncovered that maintaining the balance between quiescence and the activated state of these NSCs in adult was dependant on miR-9 function, possibly acting in the Notch cascade.

Other studies looking at the NSCs highlighted the importance of the cellular structure of the niche in controlling their homeostasis. On the one hand Isabel Farinas (CIBERNED, Spain) demonstrated that in the sub-ependymal zone of the adult mouse brain the quiescent population of radial glia/neural stem cells contact both the cerebrospinal fluid and blood vessels within the striatum. These contacts ensure the availability of neurotropic factors that seem to induce intrinsic regulators of the quiescent state of these stem cells. On the other hand, Andrea Brand (The Gurdon Institute, UK) tackled the issue of how the quiescence and the proliferation of neural stem cells within the Drosophila ventral nerve cord are controlled by the global nutritional status of the larva. She showed that GAP junctions between glial cells enable glia to secrete insulin-like peptides in response to amino acids in the larval diet.  This local insulin signaling induces neural stem cells to exit quiescence and resume proliferation after embryogenesis.

Several talks were based on tissue Growth in development and pathology, focusing mainly on the neoplastic behavior of stem/progenitor cells. Work from the laboratory of Maarten van Lohuisen (NKI, The Netherlands) showed that the loss of the Polycomb Repressive Complex 2 activity enhances the probability of appearance of glioblastoma in two distinct mouse models. Strikingly, upon these genetic perturbations, neural stem cells adopt an identity reminiscent of that of embryonic stem cells. An identity switch of neoplastic neuroblasts lacking Lethal (3) Malignant Brain Tumor function was reported by Cayetano Gonzales (IRB/ICREA, Spain), who gave the keynote lecture. Unexpectedly, in this context, neural progenitor cells express a set of genes normally found in the germline. The activity of some of these genes was shown to contribute the growth potential of the neoplastic neuroblasts, while others control the stability of their genome, presumably ensuring the “immortality” of these cells. Cédric Maurange (IBDM, France) pointed out that the potential of a factor to trigger Drosophila neuroblasts to adopt a neoplastic behavior is temporally restricted. Finally, Chiara Ragni (Pasteur Institute, France) identified a new component in the Fat pathway, independent of Hippo, which regulates the growth and the size of cells in the embryonic myocardium in mice.

Exciting hypotheses were proposed in the laterality session. Using zebrafish (Myriam Roussigné: CBD, France; Steve Wilson: UCL, UK) and see urchin (Thierry Lepage: UPMC, France), considerable advances have been made towards understanding how the initially asymmetric expression of Nodal impacts on the functional left/right asymmetry in organs. What triggers this asymmetric expression and which signaling pathways control its maintenance is still under investigation. Stéphane Noselli (IBV, France) showed that asymmetric hindgut looping and clockwise genital disk rotation in Drosophila is controlled by a master gene, Abd-B. This homeotic transcription factor in turn controls myosin ID expression in a spatial but not asymmetrical manner. Frédérique Peronnet (LBD-IBPS, France) showed that fluctuating asymmetry, the random deviation from perfect symmetry, reflects developmental noise and increases when Cyclin G is deregulated in Drosophila.

Finally, three other talks also reported unexpected data. First, the functional analysis of Pax3 and Pax7 by Antoine Zalc (Institute of Myology, France) brought to light that these transcription factors control the facial closure of mouse embryos by dampening the activity of a signaling pathway normally induced by environmental toxins. Second, Uri Frank (National University of Ireland, Ireland) deciphered the site and lineage origins of adult neurogenesis in the cnidarian Hydractinia. He showed that the so-called interstitial stem cells are migratory, continuously self-renew and contribute to all somatic lineages and to the germline throughout life. Finally, Oliver Hobert (Columbia University, New York, USA) presented impressive results on embryonic priming of an miRNA (lsy-6) locus that predetermines functional asymmetry in the left-right axis in postmitotic neurons  in C. elegans.

This last talk, and others, was beautifully representative of a meeting that was a hub linking cell fate decisions, chromatin accessibility, asymmetry, signaling pathways, niches, and embryology.

Thanks Laure, Angela and Myriam for organizing this exciting meeting in Paris….

To be developmentally continued….

Report written by Julie Batut (CBD, France), Vanessa Ribes (Myology Institute, France) and Jonathan Bibliowicz (CNRS-NeD/INAF, France)

Acknowledgements

We would like to thanks Dr. Patrick Blader for reading the report.

(1 votes)

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It’s been a while since I last wrote on the Node, but I have something to share that ties in to a project I started while I was still the Node’s community manager. In 2011 I commissioned a series of career posts, where people in a variety of different non-research post-PhD careers all described how they got their job and how they are using their PhD experience away from the lab. It was a popular series of posts.  Many PhD students really like hearing from PhD graduates, to find out what kind of career options there are.

But it’s not straightforward to meet many people who left research after their PhD. Even though the majority of PhD students will eventually leave academic research, most of the PhD graduates they meet on a day-to-day basis are the ones in their institute: the ones on the academic research track.

With this in mind, Lou Woodley and I have spent the last few months working on a website that we just launched: MySciCareer. Here you can find personal stories from people with a background in research, who talk about their career. Many of them will have PhDs, but we’re also including stories from MSc and BSc graduates. We make no distinction between research careers and other careers: If you scroll through the current quotes on the front page you’ll see academic researchers, editors, writers, politicians, and others. If you see a quote you like, you can click it and read a longer excerpt.

You may recognize some of the quotes and excerpts. The launch content contains several posts from the Node, and there may be others in the future. We’re aiming for a broad coverage of scientific fields as well, so the tales from biologists are side to side with those of physicists, but with the menu in the sidebar of each entry you can search more selectively.

We’re on Twitter and Facebook, where we’ll post details about new content on the site as it is added, as well as resharing other relevant science careers discussions and letting you know if we give talks about science careers.

If you post content elsewhere that you’d like to be part of the science careers conversations, please add the #myscicareer hashtag – this will work on all major social media platforms including Twitter, Facebook, Storify, Instagram and Flickr.

So, please take a look at the site, send us your feedback, spread the word and let us know what stories we’re missing. We’re intending this to be a growing collection of resources so if you’d like to contribute we’d love to hear from you – and you can share your story on the Node as well!

(2 votes)

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