Although we all appear symmetrical from the outside, the organization of our internal organs and organ structure are highly asymmetric. Proper asymmetric positioning and patterning of our organs is very important for correct function, and loss of this asymmetry during organ formation can lead to a variety of serious congenital diseases.  Our recent study identifies a new mechanism by which the heart forms an asymmetric structure during embryonic development.

Thus far it was thought that all organs use the same mechanism to develop this left-right asymmetry by responding to the TGF-β-related growth factor Nodal, which is expressed on the left side of the developing vertebrate embryo. Using forward genetic screening in zebrafish for mutants defective in organ laterality we identified the straightforward mutant. Interestingly the straightforward mutant embryos exhibited complete randomization of brain and the visceral organ laterality, while preferential direction of heart looping was maintained. Positional cloning of the mutation underlying the organ laterality defect revealed a loss-of-function mutation in the asymmetrically expressed zebrafish Nodal-related gene southpaw (spaw).

In vertebrates, including zebrafish, the heart starts out as a linear tube that bends to the right and loops asymmetrically to form the mature functional heart. In zebrafish embryos the linear heart tube is also positioned asymmetrically with respect to the midline with the future venous pole positioned ventral to the left eye. In spaw mutant embryos this initial leftward positioning of the heart (named cardiac jogging) is compromised resulting in a midline positioned heart. Despite this cardiac jogging defect in spaw mutant embryos, the majority of the hearts bend to the right forming a normal dextral heart loop. We therefore concluded that (1) Spaw activity is required for cardiac jogging, but cardiac jogging is dispensable for asymmetric heart looping and (2) Spaw is not the only regulator of asymmetric heart looping. Since there are three Nodal-related genes expressed in the zebrafish embryo we examined whether these other Nodal-related proteins could provide asymmetry information to the heart during heart looping and thereby could compensate for the loss of Spaw activity. However, from our experiments we concluded that the other Nodal-related genes are absent from spaw mutant embryos at embryonic stages relevant to heart lateralization. In addition we observed preferred dextral looping in spaw mutant embryos in which Nodal signaling was blocked either chemically or genetically. From these results we concluded that in the absence of Nodal signaling, dextral heart looping in zebrafish embryos is regulated by an alternative mechanism.

Heart looping in a dish. (a) Cartoon showing the procedure of culturing embryonic heart tubes. Linear heart tubes were dissected from tg(myl7:GFP)-positive embryos at 26 hpf, placed into culture medium and incubated further. (b) Images of explanted heart tubes after 24 hours in culture. While control hearts completed dextral-looping after a 24 hours culturing period, treatment of explanted heart tubes with either a myosin II inhibitor (Blebbistatin) or an inhibitor of actin polymerization (Cytochalasin B) prevented normal heart looping. Reproduced with kind permission from Nature Communications.

Significantly, we found that this asymmetric development of the heart is mostly independent from external factors or forces from the rest of the embryo. We developed a heart-in-a-dish system that allowed us to culture linear heart tubes dissected from the embryo in a dish.  Linear heart tubes dissected from the embryo retain their ability to loop, and heart looping occurred predominantly in the correct dextral direction. The heart-in-a dish system allowed us to test the effect of various drugs on directional heart looping and we found that inhibiting actin polymerization or non-muscle myosin activity disrupted the looping process. From these results we concluded that the asymmetric development of the heart is regulated by different mechanisms than those governing brain and visceral organ asymmetry – specifically, heart looping is a tissue intrinsic process that requires actomyosin activity.

Cartoon illustrating proposed regulation of dextral heart looping by Nodal and actomyosin. In a wild-type situation, combined Nodal signaling and actomyosin activity provide a robust mechanism driving dextral heart looping. In the absence of Nodal signaling, actomyosin activity is sufficient to promote preferential dextral heart looping. In the absence of actomyosin activity, Nodal signaling is not sufficient to promote dextral heart looping. Reproduced with kind permission from Nature Communications.

These findings are interesting since in Drosophila, which lack Nodal genes in their genome, asymmetric organ formation is controlled by tissue- and cell-intrinsic mechanisms that require specific components of the cytoskeleton. Similarly, cultured mammalian cells show phenotype-specific left–right asymmetry that is controlled by the cells cytoskeleton. Our findings suggest now that such an intrinsic mechanisms is also important to regulate asymmetric heart development in zebrafish. Indeed, in ancestral vertebrate organisms that exhibit asymmetric embryonic Nodal expression, accompanied by brain and gut asymmetries, no heart asymmetries are observed in the developing embryo. This suggests that ancestrally the heart did not respond to asymmetric Nodal signaling and it is interesting to speculate that heart asymmetry developed independent of asymmetric Nodal.

reference:

Noël ES, Verhoeven M, Lagendijk AK, Tessadori F, Smith K, Choorapoikayil S, den Hertog J and Bakkers J. (2013) A Nodal-independent and tissue-intrinsic mechanism controls heart-looping chirality. Nat Commun. 2013 Nov 11;4:2754

(4 votes)

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Some scientists would say that postdoctoral fellows have the most desirable position in the lab. As a postdoc, you have the research experience from your PhD to give you credibility at the bench. You have the independence to run your own project and supervise students, but without the time commitments and administrative duties of a principal investigator. In addition to publishing papers, you can develop your writing by contributing to fellowship and grant proposals and maybe pen a review. These are all types of professional development opportunities that are critical to building your future career. The postdoc is, in essence, a hands-on apprenticeship to curate the next generation of scientific leaders.  But the degree of professional development for the unspoken things, so called “soft skills” that are key to running a successful lab beyond the research bit, is limited.

How do you learn these secrets? In some cases, maybe your supervisor gives you tips. Maybe you read some of the many management books like “At the Helm” or “Lab Dynamics: Management and Leadership Skills for Scientists”. But what if you still have little idea how to hire, manage, motivate, and inspire people to work with you? When faced with the next step beyond postdoc – running your own lab, whether in academia or industry – what can you do to prepare yourself?

Being a group leader may not come with an instruction manual, but training is available if you know where to look for it. For years the EMBO has been offering lab management courses for group leaders and postdocs. These courses are extremely popular – more than half of the 2014 sessions are already booked. The goal of the workshops is to improve confidence in management skills that may be overlooked in standard science career development. As an 2010 EMBO Fellow, I was able to secure a last-minute spot, and last November I spent three days secluded in a hotel outside of Heidelberg sharing ideas with other postdocs also looking to learn tips to make them better future group leaders.

One of the most surprising aspects of the course was the intensity. Spending long hours talking about interpersonal relationships is draining for anyone, especially in a room full of near strangers. At the beginning of the workshop, we learned about ways of communicating and how this plays a role in managing our interactions with our colleagues. Whether you are a graduate student or the director of an institute, how you speak to someone reflects your message and intentions. It also can garner different reactions depending on how it comes across to the listener. We practiced effective ways to address colleagues to garner the best results. (Note: if you turn your nose up at role-playing scenarios and group work, then be prepared to be out of your comfort zone during lab management training!) Communication is at the heart of everything when it comes to being a leader and a manager. This theme held true throughout the rest of the course and is one of the main take-aways.

Another characteristic of an effective scientist (and definitely one for running a successful team of researchers) is good time management. This skill is hardly a secret, and one that we can all improve for ourselves; but group leaders also have to face time management issues and problem solving for others in their labs! How do you handle that and still accomplish what you need to get done? At the workshop, we called this “who’s got the monkey?” When faced with the constant knock at the office door, successful managers help their team members solve their own problems, not by taking the problems onto themselves. The trick is making sure that the “monkey” stays with its original owner and giving the owner the necessary tools to “take care of it.” In other words, if you are going to run a productive lab, you can’t solve every problem yourself – you don’t have time! You must trust and support those who work for you to help move your lab forward.

Finally, and for me the most revealing part of the workshop, was the evaluation and discussion of personality types and how this contributes to management style. Maybe some scientists would dismiss this type of information as trivial, like taking a magazine quiz. But it is crucial to recognize that our inherent differences as individuals does play a role in our science and how we could run our lab. There are factors to consider in how we respond to stress, treat other people, and what our expectations are in professional relationships. Learning that I tend towards the “Helper” personality was eye-opening, both in terms of what I do really well and what I can do better. On a good day, I see the best in those around me and can help them to develop their potential. On a bad day, I tend to be defensive and manipulative. Knowing about ourselves, and who our allies can be in dealing with complicated situations, make us better managers. Knowing about other personalities that exist in the lab also makes us more effective in our interactions with each other. This is a critical point to building a team that enjoys not only doing research, but also working together with one another.

The steps it takes to secure an independent position from a postdoc are daunting. Developing the soft skills to run your lab shouldn’t be intimidating, and learning from management and team-building experts can help.

(13 votes)

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Development recently published an article by Ben-Zion Shilo on his recent science outreach project. In this project, Benny aimed to explain concepts of developmental biology to the public by identifying and photographing their equivalent metaphors in the ‘human’ world. For example, the regular spacing of sun umbrellas on the beach can be seen as a metaphor for the lateral inhibition mechanisms underlying the patterning of neuroblasts in the Drosophila epidermis.

The competition:

In keeping with our ongoing outreach series, in this new competition, we are asking you to follow Benny’s lead and come up with your own metaphor! We are looking for the best image pair: a scientific image displaying a specific biological concept (such as a cell type specification or cell lineage), and a photograph of its real world metaphor counterpart. As Benny discusses in his article, it need not be a visual metaphor; conceptual metaphors are also fine. The images will be judged on their aesthetics and on how well the real world metaphor can be used to explain the scientific concept.

You don’t have to necessarily work on the scientific concept that you chose and the scientific image submitted does not have to be of your authorship (although you must have permission to publish it). However, the photograph of the real world metaphor must be taken by you. You may submit up to 3 pairs of images.

The winner will win a copy of Benny’s popular science book on his recent project and a £50 Amazon voucher (or currency equivalent).

Judges:

Ben-Zion Shilo, Weizmann Institute of Science, Israel

Nipam Patel, University of California, Berkeley; Development Editor

Thomas Lecuit, Developmental Biology Institute of Marseille; Development Editor

To enter the competition:

Send both your images and a short description (50-100 words) of how your chosen metaphor can be used to explain the scientific concept, to thenode@biologists.com. The deadline for this competition is the 28^th of February, and the winners will be announced in late March/early April.

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.

(2 votes)

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This article was first published in Development, and was written by Ben-Zion Shilo, Weizmann Institute of Science, Israel.

How can the revolution in our understanding of embryonic development and stem cells be conveyed to the general public? Here, I present a photographic approach to highlight scientific concepts of pattern formation using metaphors from daily life, displaying pairs of images of embryonic development and the corresponding human analogy. By making the viewer ‘feel’ like a cell within a developing embryo, the personal experiences resonate with the scientific concepts, facilitating a new type of appreciation.

The field of developmental biology has undergone a revolution in the past three decades. The conserved signaling pathways cells use to communicate with each other during embryogenesis have been elucidated. Recent technological developments include sophisticated genetic tools to interrogate the roles of genes in distinct tissues and specific time windows in a wide range of organisms, as well as new imaging technologies for the dynamic visualization of developmental processes at subcellular resolution. Finally, the identification of stem cells in different organs, and increasing understanding of the means by which these cells differentiate, brings hope that we might be able to recapitulate these processes for regenerative therapies.

This revolution affects us as scientists on a daily basis, but also has wider implications to every human being: from the understanding of how we are formed from embryos and how similar we are to other multicellular organisms, to the medical applications of this knowledge. When asking if the public is aware of these issues, I am disappointed to say that the answer to this question is no. This is mainly because existing channels to communicate these ideas are not sufficient, rather than reflecting a lack of interest in the topic. Any effort in broadening and enhancing public understanding of developmental biology is thus extremely important.

One challenge in presenting science in a popular way is the limited background knowledge of the audience. The presentation, be it a lecture, movie or article, tends to flow in only one direction: the expert ‘takes the audience by the hand’ and guides them through the scientific paradigms presented. By contrast, developing a dialog, whereby the audience would be able to resonate their own life experiences with the new scientific knowledge, might enhance the understanding of the principles and make the process more interactive and intuitive.

The cell is the basic unit in a developing organism, and it is the interaction between cells that drives the orderly process of embryonic development. In many respects, this concept can be compared to a human society, in which rules, communication and interactions between individuals lead to the intricate organization at physical and social levels. By basing a popular presentation on such an analogy, the audience immediately becomes actively involved. People can identify themselves with the developing cells and this association allows them to ‘feel’ the processes from a personal point of view. Interestingly, Robert Hooke first coined the term ‘cell’ in a biological context in 1665 as an analogy to the human world: the cell walls of an oak tree bark under his microscope reminded him of the cells of monks.

How can this analogy be elaborated and presented? In our research, we generate microscopic images that are not only highly informative to the researcher but also exceptionally beautiful. Yet, in the absence of sufficient background knowledge, these images can be largely meaningless to the general public. I have considered the prospects of utilizing such scientific images more effectively for public education, by using them as a tool for presenting analogies between the biological microscopic world and the macroscopic human one. Concentrating on common underlying principles between the two worlds, our intuitive understanding of the human world can be harnessed in order to grasp scientific paradigms of embryonic development.

During the academic year of 2011/2012, I was fortunate to be a fellow at the Radcliffe Institute for Advanced Study at Harvard University, and dedicated my time to developing this concept. The first step was to delineate the major principles of developmental biology in a logical and balanced manner. This process was extremely beneficial and involved many inspiring discussions with members of my lab and other colleagues. Then, with the major concepts in mind, I approached scientific colleagues working on different model organisms, and asked for images that would depict these concepts. It was rewarding to see how responsive the community was, and I ended up with dozens of images and movies, from which I chose the ones that displayed the concepts most clearly, and which I found most aesthetic.

As researchers, our eye is trained to focus on the crucial aspects of an elaborate scientific image, but for the naive observer such images are extremely confusing. For example, a bright auto-fluorescence spot that researchers ignore, may become their focus of attention. Michal Rovner, a renowned Israeli video artist, suggested converting the scientific images to black and white, leaving only the main topic in a single color. Indeed, it became immediately apparent that after this manipulation the scientific images become more effective: they are minimalistic, and appear more as a work of art. The subject ‘jumps out’ at the viewer, be it spaced neuroblasts (Fig. 1, top) or a stem cell niche (Fig. 2, top).

 
Figure 1- How cell signaling establishes a repeated pattern. The outer cell layer of the fruit fly pupa displays a regular arrangement of nerve (red) and epidermal (black) cells. All cells are initially equivalent to each other. Yet, random fluctuations in the level at which each cell produces a signal, allow a given cell to accumulate sufficiently high levels to make it a nerve cell. In parallel, this cell instructs its immediate neighbors to become skin cells. Eventually, an ordered array of nerve cells is generated. Top: external cell layer of the fruit fly pupa with regularly spaced nerve cells (red) (S. Yamamoto and H. Bellen, Baylor College of Medicine and Howard Hughes Medical Institute). Bottom: sunshades distributed at regular intervals on a beach at Lefkada island, Greece (B. Shilo). Note: the legends for Figs 1 and 2 represent the original explanations at the exhibit, and are aimed at the broad audience.

 
The next phase was to match the images with human metaphors. The process of thinking about the metaphors proved to be very creative and inspiring. Just like the procedure of defining the main scientific principles, finding the human metaphors was extremely revealing, forcing me to distill the most seminal aspects of scientific paradigms and choose the analogies to illustrate them best. I was mainly looking for a conceptual similarity rather than a visual one, but of course welcomed the possibility of having a visual resemblance. Thus, the regular spacing of sun umbrellas on the beach is both a visual and conceptual metaphor for the mechanisms underlying the patterning of neuroblasts in the Drosophila epidermis (Fig. 1), whereas the yeast ‘mother culture’ used for making bread has only a conceptual resonance to the idea of a stem cell niche (Fig. 2). Similarly, a flashing ‘Pizza’ sign becomes the metaphor for different times of exposure to the Sonic Hedgehog gradient in the limb, and a game of dominos resembles the successive elaboration of pattern in the embryonic axes.

Figure 2- Stem cells and their niche. Upon division of a stem cell, one daughter will maintain the stem cell fate, and the other will produce a differentiated progeny. Stem cells are positioned in a restricted spatial niche, providing signals that maintain them in the proliferative, non-differentiated state. Following division, only one progeny is maintained in the niche, whereas the other will move out of the niche and differentiate. Top: once the eye of the zebra fish is specified, cells differentiate and produce neurons that sense light. Retinal stem cells (red) are maintained throughout the animal’s life in a niche, located adjacent to the lens (K. Cerveny and S. Wilson, University College London). Bottom: the live yeast stock termed ‘mother’ is carefully maintained in the bakery. Portions are allocated to produce dough and bread. A fine balance is kept in order to ensure a steady production of bread, while propagating the yeast stock (B. Shilo, Hi Rise Bakery, Cambridge, MA, USA).

 
Given my long-standing interest in photography, I decided to capture these images myself. As with the scientific images, the colorful pictures of the human world may contain too many hues that divert the viewer’s attention from the intended point. Therefore, I converted these pictures to black and white format as well, leaving only the topic of interest in color. By generating a common format for each image pair, the shared concept is visually reinforced. After assembling 35 pairs of images that cover the main concepts I delineated, the project was ready for presentation.

I have developed several means by which the project can be displayed. First, the images can be presented as a photography exhibit (Fig. 3), with a short introduction and a paragraph explaining the concept behind each image pair displayed next to the pictures. The images follow a scientifically logical order, starting with the pathways by which cells communicate during development, and how these allow elaborate patterns to be created. The exhibit then displays the concept of morphogens and evolution of patterns during speciation, followed by the execution of patterning that leads to the formation of tissues and organs. The exhibit ends with stem cells and the promise of induced pluripotent stem cells, and their possible utilization to create new organs. This exhibition has been displayed at the Radcliffe gallery at Harvard, at the Harvard educational portal at Allston (MA, USA) and at the Weizmann Institute of Science in Israel. I was concerned that the short explanations may not be sufficient to draw the audience into the subject matter, in the absence of a deeper explanation or a gallery talk. However, the audience response was extremely rewarding, and the best indication for the success of the approach was that people came to me with new suggestions for metaphors, indicating that they understood the concepts and were able to relate them creatively to their own world.

This work was also presented in the format of a public lecture, using the images as a way to illustrate and present in greater depth concepts of developmental biology. The fact that the storyline goes back and forth between scientific aspects, which may be more abstract, to images from daily life, which are readily appealing, keeps the audience alert and attracted to the lecture’s thread. Over the past year, I have given this lecture numerous times, in different continents and to very diverse audiences, from a lay audience including students and teachers, to scientists from different disciplines [see, for example, the lecture given at the European Molecular Biology Laboratory in 2012 (http://medias01-web.embl.de/Mediasite/Play/102f090bfa93473eb369a8c646a8d09c1d)]. The presentation proved to be highly effective for all audiences, again stimulating suggestions for new metaphors from the participants. At the outset, the most unpredictable audience was that of experts in developmental biology, as I was worried that this mode of presentation may seem trivial or over simplified. Here, I was pleasantly surprised, as the process of crystallizing complicated concepts to a single metaphor proved to be thought provoking, even for specialists.
 

Figure 3- Exhibit at the Harvard Allston Education Portal, April 2012. Photo: B. Shilo.

 
 
Finally, I have written a popular book that will be published by Yale University Press in the coming year. The text of this book flows in a manner that is independent of the images, but hopefully the accompanying pictures will make the book more accessible and stimulating. The book is aimed first and foremost at people with little or no background in developmental biology who are curious to learn about embryonic development. Although not a textbook, it could also be used as a supplement to developmental biology courses at high school or college undergraduate level. In addition, it may stimulate students to photograph their own metaphors to the developmental concepts they study, and a web forum could be constructed to display and discuss these analogies. Finally, students who begin their research in developmental biology labs are initially swamped by literature related to their future research project. It may be instrumental and inspiring if in parallel they could also read a book that provides them with a ‘bird’s eye’ view of the field and the emerging concepts, to place their particular project in the context of the broader picture.
 
Taking a wider view, one can ask if this approach of using human metaphors can be extended further, and used to present other scientific topics and disciplines. I found the analogy between a cell and a human highly effective, giving a clear and consistent definition of the individual unit. One can easily envisage extending this approach to fields such as cellular immunology or cancer biology. It may become more challenging to define the ‘quantum’ entity that would be analogous to humans, when considering other scientific fields and disciplines. I am certain, however, that creative modes could be devised to extend analogies to the human world in new ways, in order to enhance the intuitive understanding of complex scientific principles in a broad range of disciplines.
 
 
 

Ben-Zion Shilo, Weizmann Institute of Science, Israel

Follow Benny’s lead and enter our outreach competition by finding your own science metaphor!

(2 votes)

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Say goodbye to the lab books. They may let you keep it. But usually, sadly, it must stay. Despite being illegible to anyone but you, and never mind the amusing cartoons. The best you can do is a photocopy. If like me you favour the ‘pop-up lab book’ approach to data recording, the job may look slightly daunting. Personally, my lab book is a three dimensional work of art. A photocopy is just not going to convey the essence of my meaning. Yet for many of us, the urge to copy large tracts of our lab books is irresistible.

Remove all those personal touches you took years to accumulate around you. You know the ones. We all have them. For example, I have in front of me right now:

A rainbow stress ball in the shape of a brain. Courtesy of some trade display, company long since forgotten
Ditto a rubber duck wearing a lab coat.
An amusing picture of a lemur that was sent to me during my Ph.D. and is now somewhat of a mascot
One of those fluffy microbes that got popular a while back that you could give to people and joke about gifting them with mono or Ebola. This one is a rather adorable fat cell.
Countless post-it notes with essential information nuggets such as passwords, chemical formulae, how to skip blank cells in Microsoft Excel and a choice selection of French vocabulary

Unbelievably, your successor is unlikely to treasure these as you have, so you may choose to bequeath them to the like-minded souls around you, or give them a one-way trip into the bin on top of the lab book copies.

Get rid of all your solutions. There is nothing more lonely than a collection of old buffers. Here’s a sad fact: no one really trusts your buffer. It’s a personal thing, this is my buffer, I made it, and in it I trust, even though I know you made your buffer exactly the same way and you look reasonably clean. But I’ve seen that amusing bit of fungal fluff you found in your media bottle that you’ve been nurturing on your shelf to see how big it gets and it’s nothing personal, but I’m going to make my own buffer. Incidentally, now is the time to also get rid of any of your own fungal media pets.

Vintage journal articles. Is it just me or does reading other people’s article copies feel weird? Pre-loved literature (scribbled notes are the worst), makes me terribly uncomfortable, to the extent that, shamefully, I will print another copy rather than read someone else’s vintage papers. At this point it may be kindest to consign the whole pile to the recycling bin and think seriously about planting some trees.

Wipe your hard drive. Copy your data, purge your personal stuff and make sure that novel you’ve been writing during ten minute incubations is safely out of the way. Because someone is going to inherit your computer and unless you want to give them a unprecedented window into your life via your old emails, it’s time to search and destroy.

Fridge stocks. Sadly, they will either go off or grow stuff. Possible exceptions are pricy or rare things like antibodies which you should put back where you found them immediately (see next point).

Freezer stocks. Are you the one who took the second last tube of that reagent from the communal box that time you were working really late at night and forgot to put it back? We’ve all been there. It’s time for us to do the walk of shame back to the freezer with all the expensive things we’ve been hoarding. Best done last thing with as few witnesses as possible.

Now walk over to the minus 80C freezer. That cold, frozen wasteland of very important and largely forgotten samples. Samples labelled 1-10, or something similarly inscrutable that doesn’t even make sense to you anymore since the day you tucked them down the side of a box rather than safely inside it because it was only going to be in there for a couple of days. It’s time to let go and move on to…

Liquid nitrogen stocks. The pinnacle of storage paranoia. Exercise some caution here (not just for the very real possibility of frostbite). Things in here are most likely expensive and temperamental and very, very useful. Often best to walk away quietly.

All the rest of your various samples that someone might use someday. If you don’t care for your name being taken in vain throughout the ages, it’s nice to treat your tubes to a label. With a date. And perhaps even a lab book reference. When it comes to your samples, is there any such thing as Too Much Information?

So you’ve cleaned out your desk, your fridge is empty, and apart from the frostbite, you’re in good shape. You may be slightly hung-over from the leaving party, and you’ve definitely got a giant novelty goodbye card. Congratulations, you’re the perfect leaver.

(12 votes)

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We have an opening for a PhD student at the University of Amsterdam in the Netherlands.

This research project will investigate the behaviour and control of Wnt-responsive stem cells in the mammary gland. You will be part of a young research team that uses a combination of in vivo and in vitro approaches to understand normal stem cell behaviour, with the ultimate goal of translating principles of developmental and stem cell biology to cancer research and regenerative medicine. Our lab has strong ties to the Wnt-signaling community and to the field of mammary gland biology and we are looking for an ambitious PhD candidate to strengthen our team.

To apply, please visit the vacancy website. If you have any further questions, please contact dr. Renée van Amerongen

Applications will be accepted until 10 December 2013.

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Professor Daniel St Johnston is a prominent developmental biologist and the current director of the Gurdon Institute in Cambridge (UK). The St Johnston lab recently retracted two papers, in what Retraction Watch lauded as a poster case of ‘doing the right thing’. The Node interviewed Daniel and discussed the case, and how his experience highlighted the shortcomings of the current system of ‘setting the record straight’.

Tell us a little bit about the background of this case

We had published two papers, one in The Journal of Cell Biology and another in Developmental Cell, on a low energy polarity pathway. In each case the basic observation was that mutant follicle cells, marked by the loss of GFP, showed a loss of polarity under starvation conditions. Specifically they lost apical aPKC and lateral Discs large. When we tried to follow up this research we could see the phenotype, but it was frustrating because sometimes it was there and sometimes it wasn’t. We initially assumed that we weren’t starving our flies properly. We tried all sorts of drugs that mimic starvation but were not able to change the frequency at which we could see the phenotype. Two members of my lab, Dan and Timm, started to suspect that there was something wrong technically, and came up with this idea that the GFP negative cells weren’t actually real clones but damaged cells. Between our two papers coming out and realizing what was going on, Lynn Cooley’s lab showed that follicle cells remain attached to their sisters after mitosis, generating clones of cells that are connected by small cytoplasmic bridges. This meant that if you just nicked one cell, GFP – and polarity markers – could leak out from a whole cluster of cells, looking exactly like a mitotic clone. The killer experiment was marking the clones in a different way: if you positively mark them with GFP and repeat the experiment, you can observe some GFP-marked clones where you never see the polarity phenotype, and GFP-negative clones where you do. The final bit of the explanation was to clarify why the phenotype seemed to be starvation-dependent. If you starve flies, their ovaries are much smaller, it’s harder to dissect them apart and so you cause damage more frequently. Once we discovered this artefact it basically invalidated the main conclusion of both papers. We felt obliged to set the record straight.

Why did you think that a retraction was necessary? Was there an alternative way to correct the papers?

We wrote a paper (now out in Biology Open) explaining this artefact, which I forwarded to the editors of both JCB and Developmental Cell. I told them that it was important that this work was linked to the original papers, because it showed that many of the results are due to an artefact. They both came back with the same message – that this looked like a case for a retraction.

We had collaborated in both papers with labs that provided the key mutants. In the JCB paper, Jay Brenman had done a very large screen that isolated the first AMPK mutants in Drosophila on the basis of a neural phenotype. That data was in the original paper and is all still true. Actually that paper was probably more highly cited for the identification of those alleles than for the spurious low energy polarity pathway! Jay wasn’t very happy to have to retract what was a major piece of work from his lab that was still true and still being cited.

Was there a way to republish this data?

We asked JCB whether we could retract only part of the paper, but we were told that this was not possible- a retraction is a retraction. Furthermore once a paper is retracted no one can cite it because it ceases to exist after a while. That held things up for quite a long time because we were stuck at an impasse. At this point I called up Jordan [Raff, Editor-in-chief of Biology Open] and asked him whether he thought Biology Open would be prepared to republish this part of the work, as it is important data and will be cited in the future. Jordan immediately said yes.

The next step was to make sure that everything happened simultaneously, because otherwise this data would be published twice, which would also have been a major offence. The three journals, Developmental Cell, JCB and Biology Open, agreed on a date to publish our paper explaining the artefact, Jay’s paper republishing his original mutants, and the two retraction notices.

You mention your concerns regarding your collaborator. Were you worried about the impact in your lab members and your own career?

I am worried about the career of the first author, who was a member of my lab. But what can you do? –  the data aren’t true! As for the impact in my career, time will tell. In an ideal world it will be fine, as long as people look carefully enough to realise that we willingly retracted the papers. The alternative strategy would have been to just publish a paper saying that those results were wrong and hope that people would make the link. No one would have noticed, and it would have probably been better for the careers of everyone involved. But it would have meant that people, especially those in more distant research fields, might carry on citing these papers that aren’t correct.

It is actually worse to discover your own mistakes than other people’s. As scientists, we publish plenty of papers contradicting the results of previous papers from a different lab. That is how science works and it’s normal. But if you do it to yourself then you are in much worse state, career-wise.

Did you get positive feedback from the community?

I gather that it was discussed on Twitter with generally positive responses. I did talk to the author of one of the papers that erroneously attributed a polarity phenotype to a mutant because of this artefact. I asked him if he minded that we included in our Biology Open paper a repeat of his experiment, showing that you didn’t get that phenotype when you made sure that the artefact wasn’t occurring. He was great about it- he agreed that it needed to be corrected and was happy that I mentioned that his result is wrong. I think we have done the best we possibly could in terms of correcting the scientific record.

Do you think this experience highlighted problems with the current process of getting the record straight?

The main concern is that the majority of retractions take place because someone has done something deliberately wrong: manipulating figures or something worse. Those retractions are the ones that attract all the attention and people’s careers deservedly suffer as a result. Once you realise someone is faking their data, you cannot really trust anything else that they do. I view being a lab head almost as being a trademark- you have to protect the integrity of what you produce. Our case is almost the opposite of a retraction due to data manipulation. We withdrew the paper because we made an honest mistake and we wanted to clear up the record – so people know that when we make a mistake we admit it and we sort it out. The fact that these two different kinds of retractions are indistinguishable when you look at the citation does make things more complicated. Without reading the retraction notices in detail, or going to Retraction Watch, you just think: ‘oh, so and so has retracted two papers, they must be dodgy in some way’. It would be useful to have some way to distinguish between these two types of retraction.

My feeling is that the current set-up discourages people from acknowledging their mistakes. The incentives are not right for trying to get the most accurate description of what is known and what is known to be wrong in the public domain. And what we are talking about here is just the tip of the iceberg. There is much more stuff in the literature that is wrong and never gets corrected. If everyone was honest about it, and retracted papers that they found to be seriously wrong, there would be many more retractions and much less stigma.

The other problem is that, as far as I can understand, you can correct things if you get them slightly wrong but if you get things majorly wrong then you have to retract the whole paper, even if some of the data are perfectly sound. It seems wrong that reagents that are extremely useful can disappear from the literature at a blink of an eye.

– Retraction notice: LKB1 and AMPK maintain epithelial cell polarity under energetic stress, Journal of Cell Biology, vol 177 nr 3, 2007

– Retraction notice: Dystroglycan and Perlecan provide a basal cue required for epithelial polarity during energetic stress, Developmental Cell, vol 16, 2009

– St Johnston lab Biology Open paper describing the artefact: Damage to the Drosophila follicle cell epithelium produces “false clones” with apparent polarity phenotypes, Biology Open, ePress

– Brenman lab Biology Open paper republishing mutant screen: Isolation of AMP-activated protein kinase (AMPK) alleles required for neuronal maintenance in Drosophila melanogaster, Biology Open, ePress

– Retraction Watch article on this case: Data artifact claims two fruit fly papers from leading UK group- who offer model response

Image from the St Johnston lab’s Biology Open paper showing damage-induced false clones

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Here are the highlights from the current issue of Development:

One-step transdifferentiation

Terminally differentiated cells are generally considered to be in a developmentally locked state in vivo; they are incapable of being directly reprogrammed into an entirely different state. Now, on p. 4844, Joel Rothman and co-workers show that the expression of a single transcription factor can trigger the transdifferentiation of fully differentiated, highly specialised cells in C. elegans larvae and adults. They show that brief ectopic expression of ELT-7, a GATA transcription factor that regulates intestinal differentiation, can specifically convert non-endodermal cells of the pharynx into fully differentiated intestinal cells. This conversion is accompanied by an increase in the expression of intestine-specific genes and a concomitant decrease in the expression of pharynx-specific markers and structural proteins. The reprogrammed cells also exhibit morphological characteristics of intestinal cells. These, together with other findings in the study, demonstrate that terminally differentiated cells can be reprogrammed to an alternative fate without the need for cell division, without the requirement for a dedifferentiated intermediate state and without prior removal of an inhibitory factor.

Stem cells and regeneration in a new light

Zebrafish have a remarkable capacity to regenerate and, as such, are being used increasingly to study stem cells and organ regeneration. Here, Chen-Hui Chen, Kenneth Poss and colleagues establish a luciferase-based approach for visualising stem cells and regeneration in adult zebrafish (p. 4988). The researchers generate several transgenic lines that enable ubiquitous or tissue-specific expression of both firefly luciferase and mCherry. They show that, unlike the fluorescence signal, bioluminescence in these lines, which they term zebraflash, readily penetrates through adult tissues and can easily be detected. Using the cardiac zebraflash line, they demonstrate that this approach can be used to monitor the extent of heart injury and subsequent regeneration in animals in a non-invasive and high-throughput manner. Furthermore, they report, this approach can be used to detect quantitatively the progeny of engrafted stem cells in recipient animals at high spatial resolution. This methodology, along with the transgenic lines presented here, offer a valuable resource for the study of stem cells and regeneration.

Rocking the Wnt pathway

Wnt signalling plays important roles during embryonic patterning and in tissue homeostasis, and mutations that affect the Wnt pathway are associated with cancer. Despite this, the exact way in which the Wnt pathway is regulated is still not fully understood. Now, Amy Bejsovec and colleagues uncover a novel regulator of Wnt signalling (p. 4937). Previous studies have shown that the Drosophila RhoGEF Pebble (Pbl) might influence patterning mediated by Wingless (Wg), the primary fly Wnt. Following this, the authors show that both loss- and gain-of-function Drosophila pbl mutants exhibit defects that are consistent with a role for Pbl in negatively regulating the Wg pathway. Furthermore, both Pbl and ECT2, the human homologue of Pbl, downregulate Wnt reporter activity in cultured Drosophila and human cells, highlighting a role for ECT2 as a potential proto-oncogene. Finally, the researchers show that, unlike most negative regulators of the Wnt pathway, Pbl acts downstream of Armadillo/β-catenin and may act through Rho1 to negatively regulate Wnt/Wg signalling.

Opening a passage for hair growth

The hair follicle epithelium forms a tube-like structure that is continuous with the epidermis, but how the lumen of this structure is created during morphogenesis and regeneration remains unclear. Now, Sunny Wong and colleagues identify a novel population of cells that initiates hair follicle lumen formation in mice (p. 4870). The researchers first provide a detailed characterisation of the infundibulum, the region encompassing the hair follicle mouth, and identify a population of keratin 79 (K79)-positive epithelial cells within this region. Using lineage tracing, they show that these cells are specified early during hair follicle development and migrate outwards from the hair germ into the epidermis prior to lumen formation. This migratory event is also observed during regeneration of the hair follicle; K79-positive cells are specified in the secondary hair germ and migrate out, eventually forming a continuous layer with pre-existing K79-positive cells. These findings identify both a novel mode of epithelial tube morphogenesis and a unique population of cells that migrate throughout the life cycle of the hair follicle.

Insm1 controls pituitary endocrine cell development

The pituitary gland is an endocrine organ that plays a role in various physiological processes, including growth, metabolism and reproduction. The development of various pituitary endocrine cells is influenced by a number of transcription factors and signals. In this issue (p. 4947), Carmen Birchmeier and colleagues report that the transcription factor Insm1 controls the differentiation of all endocrine cells in the mouse pituitary. The researchers show that Insm1 is expressed in pituitary progenitors and continues to be expressed in differentiated endocrine cells. Using Insm1 knockout mice, they demonstrate that Insm1 controls a pan-endocrine differentiation programme; genes encoding pituitary hormones or proteins involved in hormone production and secretion are downregulated in Insm1 mutant pituitary glands. By contrast, Notch signalling components and skeletal muscle-specific genes are upregulated, suggesting that Insm1 also represses inappropriate gene expression programmes in the pituitary. Finally, the researchers show that the SNAG domain of Insm1 is required for its function, acting to recruit histone-modifying proteins and transcriptional regulators.

Split thoughts on the neural crest

The neural crest (NC) is a transient structure that gives rise to multiple lineages. Despite intense studies, it is still unclear whether the NC represents a homogeneous population of cells. Here, Jean Paul Thiery and colleagues examine this issue (p. 4890). The authors first characterise the cranial neural fold in chick and mouse embryos and show that, prior to delamination, it contains two phenotypically distinct domains: neural ectoderm and non-neural ectoderm. The researchers then show that the two domains display temporally distinct delamination patterns. Cells specifically within the non-neural ectoderm are the first to delaminate, whereas a second population of delaminating cells then originates from the neural ectoderm in both chick and mouse embryos. Importantly, they report, cells within the two domains have distinct fates: those from the non-neural ectoderm give rise to ectomesenchymal derivatives, whereas those within the neural ectoderm give rise to neuronal derivatives. These, together with other findings, prompt the authors to revisit current definitions of the NC and the origin of ectomesenchyme.

PLUS…

Mechanisms of scaling in pattern formation

Many organisms and their constituent tissues and organs vary substantially in size but differ little in morphology; they appear to be scaled versions of a common template or pattern. Here, David Umulis and Hans Othmer investigate the underlying principles needed for understanding the mechanisms that can produce scale invariance in spatial pattern formation and discuss examples of systems that scale during development. See the Review article on p. 4830

Conveying principles of embryonic development by metaphors from daily life

How can the revolution in our understanding of embryonic development and stem cells be conveyed to the general public? Here, Ben-Zion Shilo presents a photographic approach to highlight scientific concepts of pattern formation using metaphors from daily life, displaying pairs of images of embryonic development and the corresponding human analogy. See the Spotlight article on p. 4827

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Meeting report for Genetics Otago symposium 28-29^th November 2013.

The annual Genetics Otago symposium was held in the newly refurbished HD Skinner Annex of the Otago Museum in sunny (yes, really!) Dunedin, New Zealand at the end of November.   This two-day symposium is run annually by Genetics Otago, a Research Centre of the University of Otago, which has over 240 members based at Otago and right across New Zealand. This year the meeting brought together plenary, guest and postgraduate speakers from Otago and across NZ, in addition to invited speakers from overseas (Australia, Czech Republic). Highlighting the diversity of genetics research, presentation topics ranged from the genomics of NZ stick insects, liver disease, gout, brain development, chordate evolution through to cancer genetics.  Below are a few highlights; for more details check out the Storify of the live tweeting from the symposium: http://storify.com/ANZSCDB/geneticsotago-symposium-2013.

Professor Vicky Cameron’s (Christchurch Heart Institute) group has been studying the genetics of susceptibility to Takotsubo cardiomyopathy or broken heart syndrome, cases of which increased following the two Christchurch earthquakes, especially in post-menopausal women. She and Professor Martin Kennedy, also of University of Otago Christchurch, are championing differing hypothesis for the genetic origin of this condition – a single, rare causative gene mutation versus a ‘perfect storm’ of contributing SNPs.

Dr Amy Osborne (Laboratory for Evolution and Development) spoke about her work identifying the mechanisms behind transgenerational inheritance and the predictive-adaptive response (“Are you what your great grandmother ate?”) where various behaviours or health conditions can be inherited without DNA sequence changes.  In work leading on from the PhD of Sarah Morgan, Dr Osborne has been making use of Drosophila to investigate nutritionally derived transgenerational inheritance in the F3 population following feeding of the F0 generation on a restricted diet.

Sophia Cameron-Christie, a PhD student with Professor Stephen Robertson, presented on the genetics of biliary atresia, a developmental disorder of the bile duct, which is usually only treatable by liver transplants in children affected by this condition.  Sophia is using exome sequencing and linkage analysis on samples from a NZ family to identify susceptibility loci.  Two other PhD students from Professor Robertson’s group also presented their PhD work, Adam O’Neil on periventricular heterotopia and neuronal migration, and Emma Wade on mechanosensing and bone density.

Professor Neil Gemmell (Department of Anatomy) spoke on his work on the increasing evidence that the mitochondrial genome has an important impact on sperm fertility and function, through a phenomenon termed ‘Mother’s Curse’ – whereby incremental mutations can accrue of no selective disadvantage to the mother, but are detrimental to sperm performance, sperm having far fewer mitochondria and more intense energy requirements than oocytes.

Tess Sanders (a PhD student from Dr Christine Jasoni’s group) spoke on how the maternal environment affects foetal brain development. It is well established in humans and other mammals that if the mother is obese, there is a much higher risk of the child being obese.  Tessa is studying gene expression changes and axon guidance in the arcuate nucleus, the part of the brain that receives signals whether to eat or not to eat, and has found molecular evidence that gene expression in this part of the developing brain of the embryo alters depending upon the diet of the mother.

Dr Nic Waddell  (Centre for Medical Genomics, University of Queensland) gave a excellent talk updating us on the ICGC (International Cancer Genome Sequencing) initiative, in particular where they are at with the Australian focus of the project, whole genome sequence analysis of pancreatic cancer, which has a very high mortality rate in those afflicted.

Associate Professor Andrew Shelling from the University of Auckland spoke on the role of Foxl2, a transcription factor they identified as playing a role in premature ovarian failure in NZ families. In initially unrelated work, his group also found point mutations in FoxL2 in many granulosa cell tumors and are now carrying out knockdown and overexpression studies in cell lines to determine how Foxl2 acts to cause ovarian cancer, and comparing this to its misfunction in premature ovarian failure

We were very pleased to have the ANZSCDB support a postgraduate speaker prize and with 12 high quality student speakers it was a hard decision for the judges. In the end, the award was presented to Megan Leask, currently writing up her PhD with Associate Professor Peter Dearden, who investigated the molecular mechanisms behind phenotypic plasticity using the honeybee as a model – whereby dietary differences (i.e. the feeding or otherwise of royal jelly to larvae) drive the development of very different adult organisms (queens vs workers).  In the hive, worker bee ovaries are repressed due to the presence of a queen in the hive; in the absence of the queen, the worker ovaries become activated and they start to lay eggs.  Megan used microarray and RNA-seq, chromatin-immunopreciptation (for epigenetic marks) and drug inhibitor functional studies to understand the molecular changes that occur, both gene expression and chromatin organization, for ovary reactivation, and hence may give us a better idea of how this phenotypic plasticity works at the molecular level.    Sophia Cameron-Christie and Tess Sanders won the GeneticsOtago Speaker award.

This was the 5^th year for the Genetics Otago Annual Research Symposium, and it was again a big success.  It is becoming so popular that registrant numbers had to be capped this year, but given the strong interest from outside Otago, next year’s meeting will be extended, with more researchers from the North Island encouraged to attend.  Looking forward to it already!

—– Dr Megan Wilson, ANZSCDB New Zealand representative and Genetics Otago member; Developmental Biology Laboratory, Department of Anatomy, University of Otago.

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This month saw many interesting posts on the Node, in addition to several job and PhD studentship adverts in our jobs page. Here are some of the highlights!

Node series

Our two series continued at full steam this month:

– In our outreach series, the Cosy Science team presented their ongoing project of bringing science to the relaxed environment of the pub, while Worm Watch Lab is a citizen science project in which the public helps scientists study egg laying in C.elegans. The Biology Builders participated in our series by sharing their experience of organising a stand in a science festival, as well as suggesting an easy outreach activity involving ping-pong balls!

– In our ‘A day in the life’ series Stephen Freeman described a day in the life of a chick lab, while James Lloyd wrote about the mysteries of working with moss.

Research

– Atsushi Miyawaki and colleagues wrote about their recent paper in Development using Fucci technology to comparatively characterise endoreduplication and endomitosis.

– The Chicago Journal club is back  and their first post of this academic year was a Cell Stem Cell paper on the importance of cell sorting in spatial patterning.

– and Christele considered a recent paper assessing the role of dickkopf-1 (dkk1) in neural progenitors.

Meeting reports

– Megan attended ComBio, the largest annual life sciences conference in Australasia, and wrote about her highlights.

– Lauren and Ioanna reported from the UPMC/Curie Developmental Biology course 2013.

– the Node attended the first joint meeting of the French Society for Developmental Biology and for Genetics.

Also on the Node

– We interviewed cardiovascular developmental biologist and Development editor Benoit Bruneau.

– Olivier introduced Manteia, a database that allows the comparison of embryological, expression, molecular and etiological data from human, mouse, chicken and zebrafish simultaneously

– and the deadline for the next round of Company of Biologists Travelling Fellowships, to help cover the costs of visiting another lab, is fast approaching

 
Happy Reading!

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