Today’s paper comes from the latest issue of Development, and reveals a link between phenotypic variability, cell fate switching and epigenetic silencing in zebrafish. Lead author James T. Nichols, who carried out the work in Charles Kimmel’s lab in Euegene, Oregon and is now an Assistant Professor in UC Denver’s School of Dental Medicine, gave us the story behind the paper.

Can you tell me your scientific biography leading up to this work? When did you first get interested in craniofacial development?

I first got interested in the skeleton when I was a technician at the biotechnology company Amgen, working on an osteoporosis therapy. After deciding to pursue my own scientific questions I enrolled in graduate school at the University of California, Los Angeles studying Notch signalling in cell culture with Geraldine Weinmaster, that’s where I fell in love with imaging cells. After my Ph.D., I wanted to move from cells in a dish to an in vivo genetic system. Chuck Kimmel’s laboratory at the University of Oregon was the ideal fit for me because studying zebrafish craniofacial development perfectly satisfied my interest in the skeleton, my love of imaging live cells, and powerful vertebrate genetics. Plus, Chuck is the very best mentor anyone could ever ask for, his lab is a really great place to be.

The team behind the paper includes labs from across the States: how did these labs come together for the work?

I love the collaborative nature of modern science. I think that, within the zebrafish community especially, people are eager to share their unpublished findings and reagents to help each other out and that’s what happened in this case. This open communal approach to science is not only more efficient, but also more fun since you get to work with friends from all over the place.

“I love the collaborative nature of modern science… within the zebrafish community, people are eager to share their unpublished findings and reagents to help each other out and that’s what happened in this case.”

Many researchers, confronted with a highly variable phenotype, would run for the hills or move on to another mutation. What made you guys stick it out?

While this mutant phenotype is notably variable, most mutant phenotypes are more variable than that of the wild type and no one knows why. It is tempting to run for the hills, or just report a ‘representative phenotype’, but I think we are glossing over a lot of interesting biology when we do that. Because zebrafish breed frequently and give large numbers of offspring, and the allele we focused on was behaving just plain weird, we felt like we had a good system to address some important questions about variability. Also, it was very exciting to feel like we were making progress on a real mystery that has intrigued biologists for a long time, I think that kept it fun.

“It is tempting to run for the hills, or just report a ‘representative phenotype’, but I think we are glossing over a lot of interesting biology when we do that.”

Can you sum up the key results of the paper in a paragraph?

We started with an extremely variable gain of bone phenotype that some really smart people in Chuck’s laboratory had made good progress on in the past. However, this mutant had always been problematic because the extra bone phenotype would occasionally disappear. For example, when we moved the mutation onto a transgenic background to label bone cells, the mutant animals would no longer develop extra bone! In this work, we discovered that the ectopic bone was developing because of a transfating event, where bone forms instead of a previously undescribed ligament. We then showed that we could shift the penetrance of transfating up or down through selective breeding, suggesting variability is heritable. When we compared mutants from our selected high- and low-penetrance strains, we found that the high-penetrance strain had more mutant transcripts than the low-penetrance strain. These data suggested that a high level of the mutant transcript was making the phenotype more severe, which we experimentally confirmed by manipulating the transcript. These findings were a real surprise because it suggested that the allele was acting like an antimorph, or a dominant negative, yet it’s completely recessive to the wild-type allele. So it’s an unusual type of allele, a recessive antimorph. We then found that there was a transposon right at the start of the mutant gene, and this transposon was epigenetically different in the two strains. These data suggested that heritable variability in epigenetic silencing might underlie heritable phenotypic variation. Perhaps not just in this context, but in many others as well.

And your selection experiments were based on those done in the early to mid twentieth century? Did you feel like you were addressing the same issues these researchers faced decades ago?

I do, and those studies certainly shaped how we interpreted our results. C.H. Waddington’s work has enjoyed a tremendous resurgence in interest lately, and his genetic assimilation studies really influenced our thinking. Waddington unveiled cryptic variation in his lines that he could selectively breed by heat shocking his flies. We revealed cryptic variation that we could selectively breed by mutagenizing a transcription factor in our fish. Also, the important experiments from Sewall Wright in which he hybridized his inbred guinea pig strains that had an extra toe or not, just like we hybridized our inbred zebrafish strains that had extra head bones or not. Wright interpreted his results as evidence for threshold characters, where if you have enough of some unknown ‘stuff’ you develop a particular phenotype. This led us to look for levels of ‘stuff’ which turned out to be mutant transcripts. It’s so fun to read the old literature and realize that it applies to what we are seeing in the lab; I love the classics!

“It’s so fun to read the old literature and realize that it applies to what we are seeing in the lab; I love the classics!”

Does your work suggest anything about the evolution of new traits?

I think it does, the idea that all this beautiful cryptic variation is just hiding under the surface, unseen in the wild type but ready to be revealed and selected upon is very attractive to me. When conditions are stable, it’s beneficial to have reproducible development. But if conditions change, it’s beneficial to have abundant variation for natural selection to act upon. It’s like having the best of both worlds, consistent development when things are good, but also the ability to provide raw material for evolution when times get tough.

When doing the research, was there a particularly exciting result or eureka moment that has stayed with you?

Absolutely, when we were able to visualize the new ligament for the first time. We suspected it was there, but had no evidence either from us or anywhere in the literature of its existence. Convincing ourselves that it was really there was extremely exciting.

And what about the flipside, any moments of frustration or despair?

We struggled for some time with the concept of a recessive antimorph. How can an allele behave as a ‘dominant negative’ when it’s recessive to the wild type? When we found evidence in the literature from Arabidopsis that this sort of unusual allele exists in other systems it was a big relief.

You’ve just recently started as an Assistant Professor in Denver. How has the transition from Eugene been? What are your plans for the next few years?

I’m living the dream! It took me many years to get to this point and setting up my own laboratory has been everything I’d hoped it would be. There are fantastic colleagues here at the University of Colorado Denver, including some world-class zebrafish laboratories, that have welcomed me and are helping me to get started. Importantly, I have an amazingly supportive wife that enables my science habit. I’m surrounded by wonderful people and that has eased the transition.

“I’m living the dream! I’m surrounded by wonderful people and that has eased the transition.”

In the next few years I plan to follow up on the link between epigenetic variability and mutant phenotype variability. I’ve got some nice preliminary data that strengthens this, plus a whole bunch of results I don’t understand just yet. I’ve got plenty to keep me busy.

What do you like to do when you’re not playing with fish?

When I’m not playing with fish in the laboratory, I’m playing with fish outside the laboratory; I’m an aquarium and pond hobbyist and an avid angler. There are some terrific fly fishing opportunities nearby, and I’m enjoying learning my new home waters.

James T. Nichols, Bernardo Blanco-Sánchez, Elliott P. Brooks, Raghuveer Parthasarathy, John Dowd, Arul Subramanian, Gregory Nachtrab, Kenneth D. Poss, Thomas F. Schilling, Charles B. Kimmel. 2016. Ligament versus bone cell identity in the zebrafish hyoid skeleton is regulated by mef2ca. Development, 143: 4430-4440.

Browse the People Behind the Papers archive here. 

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Here are the highlights from the current issue of Development:

Syndecan 4 lets lymphatic endothelial cells go with the flow

Fluid flow is known to play a role in the development and remodelling of both blood and lymphatic vessels. But how is fluid flow sensed and transduced into a response? Here, Michael Simons and colleagues identify a role for syndecan 4 (SDC4) in regulating flow-induced remodelling of the lymphatic vasculature in mice (p. 4441). They first show that Sdc4^−/− mice exhibit lymphatic vessel remodelling defects during the late stages of embryonic development. Notably, the alignment of valve-forming lymphatic endothelial cells (LECs), and hence valve formation, is perturbed in these mutants. The authors note that these defects are similar to those seen in mice mutant for Pecam1, which encodes a known flow-sensing molecule, but that Sdc4^−/−; Pecam1^−/− double knockouts exhibit a more severe phenotype, suggesting that SDC4 and PECAM1 act via distinct pathways. Following on from this, the researchers demonstrate that SDC4 acts by regulating the planar cell polarity protein VANGL2; SDC4knockdown LECs express increased levels of VANGL2 in response to flow and fail to align under flow, whereas the reduction of VANGL2 levels in these cells restores flow-induced alignment. Together, these findings uncover new regulators of flow-mediated remodelling in the lymphatic vasculature.

Optimized inducible gene knockdown and knockout in hPSCs

Human pluripotent stem cells (hPSCs) are emerging as an attractive model for studying human development and disease. However, functional studies of these cells are limited due to a lack of efficient methods for manipulating their gene expression. Here, Alessandro Bertero and co-workers devise platforms that allow for the inducible knockdown or knockout of specific genes in hPSCs and their derivatives (p. 4405). They first validate the ROSA26 and AAVS1 loci as genomic safe harbours that can be engineered in hPSCs to support stable transgene expression in a large panel of mature cells obtained from hPSCs. The authors then develop single-step optimized inducible knockdown (sOPTiKD) – an inducible shRNA-mediated approach for gene knockdown. This method allows for strong inducible expression of shRNAs, resulting in efficient gene knockdown even following hPSC differentiation. It also uses an optimized tetracycline-responsive repressor protein that eliminates leaky shRNA expression. Importantly, the authors show that this method can be used to knock down individual and multiple genes to study developmental mechanisms. They also develop a conditional knockout system based on CRISPR/Cas9 technology, named single-step optimized inducible knockout (sOPTiKO), and show that gene knockout using this system is possible in hPSCs and mature cell types. Given their robustness, high efficiency and scalability, these platforms promise to be valuable tools for the field.

Transposing from ligament to bone

Phenotypic variation among mutant animals is common, with some mutants displaying dramatic phenotypes while their genetically similar siblings seem less affected. Why is this? Here, on p. 4430, Charles Kimmel and colleagues reveal that phenotypic variation, in the case of zebrafish mef2ca^b1086mutants, can be caused by a fate-switching event during development. Zebrafish mef2ca^b1086 mutants express a truncated form of Mef2c – a protein involved in skeletal development – and are known to develop variable ectopic bones in their heads. The researchers now reveal that these bones arise due to a fate-switching event during development, such that cells that are normally destined to be ligament variably turn into bone. Selective breeding demonstrates that the penetrance of the bone phenotype is heritable. The authors further show that the mef2ca^b1086 transcript is differentially expressed in low and high penetrance strains. Finally, they report that a transposon that resides upstream of the mef2calocus exhibits differential levels of DNA methylation; in high penetrance strains, which express high levels of the mef2ca^b1086 transcript, DNA methylation of the transposon is significantly reduced. These findings lead the authors to propose that variable epigenetic silencing of transposons underlies the variable mef2ca^b1086 phenotypes and could explain other cases of phenotypic variability.

Bringing in fresh blood: SOX7, RUNX1, AP-1 and TEAD4

Despite being the focus of intense research in recent years, the precise mechanisms that regulate the development of haematopoietic stem and progenitor cells (HSPCs), which give rise to all differentiated blood cells, remain unclear. In particular, it is not clear how various transcription factors function together to drive the emergence of HSPCs from haemogenic endothelium (HE) during development. In this issue, two papers attempt to tackle this problem.

In the first paper (p. 4341), Valerie Kouskoff and co-workers examine how SOX7 and RUNX1 regulate haemogenic fate in the yolk sac of mouse embryos. These two factors are thought to play opposing roles: RUNX1 acts as a master regulator of endothelial-to-haemogenic transition (EHT) while SOX7 downregulation is needed for this event. Now, the authors report that, when overexpressed in ESC-derived HE, SOX7 inhibits the expression of RUNX1 target genes but has no effect on the expression of RUNX1 itself. They further reveal that SOX7 and RUNX1 are co-expressed in the yolk sac and dorsal aorta HE of mouse embryos and, importantly, can physically interact with each other via their respective HMG and RUNT domains. This interaction, the authors report, inhibits the transcriptional activity of RUNX1; the binding of SOX7 to RUNX1 prevents RUNX1 from interacting with its co-factor CBFβ and with its target DNA sites. Together, these findings highlight how direct protein-protein interactions between endothelial and haematopoietic transcription factors can regulate cell differentiation programmes during development.

In a second paper (p. 4324), Nadine Obier, Constanze Bonifer and colleagues investigate how AP-1 transcription factors regulate cell fate during the differentiation of mouse embryonic stem cells (ESCs) into haematopoietic cells. They demonstrate that the global inhibition of AP-1 factors (using inducible overexpression of a dominant-negative FOS peptide) affects various stages of ESC differentiation, as cells transition from haemangioblasts (HB) into haemogenic endothelium (HE) and haematopoietic cells. In particular, inhibition at the HB stage enhances cell proliferation and affects the balance between smooth muscle and blood cells, shifting cells towards a blood cell fate. Finally, the authors reveal that AP-1 factors bind to target genes involved in vasculogenesis; these target sites colocalize with binding motifs for TEAD transcription factors, and the authors further show that AP-1 factors are required for the de novo binding of TEAD4 to these genes. In summary, these results suggest that cis-regulatory elements that bind both AP-1 and TEAD4 act as ‘hubs’ that integrate multiple signals to regulate specific gene expression programmes during haematopoiesis.

CHK2 mediates DNA damage in adult stem cells

Adult stem cells are often exposed to genotoxic stress, whether directly from the environment or from within their own stem cell niche. DNA damage accumulates in the stem cells of aged tissues and has been proposed to accelerate both cellular aging and cancer formation, yet the mechanism through which this occurs is not well understood. Now, on p. 4312, Ting Xie and colleagues investigate this issue and demonstrate that DNA damage disrupts germline stem cell (GSC) self-renewal and lineage differentiation in a checkpoint kinase 2 (CHK2)-dependent manner. The authors use an inducible system to generate widespread double-stranded breaks (DSBs) in the GSCs of the Drosophila ovary. These DSBs resolve over time but leave the tissue with significantly fewer GSCs. By contrast, the number of GSC daughter cells initially increases then remains constant, suggesting that differentiation is blocked. The authors go on to identify a role for CHK2, showing how the induction of DSBs in flies lacking CHK2 is sufficient to prevent damage-induced GSC loss. Finally, the authors provide some evidence to suggest that the loss of GSCs may be partly due to reduced BMP signalling and cell adhesion. This study offers insight into how DNA damage might affect stem cell-based tissue regeneration and provides a mechanistic target – CHK2 – for further investigation.

PLUS:

An interview with David McClay

David McClay is the Arthur S. Pearse Professor of Biology at Trinity College of Arts and Sciences, Duke University, North Carolina. His lab works on the transcriptional control of morphogenesis in the sea urchin embryo. We caught up with David at the 2016 Society for Developmental Biology – International Society of Differentiation joint meeting in Boston, where he received the Lifetime Achievement Award. Read the Spotlight article on p. 4289.

A common framework for EMT and collective cell migration

It has long been considered that epithelial cells either migrate collectively as epithelial cells, or undergo an epithelial-to-mesenchymal transition and migrate as individual mesenchymal cells. Here, Kyra Campbell and Jordi Casanova hypothesise that such migratory behaviours do not fit into alternative and mutually exclusive categories. Rather, they propose that these categories can be viewed as the most extreme cases of a general continuum of morphological variety. See the Hypothesis article on p. 4291.

Cycling through developmental decisions: how cell cycle dynamics control pluripotency, differentiation and reprogramming

A strong connection exists between the cell cycle and cell fate decisions in a wide-range of developmental contexts. Terminal differentiation is often associated with cell cycle exit, whereas cell fate switches are frequently linked to cell cycle transitions in dividing cells. In recent years, progress to address the connection between cell fate and the cell cycle has been made in pluripotent stem cells, in which the transition through mitosis and G1 phase is crucial for establishing a window of opportunity for pluripotency exit and the initiation of differentiation. Here, Abdenour Soufi and Stephen Dalton summarize recent findings in this area and place them in a broader context that has implications for a wide range of developmental scenarios. See the Review on p. 4301.

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We are seeking a successful and young postdoc candidate who can figure as Open Science Communicator at the Centre for Integrative Biology (CIBIO http://www.cibio.unitn.it) of the University of Trento.

The candidate will have the chance to apply, jointly with CIBIO, to a 3-years project aimed to communicate knowledge and innovation generated at CIBIO and to connect it with society and economy.

The project will respond to a call for funding promoted by the Autonomous Province of Trento (PAT) for training and project activities (see link – in Italian).

http://www.uniricerca.provincia.tn.it/Bandi_di_ricerca/Bandi_PAT/-I COMUNICATORI STAR DELLA SCIENZA/pagina27.html

The successful candidate is:

– a PhD, from not more than three years, in relevant scientific disciplines such Molecular Biology, Biotechnology, Biomedicine

– not older than 35-y.o.

– willing to train and start a career as an Advanced Science Communicator

– experienced in Science Communication or Technology Transfer (desirable but not compulsory)

– fluent in both English and Italian

If interested please contact Simona Casarosa (simona.casarosa@unitn.it) or Michela Denti (michela.denti@unitn.it) by December 31, 2016.

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In October I travelled to Girona, an old Catalan city surrounded by wooded hills a hundred kilometres north of Barcelona, for the 11^th meeting of the Spanish Society for Developmental Biology (SEBD). The meeting was jointly organised with the SEBD’s neighbours, the Portuguese Society for Developmental Biology, and also the Spanish Society for Cell Biology, and thus gave me a broad overview of what’s currently going on in Iberian cell and developmental biology. I had been in Girona before, but only briefly and half a life ago, and took the chance to get to know the city at a time of year when it wasn’t swamped by tourists trying to find where the Game of Thrones scenes were shot.

I also had the chance to meet some wonderful welcoming people. I don’t want to get too hung up on the financial situation in Spanish research, but it popped up again and again in conversations between talks, over beers, at breakfast. (Brexit did provide an alternate but equally downbeat conversation topic!) That there is not enough money in Spanish research is clear – public investment in research has dropped dramatically since the financial crisis began, and is well below the European average. The funding systems themselves appear to be outdated, and there is a feeling that the current government is more interested in creating a service economy than one driven by research and innovation (“more beaches and casinos than labs and fellowships,” to paraphrase one senior researcher). In this environment, new PIs are in a particularly vulnerable state, and those I talked to didn’t see the situation changing anytime soon, as recounted elsewhere.

But, against this background, there is still fantastic research being carried out in Spanish labs, and there are still Spanish researchers returning home to establish their labs after postdocs abroad (plus foreign-born researchers working in and running Spanish labs). So let’s forget about money for a moment and move on to science!

I began with a workshop organised by Xavier Trepat and María Garcia-Parajo on cell dynamics and nanobiology. The workshop aimed to highlight the new techniques that are revealing the dynamics of life at higher and higher resolution, and allowing us to measure forces and determine physical properties of tissues such as stiffness.

Jacky Goetz kicked off with a description of how multiple imaging modalities were helping his lab understand metastasis, and went through the painful-sounding process of combining intraviral imaging, micro CT and EM¹ (we previously heard about CLEM approaches in an interview featuring Jacky’s collaborator Yannick Schwab). María Garcia-Parajo then took us on a tour of the plasma membrane at the nanoscale, before Jérome Solon zoomed out to the level of the tissue. Embryogenesis strikes him as origami, a single sheet folded into a complex three dimensional structure, except there is no origamist, and the properties of the material change as you progress. Defining forces is one thing, but Solon stressed that we should not forget the tissue’s response to these forces, which is heavily influenced by the cytoskeleton and the membrane. Xavier Trepat then finished with his lab’s recent work on durotaxis – the process by which cells follow gradients in substrate stiffness – and emphasised that in this system, the sensor and activator are the same thing: the cytoskeleton.

The room then discussed the future of physical approaches in biology. Would forces come to be as important to developmental and cell biologists as genetics and biochemistry had been in the last hundred years, for instance? If the answer to this question is yes (or even, as some biophysics nuts might have it, ‘much more important!’), a member of the audience raised a problem: from school onwards, scientists are trained to be biologists or physicists, without much overlap between the two. While some wanted the two disciplines to be much more integrated, others in the audience proposed that for some problems, the more important thing is to integrate the power of specialists. The ‘superdry’ mathematician who didn’t know cells were grown in liquid media until two years into a collaboration could nevertheless help wet biologists to better understand their cells with a model. The centenary of D’Arcy Thomson’s On Growth and Form next year will undoubtedly provoke further discussion as to the future of physics and biology.

The meeting proper then began, in the chamber hall of the Palau de Congressos, a modern and well-designed conference centre near the chalky green river Ter. The place had real coffee. Having been to two meetings in the States this year², it was like manna from heaven.

Over the meeting’s three days, the three keynote lectures tackled different aspects of how brains are built and work. Claude Desplan (who it turned out was born nearby, on the French side of the Pyrenees) described his lab’s efforts in recent years to understand how the fly makes its medulla. Recent advances in single-cell sequencing – particularly drop-seq – were helping with the effort to categorise the identity and developmental pathways of the constituent neurons. The emerging picture was of an integration of spatial and temporal patterning systems in a rather rigid and determined manner. Magdalena Götz described her recent collaboration with Mark Hübener demonstrating that embryonic neurons can integrate amazingly well into injured adult brains, anatomically and functionally. She also described her collaboration with Victor Borrell, who in his own talk in the Neural Development session described a brief window in development that generates a massive number of radial glia cells, which then form a self-sustaining lineage to drive cortical expansion. Rainer Friedrich wanted to know how the architecture of neural circuits defined how the brain worked, how form provides function. He argued that uncovering a connectome was worthwhile for this aim and not just stamp collecting, and showed some stunning reconstructions of the zebrafish olfactory bulb derived from serial block face EM. This work required outsourced ‘tracers’ to manually track axons and synapses from EM slices; it seems AI is not near the task, yet.

There was a fascinating session on oscillations across life’s kingdoms. Paloma Mas talked about how different organs in the plant maintained their own circadian rhythms and how each clock influenced the others, while Jordi Garcia-Ojalvo gave a bacteriologists view of self organisation and oscillating patterns. He wanted to convince us that bacteria are a good model for developmental questions, and described how oscillations of growth in bacterial biofilms are driven by nutrient restriction and electrical communication. I was brought back to more familiar ground with Alexander Aulehla, and live imaging of the somitogenesis clock as it ticks in mouse embryos and cultured cells. “Information,” he said, “might be encoded not just in the presence or absence of a signal, but its phase and frequency.” His was one of many talks that used mathematical descriptions to try and understand patterning – another being Luis Escudero, who described how his lab was using Voronoi diagrams (yep, had to Google this!) to explain the distribution of cell shapes within a packed epithelium, and how pathological examples provided useful deviations from the normal distributions.

Since my PhD days studying wing development, I have always associated Spanish developmental biology with fly research. I was pleased to hear from Marco Milan about the legend of the flies of Saint Narcís, who in the 13^th century protected Girona from the French troops that were besieging it. Judging by the drawings and the behaviour, maybe not Drosophila, but close enough!

700 hundred years later, flies were represented in the SEBD in plenty of posters and talks. Benjamin Prud’homme gave a neat story of how a species of Drosophila evolved male-specific spots on its wings, giving us an update on previous work. The message I took home from the talk was that a seemingly simple morphological change could have quite complex genetic underpinnings: it wasn’t as simple as just recruiting a pigment-promoting gene by evolving a new enhancer. Sofia Araujo described how a mutant found in a screen for defective tracheal development led to the discovery of a role for centrosomes in the branching of single cells, independent of any affect on mitosis. The idea is that the centrosomes act as microtubule organising centres to dictate cytoskeletal organisation and membrane behaviour. Isabel Guerrero also looked at cell membranes, and the thin extensions called cytonemes that promote cell signalling. She proposed that cell-cell contacts along the length of cytonemes promoted signalling in a synapse-like manner.

I was delighted to hear the latest from Juan-Pablo Couso, whose lab was next door during my PhD and is soon to be moving from the UK to the CABD in Seville, a dedicated centre for developmental biology (something I don’t think we have here in the UK?). When I started my PhD, the Couso lab had just published their characterisation of tarsal-less, a Drosophila gene involved patterning and morphogenesis, the function of which is provided by a small open reading frame encoding a peptide only 11 amino acids long. Over the years, the lab have chased other smORFs, characterising specific functions in phagocytosis and calcium uptake, as well as taking genome wide surveys of their potential numbers. It’s a nice example of how a chance finding can radically alter the direction of a lab (the original tarsal-less allele was a spontaneous mutation). His talk ended by trying to situate smORFs into a cycle of gene birth and death over evolutionary time in the genome, which will be the subject of an upcoming review from the lab.

And these were some of my scientific highlights among a lot of fascinating work. I can only wish Spanish researchers a more stable financial future to continue it.

~

Girona itself turned out to be beautiful: old buildings, winding lanes, church bells. I ate well (not always a given at conferences), particularly in the final night at the conference meal in this place, got to watch Lionel Messi humiliate Pep Guardiola in a bar full of Catalans, and even take in some nightlife (scientists, it seems, dance the same the world over).

1 – I once spent a few months mapping somatic clones in the adult Drosophila wing onto templates, before prepping the wings for EM. I needed to know where the clone was, and whether it covered both surfaces of the wing or not, before mounting on the sticky EM stub. The first opportunity for disaster was a misplaced breath, launching the wings into orbit. The second was to mount the wings on the wrong side, which I would only realise after an hour setting up the EM in the cold and the dark. In retrospect, this was a breeze compared to CLEM.

2 – If you’re interested, you can read my previous reports from Boston and Southbridge. Girona was my third conference representing the Node, and I’ve become used to the strange feeling of being in a new place knowing perhaps a handful of people but being familiar with the rituals – talk followed by questions followed by talk followed by questions, the phrases that have become almost clichés (“In my lab we’re interested in…”, “A very talented postdoc in the lab…”, “I hope I can convince you that…”), the coffee and the posters and the pastries, the emptiness of hotel rooms, the excitement of a new town. It makes me think we lack a literature or culture of conferences (or at least that I haven’t found one yet – any suggestions?)

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https://www.recruit.ox.ac.uk/pls/hrisliverecruit/erq_jobspec_version_4.jobspec?p_id=126188 

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“It’s fair to say that we currently know more about the moon than about our own embryonic development. The current textbooks all show the same kind of images based on a few embryonic specimens from the 1930s. Some of those are not even human embryos. New version of these books keep using those images, often without reference, only updating new molecular information”

This leads to the situation that the origin of the knowledge on human embryology became forgotten and that some of the knowledge was based on chicken, axolotl and mouse specimens. Moreover, the complex morphological changes during development cannot be well illustrated on the flat two-dimensional pages of text books.

To remedy this situation we proposed to use the sections of the embryos available in the Carnegie Collection to generate a comprehensive series of interactive 3D reconstructions of human embryonic development; a proposal that was based on the availability of 3D reconstruction and visualisation software.

This project, initiated by Professor Antoon Moorman, with dedicated financial support of the Academic Medical Center in Amsterdam, the Netherlands, was carried out by Bernadette de Bakker. The educational angle made that the project was ‘by students – for students’. De Bakker obtained a duplicate series of images of stages 7 to 23 (15 – 60 days of development) from the Carnegie Collection in Washington DC. After alignment in a 3D reconstruction program, a total of 75 medical students manually annotated every structure and organ in each of the about 15,000 images as part of their scientific internship; an effort that took more than 45,000 hours.

Another 15 students, this time from the game development faculty, then ‘modelled’ the resulting 3D reconstructions to reduce the complexity without losing biological detail. Their results, turned into 3D-PDF files, thus represent the actual morphology of the series of embryos in a format that can be easily interactively handled with the commonly used PDF reader. This was all supervised and supported by the expert embryologists of the department.

“The 3D Atlas and Database of Human Embryology is the first to present such a large amount of data based on such a large number of human embryos. With this atlas and database we are able to quantify very precisely embryonic growth and the growth and position of specific organs”

The 3D atlas, that contains morphological reconstructions of 14 stages, is accompanied by a database with quantitative data based on 17 duplicate stages of reconstructed embryos. This database shows the total volume of the embryo grows exponentially with a constant volume increase of 25% per day. However, different organs grow with different growth rates, depending on their function during development. The project team established a tool to determine the position of organs relative to the developing vertebral column of the embryo. Application of this tool can help to solve ambiguities with respect to the relation between organs. The third series of data relates the chronology of human development to that of the mouse and the chicken. These data show that each species runs its own embryological script.

Already during the construction of the atlas, discrepancies between the observed embryology and the embryology textbooks became apparent. The textbook descriptions of the development of the venous system and the notochord clearly show influence of knowledge dissipating from studies on lower vertebrates. Descriptions that could not be corroborated in the current reconstructions based on the real human substrate. The interactive 3D atlas, and the source images that are also available from the website, allow every user, be it student or biomedical specialist, to independently verify those discrepancies and form their own opinion.

“The atlas is useful because to study how congenital malformations appear it is important to know how normal human embryonic development occurs. Experimental embryologists will know how the changes in their experimental animals relate to the human situation. Scientists who study how toxic substances can affect embryonic development, are helped to refine the chick and mice models they work with. Moreover, also gynaecologists can use this atlas to show pregnant women how their child develops.”

Contributors: Bernadette de Bakker, Jan M Ruijter and Antoon Moorman

The 3D atlas of human embryology is available here: 

http://www.3dembryoatlas.com/

The Research Article in Science reporting the atlas is available here, Open Access:

http://science.sciencemag.org/content/354/6315/aag0053

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We are delighted to invite you to our one-day STORM symposium, which aims to bring together expertise from fields of biology and physics as well as microscope software engineers to discuss the challenge of Stochastic Optical Reconstruction Microscopy (STORM).

This symposium is aimed at those researchers who are currently using STORM. We aim to provide a platform for discussion and collaboration to highlight the problems researchers are facing with STORM; and together we can try to find solutions.

There will be talks from researchers, addressing issues such as sample preparation, labelling and image analysis. As well as talks from experts including Nikon, and those using the Thunderstorm imageJ plugin. We encourage you to bring along a A3/A2 poster of a current image. These images do not have to be perfect, please bring along images you are having problems with or have questions about. See website for details. The images will be displayed during the day to allow you to get feedback from other attendees and prizes will be awarded to the most interesting. Registration closes 8th January 2017 but places are limited.

Registration is now open – please check our website for details:

https://sheffieldstorm.wordpress.com

Attached is a flyer – please feel free to pass on to other interested parties at your Universities/Institutes:

storm-symposium-registration-flyer-oct2016

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Cytokinetic Abscission In the final step of cell division, the bridge connecting the cells is cut to give rise to two separate daughter cells – a fascinating process I have been working on since I started my PhD. This is a variation of my very first science-themed drawing, which I overlaid with an immunofluorescence staining labeling microtubules (green) and DNA (blue) – a combination of a hand-drawn illustration with real microscopy images that quite literally fuses science and art.

I have always loved science, and have always loved art – I combine these passions to illustrate scientific themes with an artistic twist. With my illustrations, I aim to highlight fundamental scientific aspects in an unconventional and refreshing way. I want to add some creativity to the conventional forms of scientific communication, with the aim to spark interest inside and outside the scientific community. I create my drawings for everyone to enjoy – for scientists to appreciate biological findings in a less serious way, and for non-scientists to grasp fundamental biological principles.

I used to draw a lot before studying Molecular Biology at the University of Vienna and the ETH Zürich in Switzerland. I recently completed my PhD in Daniel Gerlich’s group at the Institute of Molecular Biotechnology (IMBA), during which I made my very first science-themed drawing back in 2013. My PhD research focused on cytokinetic abscission, the final step of cell division (shown above, click on images for full size). When I showed that drawing as part of my scientific presentations, I realized that it sparked interest and tended to stay in people’s memories. This is when I discovered that adding an artistic twist to science creates a unique way to communicate science.

An Unconventional Take on Scientific Presentations. This picture was taken during my presentation for the Kirsten Peter Rabitsch Award, which I had the honor to receive for my PhD research earlier this year – in it you can see a new version of my very first science drawing.

An Unconventional Take on Scientific Presentations.This picture was taken during my presentation for the Kirsten Peter Rabitsch Award, which I had the honor to receive for my PhD research earlier this year – in it you can see a new version of my very first science drawing.

Being part of an institute that encourages creativity has helped me immensely to develop my artistic approaches. I participated in yearly campus-wide ‘Art & Science’ contests, where I experimented with drawing portraits of my colleagues and making a dress to illustrate my research project.

When Devotion Begets Emotion. These portraits of my fellow PhD students illustrate the intense emotions researchers face in everyday life in the lab. These drawings were part of a contribution to the Art & Science contest at the Vienna Biocenter, for which my team received the first prize in 2013.

The ‘ESCRT’ Dress. Cytokinetic abscission is mediated by a machinery composed of the Endosomal Sorting Complex Required for Transport (ESCRT)-III, which forms polymers that constrict the intercellular bridge until the membranes split. I created this “ESCRT” dress to illustrate how ESCRT-III separates the emerging daughter cells during abscission.

The ‘ESCRT’ Dress. Cytokinetic abscission is mediated by a machinery composed of the Endosomal Sorting Complex Required for Transport (ESCRT)-III, which forms polymers that constrict the intercellular bridge until the membranes split. I created this “ESCRT” dress to illustrate how ESCRT-III separates the emerging daughter cells during abscission.

I began pursuing scientific art after having my drawing selected for the cover and abstract book of the Cell Cycle Meeting in Cold Spring Harbor. The positive feedback I received there was an incredibly rewarding experience that encouraged me to start creating artwork for other people’s research as well as my own. Since then, I continue making scientific illustrations, one of which was recently featured on the EMBO Journal cover.

This EMBO Journal cover accompanies a paper on mammalian brain development I was involved in during my Master’s Thesis. The compass represents how the angle of the mitotic spindle in dividing cells affects their ultimate position within the brain – similar to a compass guiding the way to a location on a map.

EMBO Journal Cover. This EMBO Journal cover accompanies a paper on mammalian brain development I was involved in during my Master’s Thesis. The compass represents how the angle of the mitotic spindle in dividing cells affects their ultimate position within the brain – similar to a compass guiding the way to a location on a map.

I also began making artistic interpretations of recent scientific discoveries. Below is a small gallery of my illustrations for press releases that highlight recent publications.

Before chromosomes can be segregated during cell division, they have to cover themselves with a protein that acts similar to soap to prevent them from sticking together. This drawing is part of a press release for a recent discovery of a protein that acts as a surfactant to disperse chromosomes during anaphase.

The ribosome is a fascinating molecular machine that produces proteins. It reads the genetic code on our messenger RNA and translates them into proteins by linking the correct amino acids into a long chain. The ribosome consists of two huge subunits that twist against each other to drive this process of translation

Aside from highlighting research findings, I also began making illustrations for other purposes. For a popular science magazine, I created a less serious drawing illustrating the myth of the “five-second rule”, which suggests that bacteria will wait patiently before contaminating food that has been dropped on the ground.

Illustration for an article in the German version of Scientific American ‘Spektrum der Wissenschaft’.

Five-Second Rule.  Illustration for an article in the German version of Scientific American ‘Spektrum der Wissenschaft’.

I also had the wonderful opportunity to design the poster for the PhD symposium at the Vienna Biocenter titled ‘Mind the App’, as part of the organizing committee. For this illustration, as well as many of my others, I started by making a hand-drawn black and white sketch using pencils, and overlaid the colors digitally afterwards. I then added the apps on the phone to highlight the diverse applications of basic research that were covered at the conference.

Basic research gives rise to many ‘applications’. Poster of the ‘Mind the App’ VBC PhD Symposium at the Vienna Biocenter.

Basic research gives rise to many ‘applications’. Poster of the ‘Mind the App’ VBC PhD Symposium at the Vienna Biocenter.

Mind the App. Basic research gives rise to many ‘applications’. Poster of the ‘Mind the App’ VBC PhD Symposium at the Vienna Biocenter.

When I first started drawing, I mainly focused on creating portraits – in this illustration I got back to my roots to make a short animation about everyday life in the lab.

Failed Experiment. An unsuccessful experiment can bring up very intense emotions, which every scientist is certainly familiar with. I created these drawings for an animation to be used in a video for the PhD Program at the Vienna Biocenter

I love the challenge of capturing the essence of scientific discoveries in an aesthetic and abstract way, and I am very excited for many more artistic adventures to come. Every drawing is an experiment!

Check out my website (www.beatascienceart.com) for recent updates and a complete gallery.
 
All images © 2016 Beata Edyta Mierzwa

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On April 3-4, 2017 scientists from around Europe will be converging on Munich, Germany for the next meeting in the Abcam Brain meeting series – Programming and Reprogramming the Brain. Organizers, Benedikt Berninger (Johannes Gutenberg University Mainz) and Paola Arlotta (Harvard University) have put together a fantastic line up of speakers (see preliminary program).

This two-day meeting will provide a forum for presentations and discussions on the emerging field of brain development, reprogramming and modeling with a focus on new genome wide tools to understand biological processes with single-cell resolution.

Call for abstracts

Talk and poster places are available, so don’t wait, submit your abstract today!

• Talk deadline: December 15, 2016
• Poster deadline: February 6, 2017

We hope to see you in beautiful Munich next year!

Meeting topics

• Modeling human brain development from pluripotent stem cells
• Programming and maintenance of cell identity in the CNS
• Development-inspired reprogramming of the brain
• Decoding CNS complexity with single-cell resolution

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A new eLearning resource that provides short and interactive vignettes in embryo (primarily vertebrate) development, from gametogenesis through to organogenesis, is available from the eMouseAtlas^1,2 website (www.emouseatlas.org).

The current eLearning content are the tutorials produced by Professor José García Monterde of the University of Córdoba, and the presentation from collaboration between Professor Monterde and the eMouseAtlas project.

The resource describes the development of various anatomical systems including the cardiovascular system, nervous system, and musculo-skeletal system, and additionally introduces core developmental biology concepts such as gastrulation, placentation, and the formation of the germ layers.

eLearning Topics

• Gametogenesis and fertilization
• Cleavage
• Gastrulation
• Some Basic Concepts
• Germ layer derivatives
• Fetal Membranes and Placentation
• Cardiovascular System
• Pharynx and branchial arches
• Respiratory System and Coelomic Cavities
• Digestive System
• Urogenital system
• Musculo-Skeletal system
• Nervous system

The resource combines illustrative animations of embryonic development with interactive 3D visualisations of mouse developmental anatomy. The newly developed 3D viewer enables arbitrary sections to be sliced through embryo models.

The eLearning tutorials additionally link to gene expression patterns associated with developing organ systems, the cellular-resolution eHistology atlas and the DMDD (DMDD.org.uk) database of embryonic lethal phenotypes.

eLearning is freely available for both teaching and research purposes. eMouseAtlas continues to develop tools and resources that enable students and researchers to understand the concepts underpinning embryonic development. In this context we are willing to host learning materials on behalf of the community.

References

1. Armit C, Richardson L, Hill B, Yang Y, Baldock RA (2015) eMouseAtlas Informatics: Embryo Atlas and Gene Expression Database. Mamm Genome. 26:431-40. doi: 10.1007/s00335-015-9596-5
2. Richardson L, Venkataraman S, Stevenson P, Yang Y, Moss J, Graham L, Burton N, Hill B, Rao J, Baldock RA, Armit C (2014). EMAGE mouse embryo spatial gene expression database: (2014 update) Nucleic Acids Res. 42(1):D835-44. doi: 10.1093/nar/gkt1155

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