Cell polarisation is crucial for normal development and controlled by complex molecular interactions in the cytoplasm and at the membrane. Today we feature a paper recently published in Developmental Cell that describes  a single-cell biochemistry technique and its insights into polarity protein dynamics the developing worm embryo. We caught up with first author Dan Dickinson, who carried out the work as a postdoc in Bob Goldstein‘s lab in UNC Chapel Hill, and has recently started his own lab in the University of Texas.

Looking back, did you always want to be a scientist?

Well, math and science were always my favorite school subjects, even going back to my elementary school years. I was most interested in astronomy early on – I wanted to be an astronaut in second grade, and most of my early science fair projects involved the solar system or telescopes in some form. I got excited about biology in 7^th grade, when we were introduced to Mendelian genetics in a science unit. It was my first introduction to the idea that living things behaved according to a set of knowable rules, and I was hooked almost immediately.

And can you tell us your scientific biography up until now?

My first “real” science experience was the year after I graduated from high school. I was younger than most of my classmates, and so I decided to take a year off before college. I got a job as a tech with a small startup pharmaceutical company that was trying to develop generic versions of several chemotherapeutic drugs. In return for washing dishes half-time, they let me do some small research projects trying to optimize drug yields. It was a fun year and a great window into how corporate research works.

I went to college at Iowa State and joined Gloria Culver’s lab halfway through my freshman year.  The lab studied the biochemistry of ribosome assembly in E. coli, and I worked on a couple of different projects related to how one particular protein, called S15, binds and alters the structure of the ribosomal RNA.

During my senior year, I got invited to apply for a Fulbright scholarship, and received an award to go to Switzerland for a year and work in a research lab. I got connected with Martin Pruschy at University Hospital in Zurich, who was studying the signalling pathways that are activated in response to ionizing radiation in cancer cells. My project in that lab was trying to identify novel proteases that were activated by radiation. It was pretty high-risk and the project never really went anywhere, but it was my first time working full-time in an academic lab and I learned a lot about how science really works. It was great preparation for grad school.

I got my Ph.D. at Stanford, where I was jointly advised by James Nelson (a cell biologist) and Bill Weis (a crystallographer and biochemist). I proposed a new project for the two labs, studying the evolution of cell-cell adhesion in the slime mold Dictyostelium. The projected started out because I got curious about evolution, started doing blast searches, and found out that Dicty has homologs of beta-catenin and alpha-catenin, two cell-cell adhesion proteins that we had previous assumed were only present in animals. I wanted to figure out what Dicty was doing with these proteins, and we went in with the hypothesis that it might have something to do with adhesion during the multicellular phase of its life cycle. We were surprised to learn that in fact, during the multicellular phase, Dicty forms a tissue that looks very much like an animal epithelium, and this tissue required the catenins for its structure and polarity. This was a big deal because it suggested that the basic organizational principles behind animal multicellularity might be much more ancient than anyone thought.

I wanted to move into an animal model system as a postdoc, and picked the Goldstein lab after interviewing in several worm and fly labs. I was attracted to the simplicity of C. elegans embryos and the ability to study development at single-cell resolution.

Before this paper, you were among the first to adapt CRISPR/CAS9 in worms. Have you always liked developing new methods?

It’s funny – I can see why someone would ask that after having read my papers (especially from my postdoc).  But I don’t think of myself as a “methods guy” at all.  I didn’t start working on methods until the second year of my postdoc, and it was only because I got frustrated by the lack of available tools for the experiments I wanted to do.  In hindsight, I guess I do enjoy the challenge of working out new techniques, but I’ve always been motivated by the biology.

What do in vivo biochemical methods like the one described in your paper promise to tell us about development?

Well, at the risk of over-generalizing, I’d say that most developmental problems have historically been inaccessible to biochemistry. There are exceptions, of course – Xenopus egg extracts come to mind as a beautiful biochemical system with developmental relevance – but broadly speaking, it’s been hard to get pure populations of cells or tissue from in vivo models in sufficient quantity for biochemistry. The sc-SiMPull approach we developed, combining nanoscale microfluidic lysis and single-molecule biochemistry, represents one solution to that challenge.

Can you give us the key results of the paper in a paragraph?

There were two really key findings. The first was a demonstration that technically, it is possible to get dynamic information about protein-protein interactions in single C. elegans zygotes by lysing them and performing single-molecule pull-down.  Second, by applying this approach, we found that the PAR complex – a critical cell polarity determinant in many systems – dynamically oligomerizes during polarity establishment.  We studied the significance of that transient oligomerization using targeted mutants and live imaging, and found that PAR complex oligomerization is essential for PAR proteins to get transported to the anterior of the cell by the cortical flows that establish polarity. We also found that a cell cycle kinase, PLK-1, controlled PAR complex oligomerization by directly phosphorylating one of the complex members (a protein called PAR-3). This was exciting because prior to our work, I don’t think anyone really understood how the timing of polarity establishment was controlled.

How applicable do you see sc-SiMPull being to other systems?

I think it should be straightforward to apply to other systems, and in fact that’s one of the things we’re going to work on in my own lab (which just started this past month, at the University of Texas at Austin). Now that the basic approach is worked out, applying it to other systems should be as simple as adjusting the design of the microfluidic chips to accommodate whatever sample we want to study.

Your paper came out alongside two others – one in the same issue of Developmental Cell and one in Nature Cell Biology. Was there any coordination between the groups in the publication process, and are the results you describe broadly consistent?

I was fortunate to be in touch with the PIs on those other papers, Nate Goehring and Fumio Motegi, before any of us submitted, and we communicated periodically during the review process. I think all three of us had a genuine desire to see everyone get credit for their work – which I believe is the right attitude to have. All three papers reached a similar conclusion about the role of PAR complex oligomerization in polarity establishment, but there’s actually very little overlap in terms of the experiments each group did.  That’s an ideal situation, because the papers reinforce each other and increase our confidence that the conclusions are correct.

When doing the research, did you have any particular result or eureka moment that has stuck with you?

The first time I saw single molecules that I’d pulled out of an embryo, that was a big moment when I knew this was going to work.  Also, when I first put the oligomerization-blocking mutant embryos on the microscope and saw that they had an interesting polarity defect, that was a big day when it became clear we’d actually discovered something interesting.

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

I actually starting working on sc-SiMPull almost 5 years ago – before CRISPR – and the CRISPR work was kind of a detour along the way.  In fact, the whole reason I started doing CRISPR in the first place was because I thought that endogenous gene tagging was a pre-requisite for the kind of quantitative biochemistry I envisioned (we could have counted complexes of overexpressed proteins, but what would we really have learned?).  CRISPR turned out to be a much longer detour than I’d expected.  In hindsight, it was worth it, of course, but there were some struggles along the way and times when I wondered whether I’d ever get back to the work I actually wanted to be doing.

You’ve just started your own lab in the University of Texas. How are you settling in to Austin, and what do you aim to achieve in the next few years?

Austin is great.  It’s a really fun place to live, it’s relatively affordable, and from a scientific standpoint I think the department is phenomenal.  I’ve felt very welcome here and am excited to be getting the lab up and running.  This is an exciting time because I feel like we finally have the tools for the kind of science I want to do, and I’m looking forward to deconstructing the PAR polarity system at a level of mechanistic understanding that hasn’t been possible previously.  We’ll keep working on worms, but I want to expand into some other systems too.

Finally, what do you get up to when you are outside of the lab?

I have two little boys, ages 3 and 5, who are just tremendous fun.  I love watching the reactions they get when they tell their friends and teachers that their dad smashes worms for a living.  Since we moved here I’ve been spending most of my weekends building various backyard climbing structures for them to mess around on.  I also love to cook (and eat), and I compensate for all the cooking and eating by road cycling about 100 miles a week.  One of my favorite things about Austin so far is the cycling culture – there are bike lanes everywhere, and they are widely used even in the heat of the summer.  It’s been a lot of fun to explore the city and surrounding area that way.

Daniel J. Dickinson, Francoise Schwager, Lionel Pintard, Monica Gotta, Bob Goldstein. 2017. A Single-Cell Biochemistry Approach Reveals PAR Complex Dynamics during Cell Polarization. Developmental Cell. Volume 42, Issue 4, p416–434.

This is #28 in our interview series. Browse the archive here. 

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The story behind our recent paper  ‘Hierarchical patterning modes orchestrate hair follicle morphogenesis‘ , finding that distinct patterning mechanisms can co-exist during embryonic organ formation.

From the spots of a leopard and stripes on a zebra to the pigmentation of sea shells and arrangement of sand dunes in a desert, repeating patterns are present at vastly different scales throughout the natural world. During embryonic development, repeating patterns are also prevalent and lead to diverse structures such as the digits of the limb, intestinal villi, cartilaginous rings of the trachea and rugae of the palate. But how do these patterns form in the first place?

A common feature with repeating patterns is that they arise through a process of self-organisation from local interactions within the system. The ability to self-organize is nowhere more apparent than in an embryo, where a single fertilised cell can develop into a complex organism with many different structures. To the mathematician and famous war-time code breaker Alan Turing, this emergence of a body plan (morphogenesis) was an example of symmetry breaking; where homogenous or ‘symmetric’ tissue, in terms of it being developmentally equivalent, transitions from a uniform to an organised heterogeneous state. This phenomenon inspired Turing to publish his seminal 1952 work ‘The chemical basis of morphogenesis’[1]. In his paper, Turing theorised that a pair of interacting chemical molecules (which he termed ‘morphogens’) that are both diffusible but at different rates, when acting across an entire field with local fluctuations can break symmetry and produce a regularly spaced pattern. This concept is now commonly referred to as the Turing reaction-diffusion model.

Some 20 years later two German scientists, Hans Meinhardt and Alfred Gierer, provided a general mechanism for such pattern formation [2]. Meinhardt and Gierer showed that a system only requires a network where a self-enhancing molecule with a short diffusible range known as the ‘activator’ stimulates the production of its own ‘inhibitor’ molecule that operates over a larger spatial range.  Simply put, for a pattern to form, there needs only be local self-enhancing activation coupled with long-range inhibition.

Although this Meinhardt-Gierer model originally described biological molecules, the fundamental interactions of the network can explain the formation of non-biological patterns.  Indeed, a nice example to introduce their model is during the formation of sand dunes. In this system, grains of sand are blown across a desert by the prevailing wind. Tiny random fluctuations in the system (such as a small rock making a bump) will cause sand grains from the wind to be deposited and soon a small mound will begin to form. This deposition of sand is the activator. Now as the wind continues to blow, this new mound will trap more sand and consequently will increase in size. This can be thought of as local self-activation. However, this increasing deposition of sand at the growing mound means that the number of sand grains remaining immediately downwind is vastly depleted. As a result, no sand is deposited in the area immediately behind the mound, generating a space until the next dune can form. This is the long-range inhibition in the system.

Reaction-diffusion systems are signal driven processes based on diffusing elements (e.g extracellular proteins, such as growth factors) that lead to a spatially patterned change in cell state usually resulting in altered gene expression. This arrangement of cell states then acts as a template or ‘prepattern’ from which anatomical structures are produced by inducing local cell aggregation, growth or survival (Fig. 1). However, importantly, these models are not the only type of mechanism that can produce pattern. A second class of model relies upon the ability of cells to self-organise directly, requiring no prepattern. In these systems periodic focal points of high cell density are created through chemotaxis, mechanical deformation of the environment, or cell-cell adhesion (Fig. 1). Although no prepattern is required, this type of pattern formation shares the same constraints as the first class of reaction-diffusion systems (local activation coupled with long range inhibition), but in these systems local cell clustering provides the activation whereas the inhibition results from depletion of cells around the emerging aggregates. Thus, these two classes of patterning mechanism are distinguished by the entity that moves to break symmetry – whether diffusible signals (reaction-diffusion) or cells (mesenchymal self-organisation).

The developing skin is a good model in which to study periodic pattern formation as it is structurally quite simple and readily produces easily appreciated repeating patterns. At embryonic day 13, mouse skin is composed simply of an epithelial sheet (epidermis) lying atop a loose mesenchyme (dermis). As far as we can tell no pre-programmed information relevant to defining hair follicle positions is in there at the start and so the tissue can be deemed symmetric at this stage. Yet, only a day later (either in vivo or in culture) the skin has partitioned itself into a dotted pattern of altered gene expression and cell aggregations that form the hair follicle primordia (Fig. 2). This model system allows us to investigate pattern formation in a tightly framed way as we do not need to worry about the (admittedly interesting) earlier problem of how the skin develops to that stage, nor the (also interesting) question of how the primordia go on to make fully functional hair follicles and the intervening space becomes mature skin. So how is the symmetry of the homogeneous tissue broken to give a repeating spatial pattern of cell clusters and divergent cell fates? More specifically, instead of concerning ourselves with determining how the pattern produces an exact density and size of spots, we wanted to understand how the tissue symmetry is broken to give a spatially ordered arrangement.

A more complete reaction-diffusion system

As several signalling pathways have been shown to be essential for early hair primordium formation, we were interested in the integration between them and whether this integration might constitute a pattern forming reaction-diffusion system. We restricted our consideration to molecules that are members of three major pathways (BMP, FGF and WNT) known to be involved in hair follicle development [4-6], and to those mRNAs that have short half-lives and so can undergo rapid regulation at the timescale of the primary hair pattern formation. We assessed the transcriptional regulatory interactions between these molecules to define the network of interactions between them. To test whether our experimentally derived network was capable of creating a periodic pattern we sought the expertise of Dr Vaclav Klika (Czech Technical University, Prague). Vaclav’s mathematical analysis showed that this multiple species reaction-diffusion system is capable of breaking symmetry to produce a periodic pattern. From this it is plausible that interactions between WNT, FGF and BMP pathways are sufficient to generate the hair follicle pattern.

More than signals alone

Because complete hair follicle development also requires the formation of dermal condensates that underlie each placode, we wanted to explore how these mesenchymal cells aggregate and how this is regulated by the pathways and molecules we identified in our gene regulatory network. To answer this question we enlisted the help of Dr Richard Mort (based at the University of Lancaster) to track dermal cell movement during condensate formation. Using live cell imaging we found that the mesenchymal cells that form the dermal condensate are those located in its immediate vicinity, suggesting that local cues arising during patterning guide the dermal cells. As it was likely that any such signals would come from the epidermis we examined the timing between the epidermal signal driven pattern and corresponding dermal cell rearrangement. By analysing the gene expression of early placode markers and comparing this with the cellular organisation we found the existence of a molecular prepattern in the epidermis that precedes condensate formation. Further investigation revealed that this prepattern provides a template of local FGF sources that attract dermal cells ultimately leading to condensate formation.

Making everything a hair follicle

Prior literature indicated that hair follicle primordia are distinguished by their high FGF and low BMP activity [5, 7]. We wondered what would happen if we imposed these conditions across the entire skin. Using a pharmacological inhibitor of BMP signalling and a recombinant FGF protein, we treated unpatterned skins to achieve this effect. The resulting pattern of the skins cultured in these conditions looked rather similar to control skins, based on dermal cell aggregation, but we found that expression of epidermal placode marker genes was absent in these skins (Fig. 3A). We realised that this condition had revealed a previously unrecognised developmental potential in the skin; that the dermis has the capability to pattern by itself without instruction from of an epidermal prepattern.

To analyse the formation of these mesenchyme-only patterns we enlisted the help of Dr Franziska Matthäus (FIAS in Frankfurt) who specializes in methods to analyse cell motility. Through particle image velocimetry (PIV) analysis we began to identify distinct differences, such as far greater cell movement and incorporation into condensates, between the mesenchyme-only and the unperturbed patterning processes.

Living on the edge

To work out whether the mesenchymal cell only patterns arise through a fundamentally different patterning system we used the fact that although the skin appears developmentally homogeneous, it is unavoidable that it has edges where dissected away from the embryo to put into culture. The behaviour of patterns at these tissue edges can be very informative when trying to distinguish the underlying mechanism of a pattern’s generation (Fig. 3B).

Patterning systems relying on active inhibitory signals will form a row of foci close to the edge as the inhibitor diffuses off the edge, thereby giving a competitive advantage to those cells at the perimeter. Conversely, in cell driven patterning systems the pattern will stay away from the edge as cell number becomes limiting for the nucleation of new cell aggregates, and at the edge there are simply fewer cells available to recruit. By inserting cuts into skins cultured in both control and in our conditions recreating the hair follicle primordium, we see that the mesenchymal only patterning is characteristic of a cell driven mechanism rather than a signal driven reaction-diffusion system as is observed for the control experiments. This suggested that these two systems rely on fundamentally different mechanisms.

We then searched for a molecular mechanism for mesenchyme-only patterning. We found that disruption of TGFβ signalling abolished mesenchyme-only patterning, but that these perturbations had only modest effects on normal patterning, which would fit the idea that these patterning processes occur through divergent mechanisms with a different reliance on TGFβ signalling. In addition, we found that local sources of TGFβ2 attract mouse dermal cells, revealing that TGFβ2 serves as a widely expressed attractant that draws mesenchymal cells together.

Finally, having determined that restricted TGFβ signalling was critical for mesenchyme-only patterning we wanted to determine its role in the interplay between normal and mesenchymal patterning mechanisms during hair development. We found that TGFβ2 treatment substantially enhances dermal cell attraction to FGF sources and that when TGFβ signalling is inhibited dermal cells migrate very poorly towards to local FGF sources. Thus, in normal development TGFβ signalling creates an environment conducive to cell recruitment to the local epidermal FGF sources. These sources, defined by the signal driven network as the prepattern, create restricted microenvironments that provide the conditions for mesenchyme-only patterning to occur such that a dermal condensate is formed. This demonstrates that fundamentally distinct patterning systems can operate together during embryonic organ formation, but in this case a hierarchy exists wherein one system guides the other.

Conclusions

Research into biological pattern formation has been enjoying a resurgence in recent years. Examples of Turing systems underpinning the formation of the limb digits [8], villi of the intestine [9] or the transition of colour spots on lizard skin [10] have been described. In addition to signal focused patterning mechanisms, during the weeks following the release of our work, two new papers [11, 12] have described cell processes driving chicken feather patterning and mouse hair follicle assembly, highlighting the ability of mesenchymal cells to self-organise. Studying the interplay between cell and signal driven processes during embryogenesis promises to be an exciting field of investigation in the future, which could provide fresh insight in the fundamental areas of developmental biology.

This work would not have been possible with the input of many collaborators. The mathematical guidance, simulations and models provided to us by Kevin Painter, Vaclav Klika and Franziska Matthäus has allowed us to confirm our preliminary laboratory findings and provide a more comprehensive answer to the initial question we asked. The imaging experiments and tools for cell tracking designed by Richard Mort enabled us to accurately follow dermal cells during hair follicle formation making it possible for us reject a hypothesis of pre-determined cell sorting, highlighting the utility of live cell imaging when studying developmental processes. Collaborations such as these, where scientists specialising in a range of different fields and from different locations work together on a single problem is the basis for outstanding research and I strongly encourage establishing similar relationships to help advance your own research.

This work was funded by the BBSRC and carried primarily in Dr Denis Headon’s group at The Roslin Institute near Edinburgh. You can discover the full story, findings and experiments in our paper:

Hierarchical patterning modes orchestrate hair follicle morphogenesis. J. D. Glover et al., PLOS Biology, 2017.15 (7):p.e2002117 http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2002117

James D. Glover

References

1. Turing, A.M., The Chemical Basis of Morphogenesis. Philosophical Transactions of the Royal Society of London Series B-Biological Sciences., 1952. 237(641): p. 37-72.
2. Gierer, A. and H. Meinhardt, A theory of biological pattern formation. Biological Cybernetics, 1972. 12(1): p. 30-39.
3. Glover, J.D., et al., Hierarchical patterning modes orchestrate hair follicle morphogenesis. PLoS Biol, 2017. 15(7): p. e2002117.
4. Mou, C., et al., Generation of the primary hair follicle pattern. Proc Natl Acad Sci U S A, 2006. 103(24): p. 9075-80.
5. Huh, S.H., et al., Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles. Genes Dev, 2013. 27(4): p. 450-8.
6. Andl, T., et al., WNT signals are required for the initiation of hair follicle development. Dev Cell, 2002. 2(5): p. 643-53.
7. Botchkarev, V.A., et al., Noggin is a mesenchymally derived stimulator of hair-follicle induction. Nat Cell Biol, 1999. 1(3): p. 158-64.
8. Raspopovic, J., et al., Modeling digits. Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients. Science, 2014. 345(6196): p. 566-70.
9. Walton, K.D., et al., Villification in the mouse: Bmp signals control intestinal villus patterning. Development, 2016. 143(3): p. 427-36.
10. Manukyan, L., et al., A living mesoscopic cellular automaton made of skin scales. Nature, 2017. 544(7649): p. 173-179.
11. Shyer, A.E., et al., Emergent cellular self-organization and mechanosensation initiate follicle pattern in the avian skin. Science, 2017. 357(6353): p. 811-815.
12. Lei, M., et al., Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells. Proceedings of the National Academy of Sciences, 2017. 114(34): p. E7101-E7110.

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It’s rare to see your working life captured in a music video.  This made me happy, I hope you enjoy it. Click the title above.

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SUMMARY

An exciting interdisciplinary opportunity has come up in the newly established Quantitative Cell Biology laboratory headed by Dr Silvia Santos. We are seeking a creative, highly motivated postdoc with a strong quantitative background, who enjoys working in a collaborative research environment, to investigate how cells decode signals and irreversibly commit to different cell fates.

The Francis Crick Institute is a biomedical discovery institute dedicated to understanding the fundamental biology underlying health and disease. Its work is helping to understand why disease develops and to translate discoveries into new ways to prevent, diagnose and treat illnesses such as cancer, heart disease, stroke, infections, and neurodegenerative diseases.

An independent organisation, its founding partners are the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King’s College London.

The Crick was formed in 2015, and in 2016 it moved into a brand new state-of-the-art building in central London which brings together 1500 scientists and support staff working collaboratively across disciplines, making it the biggest biomedical research facility under a single roof in Europe.

The Francis Crick Institute will be world-class with a strong national role. Its distinctive vision for excellence includes commitments to collaboration; to developing emerging talent and exporting it the rest of the UK; to public engagement; and to helping turn discoveries into treatments as quickly as possible to improve lives and strengthen the economy.

PROJECT SCOPE

The Quantitative Cell Biology laboratory focuses on understanding control principles in cell-decision making. Current areas of research include understanding the interplay between cell division and cellular differentiation during early development. In this context, we have been studying spatio-temporal control and remodelling in cell cycle regulation (Santos et al Cell 2012, Araujo et al Mol Cell 2016) and trying to understand commitment to differentiation, using embryonic stem cells as a model system (Santos et al Nature Cell Bio 2007). There is a strong focus on single cell analysis and combining experimental approaches (based on imaging, proteomics and genomics) and mathematical modelling. Informal inquiries can be sent to silvia.santos@crick.ac.uk

For more information see: https://www.crick.ac.uk/research/a-z-researchers/researchers-p-s/silvia-santos/.

If you are interested in applying for this role, please upload your CV, a cover letter stating your research background and interests and your motivation. Please include names and contacts of two referees.

The closing date for applications is Monday 30^th October 2017 at 23:30 pm.

Please note: all offers of employment are subject to successful security screening and continuous eligibility to work in the United Kingdom.

To apply please click https://goo.gl/AJLQps

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Getting the next generation of scientists excited about Biology is an important part of our jobs as researchers. To that end Karine Nedoncelle, Aurelien Doucet and I created PokeMod cards. Each card features a model organism and highlights some of its contribution to the field of biology. The cards are easy to deploy at your next outreach event or in the classroom. All you have to do is download them, and have them printed at your local or university’s print shop (we provide tiled front and back files in both A3 and A4).

A little Background

Model organisms have become indispensable tools in biological research and have enabled innumerable advances in our understanding of life. But while many people are versed in core concepts involving cells, DNA and genes (my mother can give a pretty good explanation of CRISPR!), they are sometimes un-aware that the majority of the research behind these concepts is attributed to a handful of unique, sometimes exotic, organisms. Occasionally, particularly ignorant politicians have attacked such research as frivolous! Clearly there is a need to familiarize the greater public with the existence of our beloved model systems. We made PokeMods as an introduction and tribute to some of these models. We hope that after interacting with the cards, someone will walk away with a greater appreciation for these organisms.

Learning Objectives

A basic objective is the awareness that biological research is carried out using a variety of interesting organisms. This objective can be built upon in the classroom to include knowing which models are good for which types of research.

Target Audience

These cards are intended for children (and adults!) aged 8+. Younger children can certainly enjoy the cards but may not benefit from the learning objectives above. We also hope to reach a secondary audience that includes the ecosystem around the children (parents, educators, etc.)

Suggested activities

There are lots of ways these cards can be distributed. During the 2016 fête de la science, an open house for the university, we ‘hid’ the cards at different exhibitions. For example the zebrafish card was found at a stall that was highlighting zebrafish research. When the students found all of the cards they got a prize, in our case a 3D printed DNA molecule. We also provided a flyer that displayed all the model organisms to find, connected by a phylogenetic tree (which we also include here in download package!). This aspect can be used with a more advanced audience to highlight the evolutionary relationship between the model organisms and the benefits to study them.

In a classroom the cards could be provided as a reward for correct responses or good behaviour. Then when students collect all of them they get a prize. A more advanced classroom activity could be to create a game by assigning biological problems to groups of students. They then ‘attack’ the problem using their model systems and explain why.

Have your own idea to share?? Let us know below in the comments below or send us a note! Study them all!

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In addition, the founder cells also show heterogeneous abilities to produce daughters that make digestive enzymes or cells that make hormones that regulate blood sugar.

This fundamental finding could also be true for other organs and could be exploited to select the most powerful “organ making cells” in vitro. Selecting such powerful cells assumes that the ability to generate large families is predetermined and that such cells can be identified by certain markers.

Investigating a battery of markers, Hjalte list Larsen, the primary investigator of the study, showed that one gene activity discriminates the cells that make small families composed only of hormone-making cells. Surprisingly, half of the organ-founder cells were of this type, although the hormonal cells form only 1% of the adult organ. ”We wondered why so many of these hormone-making cells were set aside so early. We think that it is important to make many of these cells early because they nurture their neighbors, enabling them to divide extensively.” says Anne Grapin-Botton.

In the video: The cells of the two embryonic pancreas buds (round) are marked in bright red while the lighter red shows their connection to the intestine. The two green cells in the pancreatic bud (top) are two daughters made by one mother cell.

This study also illustrates how powerful the collaboration between biologists and physicists can be. This was the aim of Grundforskningsfonden when they promoted the STEMPHYS project enabling these interactions. Ala Trusina and her team from the Niels Bohr Institute could indeed use computer modelling to reveal that many decisions observed are not predictable and are likely triggered by a communication signal released by some cells, with a probability that it reaches another cell. The ‘ball’ is back on the biologists’ side to find it, to realize the promise of producing organs or specific cells types for regenerative purposes in a petri dish!

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An exciting role has come up to be a part of a pioneering biomedical research institute, dedicated to innovation and science. Dr Frickel’s laboratory focuses on elucidating the immune mechanisms targeting the parasite Toxoplasma gondii, as well as deciphering pathways mediated by immune-activated large GTPases. Dr Frickel is seeking a talented and motivated postdoc to further develop this study in human stem cell-derived macrophages and dendritic cells, as a complement to studying these pathways in conventional macrophage cell lines.

Infection with the parasite Toxoplasma gondii causes the production of the cytokine gamma interferon (IFN) that in turn leads to the upregulation of a multitude of host defence pathways. Specifically, the lab is interested in ubiquitin-mediated pathogen control (Clough et al, 2016, PLoS Pathogens) and restriction of pathogens by guanylate binding proteins (Johnston et al, 2016, Cellular Microbiology). We are now looking to extend these findings to macrophages as these present the most relevant cell type for Toxoplasma and other infectious agents. We have generated iPSC-derived macrophages as a tool to study IFN-dependent host defence mechanisms. This project will examine how relevant ubiquitin-mediated pathways are to Toxoplasma control in these macrophages and/or how guanylate binding proteins mediate immune defences.

The Francis Crick Institute is a biomedical discovery institute dedicated to understanding the fundamental biology underlying health and disease. Its work is helping to understand why disease develops and to translate discoveries into new ways to prevent, diagnose and treat illnesses such as cancer, heart disease, stroke, infections, and neurodegenerative diseases.

An independent organisation, its founding partners are the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King’s College London.

The Crick was formed in 2015, and in 2016 it moved into a brand new state-of-the-art building in central London which brings together 1500 scientists and support staff working collaboratively across disciplines, making it the biggest biomedical research facility under a single roof in Europe.

The Francis Crick Institute will be world-class with a strong national role. Its distinctive vision for excellence includes commitments to collaboration; to developing emerging talent and exporting it the rest of the UK; to public engagement; and to helping turn discoveries into treatments as quickly as possible to improve lives and strengthen the economy.

The closing date for applications is Sunday 29^th October 2017 at 23:30.

To apply please click https://goo.gl/2Xg2Ku

Please note: all offers of employment are subject to successful security screening and continuous eligibility to work in the United Kingdom.

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Applications are invited for a Research Assistant/Associate within the Division of Infection & Immunity at UCL in Dr Gillian Tomlinson’s laboratory.

We are seeking a highly motivated individual interested in integrating cutting-edge human and zebrafish models to study the immunopathogenesis of tuberculosis. The post is funded by a Medical Research Council Clinician Scientist Fellowship entitled “Tuning the immune response in tuberculosis”, and combines a human experimental tuberculosis challenge model with studies using Mycobacterium marinum infection of zebrafish to identify and validate host factors that calibrate a favourable immune response in tuberculosis.

The post-holder will be supervised by Dr Gillian Tomlinson based in the Cruciform Building at UCL. Dr Tomlinson works closely with Dr Mahdad Noursadeghi’s and Professor Benny Chain’s group’s which study host immune responses to infectious diseases at genome‑wide level with a particular focus on tuberculosis (www.innate2adaptive.com). The zebrafish work will be supported by the fully managed world class research aquarium at UCL.

The post is available until 1^st March 2020, subject to satisfactory probationary and annual appraisals. There is an established track record for department post-doctoral staff gaining personal fellowships. Independently minded and talented investigators will be encouraged and supported in seeking such fellowship support.

Key requirements

Applicants must have an MSc (or equivalent degree) and/or a PhD (or equivalent degree) in a relevant subject.

Candidates must be competent in molecular and cellular biology techniques including RNA and DNA extraction, qPCR, PCR, cloning and tissue culture.

To apply please use this link:

https://atsv7.wcn.co.uk/search_engine/jobs.cgi?owner=5041178&ownertype=fair&jcode=1673802

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I recently participated in “Skype a Scientist” – a program self-described as one that “matches scientists with classrooms” and “give(s) students the opportunity to get to know a ‘real scientist’”. Pretty accurate. Basically, if a scientist signs up, she will be matched with a k-12 classroom somewhere around the world. After some coordination with the classroom teacher, she will get the chance to describe her work to a group of eager youngsters in about half an hour to an hour. Needless to say, it is an opportunity worth exploring.

For those of us unsettled by science’s recently more pronounced credibility crisis, marked by uninformed, hence unhealthy skepticism, we can take comfort in the fact that this program is exactly what is needed to (1) spread the word – that science is interesting, thorough and important, and (2) pique the next generation’s interest in science. The underlying importance of this initiative aside, there are some incredibly gratifying reasons to participate.

First, you get to figure out how to explain your work to kids and why you are doing it – which is not easy. This is the stuff of grant-writing ! I work on understanding growth dynamics in developing fruit fly egg chambers, and when I presented to third graders, I was asked questions such as what can we learn from the fruit fly that would help us humans? Try answering that without using the word ‘conserved’. It is no secret that scientist often find it challenging to explain their work to others outside their field, and there is hardly a better exercise in distilling one’s work to the absolute basics than “Skype a Scientist”.  Second, you get to inform kids and get them excited about novel and potentially game changing work, and perhaps even to express a desire to pursue a career in science. I often think of scientists as individuals who wander through the world and ask questions about their environment – the whys and the hows. In that sense, kids are already scientists: indeed, there is a hardly a group of individuals more curious about their surroundings, and if we can find ways to nourish and support their interests, then we are doing each other and the pursuit of science a great favor.

So if you find half an hour to spare, please do participate !

Jasmin Imran Alsous

Chemical & Biological Engineering

Princeton University

(7 votes)

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