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By Hannah Long 

From the almost identical faces of monozygotic twins, we can appreciate that facial appearance is encoded for the most-part in the DNA of our genomes. Therefore, changes to this DNA sequence can contribute to the variation in facial appearance seen between humans, and at the more extreme end of the spectrum can cause human disease. Consequently, improving our understanding of how genetic sequence encodes for our physical traits remains an exciting and important question in developmental biology.

Interestingly, many of the genetic changes that contribute to facial variation or dysmorphology in disease occur in the non-gene encoding parts of the genome. And this raises the question how non-coding DNA mutations can impact development and drive morphological change. To answer this question, in the Wysocka lab we study facial progenitor cells called the cranial neural crest which give rise to the majority of the facial structures, and investigate how genetic changes can drive alterations in physical traits.

At the beginning of our recent study, published last year in Cell Stem Cell, we set out to determine the molecular mechanisms that cause a human craniofacial disorder, called Pierre Robin sequence (PRS) [1]. In this disorder, under-development of the lower jaw (micrognathia) leads in sequence to posterior displacement of the tongue, and in some cases cleft palate [2, 3] (Figure 1). Several labs had previously utilised genomic methods to identify a number of large deletions and chromosomal translocations in PRS patients that cluster in a gene desert region far upstream of the SOX9 gene .

SOX9 is an important DNA-binding transcription factor that plays crucial roles in the differentiation of numerous cells types, and is expressed broadly during development including in chondrocytes, testis, pancreas, heart valve, lung, kidney, liver, hair follicle stem cells, and progenitors of the face (cranial neural crest) [8]. In keeping with its broad roles during development, heterozygous loss-of-function mutations in the SOX9 gene cause a devastating multisystemic syndrome called campomelic dysplasia. Patients typically exhibit skeletal abnormalities including bowing of the long bones, disorders of sex determination and facial dysmorphism, and occasionally have additional malformations of the heart, lung, kidney and pancreas suggesting differential sensitivity to SOX9 gene dosage (Figure 1). Importantly, selective knockout of Sox9 in mouse facial progenitors results in developmental defects of the facial skeleton [1, 9] emphasizing the importance of Sox9 in the development of the face. Given the non-coding nature of the mutations in PRS patients, it had been suggested that gene regulatory elements called enhancers may be perturbed [4–7]. However, it remained to be functionally demonstrated how these mutations impacted genome function, and whether SOX9 was the target gene to cause this disorder.

Enhancers are non-coding DNA sequences elements that can act across large genomic distances to regulate gene expression in a cell-type specific manner. And key developmental genes are often associated with complex regulatory landscapes with many such context-dependent enhancers [10]. Therefore, unlike mutations in coding sequences which will alter gene function in all cell-types in which that gene is expressed, mutations in enhancers will have a more developmental stage and cell-type specific impact leading to tissue-restricted phenotypic consequences.

Studying human facial development presents a challenge, as formation of the face occurs early during gestation. However, leveraging a robust in vitro differentiation model of cranial neural crest cells (CNCCs) developed in the lab we have been able to model human craniofacial disorders in culture [11–13]. Utilising this model, and genomic enhancer profiling, we identified three clusters of enhancer elements overlapping the human PRS mutation region. We rationalised that these elements may regulate SOX9 expression during development, and that their loss could cause mis-regulation of SOX9 in the neural crest with detrimental consequences for facial development. Indeed, using CRISPR/Cas9 genome editing we demonstrated that SOX9 expression is specifically perturbated by PRS mutations in the neural crest (and not during cartilage formation when SOX9 is also expressed), defining a developmental window for disease causation in this disorder (Figure 2).

To further understand the morphological impacts of enhancer ablation, we set out to generate mouse models to investigate Pierre Robin sequence disease mechanisms. However, we soon appreciated the challenges associated with modelling human genetic disorders of the non-coding genome in mouse. Unlike genic regions, which make up 1-2% of the genome and are deeply conserved, the remainder of the genome is highly divergent between human and mouse. Indeed across mammalian species, enhancers can vary greatly in their location, sequence composition and activity [14]. Therefore, while one of the PRS-associated enhancer clusters (named EC1.45) was at least partially conserved in activity during mouse facial development, the second enhancer cluster (EC1.25) was not, limiting our further morphological investigation of PRS mutations to EC1.45 alone. Given that directly addressing the functional impact of specific human non-coding mutations in model organisms poses a huge challenge due to a limited sequence conservation of the non-coding genome, future studies exploring the genotype to phenotype connection in human development and disease will greatly benefit from improved models of human development, including advances in organoid models.

Despite the limitations, our models of Sox9 perturbation in mouse led to a number of intriguing observations. Firstly, we determined that lower jaw development is highly sensitized to reduction in Sox9 gene expression compared to the rest of the skull. Therefore, despite the PRS enhancers being widely active across the developing face, this regional sensitivity in the lower jaw to Sox9 gene dosage may drive the phenotypic specificity seen in patients (Figure 3). Secondly, we observed that even small changes in Sox9 expression during development lead to alterations in lower jaw morphology, demonstrating how subtle changes in enhancer activity may drive morphological change and fitness between members of the same species and across evolutionary timescales.

Together, our study uncovers the workings of a complex regulatory domain that controls SOX9 expression during a narrow window of facial development. We further explore the sequence motifs and trans-regulatory factors that regulate enhancer function at the PRS locus, and the conservation of enhancer activity across vertebrate and recent hominin evolution – and we invite you to see our paper for more details. Importantly, the enhancer clusters we characterised at the PRS locus represent the longest-range human enhancers involved in congenital malformations described to date and their deletion in mouse illustrates how small changes in gene expression can lead to morphological variation.

Combined, our work provides a clear illustration and mechanistic details how large deletions and translocations in the non-coding genome can cause human congenital disease. This joins a number of recent studies that have explored how genetic aberrations such as inversions, duplications and topological domain boundary perturbations can either displace enhancers away from their target gene, or can lead to de novo enhancer co-option and ectopic gene expression [15–17].

Looking forward, it is exciting to speculate how such long-range gene regulatory elements (at up to 1.45 megabases away) such as those at the PRS locus find their target gene. From our study, we speculate that perhaps a third element at the PRS locus may play a structural role to bridge these long genomic distances. The developmental importance of this genetic feature, and whether this is a generalisable feature of long-range regulation will be an exciting avenue for future research.

References

1. Long HK, Osterwalder M, Welsh IC, et al (2020) Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder. Cell Stem Cell 27:765-783.e14. doi: 10.1016/j.stem.2020.09.001
2. Robin P (1994) A fall of the base of the tongue considered as a new cause of nasopharyngeal respiratory impairment: Pierre Robin sequence, a translation. 1923. Plast Reconstr Surg 93:1301–1303.
3. Tan TY, Kilpatrick N, Farlie PG (2013) Developmental and genetic perspectives on pierre robin sequence. Am J Med Genet Part C Semin Med Genet 163:295–305. doi: 10.1002/ajmg.c.31374
4. Benko S, Fantes J a, Amiel J, et al (2009) Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence. Nat Genet 41:359–364. doi: 10.1038/ng.329
5. Amarillo IE, Dipple KM, Quintero-Rivera F (2013) Familial Microdeletion of 17q24.3 Upstream of SOX9 Is Associated With Isolated Pierre Robin Sequence Due to Position Effect. Am J Med Genet Part A 161:1167–1172. doi: 10.1002/ajmg.a.35847
6. Gordon CT, Attanasio C, Bhatia S, et al (2014) Identification of Novel Craniofacial Regulatory Domains Located far Upstream of SOX9 and Disrupted in Pierre Robin Sequence. Hum Mutat 35:1011–1020. doi: 10.1002/humu.22606
7. Gordon CT, Tan TY, Benko S, et al (2009) Long-range regulation at the SOX9 locus in development and disease. J Med Genet 46:649–56. doi: 10.1136/jmg.2009.068361
8. Symon A, Harley V (2017) SOX9: A genomic view of tissue specific expression and action. Int J Biochem Cell Biol 87:18–22. doi: 10.1016/j.biocel.2017.03.005
9. Mori-Akiyama Y, Akiyama H, Rowitch DH, de Crombrugghe B (2003) Sox9 is required for determination of the chondrogenic cell lineage in the cranial neural crest. Proc Natl Acad Sci 100:9360–9365. doi: 10.1073/pnas.1631288100
10. Long HK, Prescott SL, Wysocka J (2016) Ever-Changing Landscapes: Transcriptional Enhancers in Development and Evolution. Cell 167:1170–1187. doi: 10.1016/j.cell.2016.09.018
11. Bajpai R, Chen D a, Rada-Iglesias A, et al (2010) CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature 463:958–962. doi: 10.1038/nature08733
12. Calo E, Gu B, Bowen ME, et al (2018) Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders. Nature 554:112–117. doi: 10.1038/nature25449
13. Greenberg RS, Long HK, Swigut T, Wysocka J (2019) Single Amino Acid Change Underlies Distinct Roles of H2A.Z Subtypes in Human Syndrome. Cell 178:1421-1436.e24. doi: 10.1016/j.cell.2019.08.002
14. Villar D, Berthelot C, Aldridge S, et al (2015) Enhancer Evolution across 20 Mammalian Species. Cell 160:554–566. doi: 10.1016/j.cell.2015.01.006
15. Laugsch M, Bartusel M, Rehimi R, et al (2019) Modeling the Pathological Long-Range Regulatory Effects of Human Structural Variation with Patient-Specific hiPSCs. Cell Stem Cell 24:736-752.e12. doi: 10.1016/j.stem.2019.03.004
16. Lupiáñez DG, Kraft K, Heinrich V, et al (2015) Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell. doi: 10.1016/j.cell.2015.04.004
17. Franke M, Ibrahim DM, Andrey G, et al (2016) Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature 538:265–269. doi: 10.1038/nature19800

(2 votes)

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The second in our new series of SciArt profiles features Justine Renno, a Master’s student in Bordeaux.

Where are you originally from, where do you work now, and what do you work on?

I am originally from Alsace in France. I got a Master’s in developmental biology which I ended with a 6 months internship at EMBL in Heidelberg. This successful internship and the interesting Masters courses led me to pursue a Ph.D. at the Institute of Science and Technology in Austria at IST Austria.

Unfortunately this Ph.D. had to end prematurely due to emergency brain surgery I had to undergo in the third year. but at the same time as doing my Ph.D., IST Austria had given me the opportunity to discover the exciting field of science communication. The experiences I took part in made me realize that this was the job I wanted to do, and therefore I decided to enrol in another program to get the set of skills needed in science communication.

I am currently in the process of getting a Master’s degree from the University of Bordeaux Montaigne in France. Because I want to help to bridge the gap between research and innovation, I’ll do a 6 months internship at the scientific research and innovation board of Loreal. 

Were you always going to be a scientist?

Science was my first love. From very early on I was fascinated by the biological processes which govern life. I couldn’t imagine myself feeling as happy and useful in any other discipline. So I hesitated for a long time before commuting from academia to science communication but this change has been really positive so far and allows me to keep updated with scientific discoveries in various fields. It is very rewarding. 

And what about art?

I started drawing at a very young age, mainly drawing my favourite animals, especially horses and dogs. In recent years I started making illustrations for the new papers of my fellow colleagues. I really enjoy conveying scientific discoveries through art. Asking questions and listening to the scientists somehow triggers my artistic imagination in a way that I always end up having tons of illustration ideas.

“I really enjoy conveying scientific discoveries through art”

What or who are your artistic influences?

I love surrealism, and artists such as Salvador Dali, Yves Tanguy, René Magritte and Frida Kahlo.

How do you make your art? How do you approach making a new piece of art?

I used to start with a simple pencil and paper but after a few years of experience with numerical drawing, I directly started drawing on my tablet or my laptop with the touchpad. I start with a broad idea, a drafty sketch, which I turn very dim in the background. I draw a more realistic vision on top of it with larger and darker brushes, making use of many layers on top of each other to go more in detail. 

Does your art influence your science at all, or are they separate worlds?

Science certainly influences my art. I love to make illustrations of beautiful data, something catchy which attracts the reader’s attention. Nature is so perfect and beautiful, it’s a never-ending source of inspiration. 

We’re looking for new people to feature in this series throughout the year – whatever kind of art you do, from sculpture to embroidery to music to drawing, if you want to share it with the community just email thenode@biologists.com (nominations are also welcome!).

(8 votes)

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Our group is seeking a highly motivated candidate strongly interested in interdisciplinary science, to join the Guignard lab and work on a project at the crossroad between Computer Science and Developmental Biology as a Postdoc fellow.

Deadline: Until filled

Link to the poster

Link to the offer

Apply directly by email to leo.guignard+lab[at]gmail.com

Automatic reconstruction of Drosophila average embryonic development at the single-cell scale

The role

We are seeking a highly motivated candidate, strongly interested in interdisciplinary science, to join our group and work on a project at the crossroads between Computer Science and Developmental Biology.

The project aims at developing computational methods and models to better understand how robustness to biological noise is achieved during the development of Drosophila embryos. This will be done by first quantifying and characterising Drosophila embryogenesis variability at the single cell scale.

The successful candidate will be tasked to build statistical representations of the morphogenesis of Drosophila embryos at the single cell scale by combining image analysis, big-data science and data visualisation. To this end, the candidate will first develop novel image and big-data analysis algorithms. These algorithms will be first applied to 3D movies of Drosophila embryos acquired with state-of-the-art light-sheet fluorescence microscopes. The successful candidate will then develop novel algorithms to combine the set of recorded embryos together to build a single-cell scale, in-toto, atlas of Drosophila embryogenesis.

Depending on the advancement of the project and the candidate preferences, the second part of the project will then focus around either integrating complementary single-cell omic data to the atlas or developing machine-learning based methods to analyse, detect and classify cell patterns in the developing embryo.

Keywords

Computer Science, Image Analysis, Big-data, Developmental Biology, Drosophila Embryogenesis

Who would we like to hire?

Required experience

The candidate must have at least one of the following expertises:

• Computer Science: Image Analysis, Graph Theory, Data Science
• Developmental Biology (sole experience in Developmental Biology requires to be able to show good coding skills)

Education and training

You hold a master degree in Bioinformatics, Computer Science, Developmental Biology (with good computational skills) or equivalent

Competences

• You are eager to learn
• You are creative
• You have good communication skills
• You want to work as part of a collaborative team

Languages

You have French or English fluency (at least B2 on the CEFR)

The Offer

• Contract duration: 2-year position, extension possible
• Target start date: from July 2021
• The salary will be based on Aix-Marseille University’s salary scale, depending on the candidate’s profile and experience

Application Procedure

All applications must include:

1. A motivation letter addressed to Léo Guignard.
2. A complete CV including contact details.
3. Contact details of at least two referees.

All applications must be sent to Léo Guignard by email with the mention [Job-2021] in the subject at the address leo.guignard+lab[at]gmail.com.

Selection Process

Pre-selection: The pre-selection process will be based on qualifications and expertise reflected in the candidates CV and motivation letter. It will be merit-based. All candidates will be informed whether they have been pre-selected or not.

Interview: Pre-selected candidates will be contacted to coordinate a set of interviews with a set of selected members of CENTURI (including Léo) and a seminar. The interview will include a computational skill test (no specific coding language is required).

Relevant publications

• Guignard L.*, Fiuza U.-M.*, et al., Contact area-dependent cell communication and the morphological invariance of ascidian embryogenesis, Science, 369(6500):eaar5663, (2020)
• McDole K.†, Guignard L.†, et al., In Toto Imaging and Reconstruction of Post-Implantation Mouse Development at the Single-Cell Level, Cell, 175(3):859-876, (2018)
• Amat F., et al., Fast, accurate reconstruction of cell lineages from large-scale fluorescence microscopy data, Nature Methods 11, 951 (2014)

About the team

We are a group of computer scientists with a strong interest in biology in general and more specifically in embryonic development. We develop novel computational methods and models that allow the analysis of very large 3D movies of animal embryonic development (up to 2TB per movie). We work closely with biologists to tailor our methods so that they help to address fundamental biological questions.

The developmental biology question that mainly animates us is to better understand the mechanisms driving the reproducibility of embryogenesis.

For further information about the lab you can visit our website guignardlab.com, our twitter @guignardlab or contact directly Léo Guignard via email: leo.guignard+lab[at]gmail.com

The Institute

The Turing Centre for Living Systems (CENTURI) is an interdisciplinary project located in Marseille (France).

CENTURI aims at developing an integrated interdisciplinary community, to decipher the complexity of biological systems through the understanding of how biological function emerges from the organization and dynamics of living systems.

The project federates 15 teaching and research institutes in biology, physics, mathematics, computer science, engineering and focuses on Research, Education and Engineering, 3 missions that hold interdisciplinary as their core principle.

The research and training programmes implemented under the auspices of CENTURI will foster new collaborations, transform practices, attract new talents and thereby contribute to making the Luminy campus a leading site for the ​​interdisciplinary study of biological systems.

(1 votes)

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Our group is seeking a highly motivated candidate strongly interested in interdisciplinary science, to join the Guignard lab and work on a project at the crossroad between Computer Science and Developmental Biology as a Ph.D student.

Deadline: Until filled

Link to the poster

Link to the offer

Apply directly by email to leo.guignard+lab[at]gmail.com

Automatic reconstruction of Drosophila average embryonic development at the single-cell scale

The role

We are seeking a highly motivated candidate, strongly interested in interdisciplinary science, to join our group and work on a project at the crossroads between Computer Science and Developmental Biology.

The project aims at developing computational methods and models to better understand how robustness to biological noise is achieved during the development of Drosophila embryos. This will be done by first quantifying and characterising Drosophila embryogenesis variability at the single cell scale.

The successful candidate will be tasked to build statistical representations of the morphogenesis of Drosophila embryos at the single cell scale by combining image analysis, big-data science and data visualisation. To this end, the candidate will first develop novel image and big-data analysis algorithms. These algorithms will be first applied to 3D movies of Drosophila embryos acquired with state-of-the-art light-sheet fluorescence microscopes. The successful candidate will then develop novel algorithms to combine the set of recorded embryos together to build a single-cell scale, in-toto, atlas of Drosophila embryogenesis.

Depending on the advancement of the project and the candidate preferences, the second part of the project will then focus around either integrating complementary single-cell omic data to the atlas or developing machine-learning based methods to analyse, detect and classify cell patterns in the developing embryo.

Keywords

Computer Science, Image Analysis, Big-data, Developmental Biology, Drosophila Embryogenesis

Who would we like to hire?

Required experience

The candidate must have at least one of the following expertises:

• Computer Science: Image Analysis, Graph Theory, Data Science
• Developmental Biology (sole experience in Developmental Biology requires to be able to show good coding skills)

Education and training

You hold a master degree in Bioinformatics, Computer Science, Developmental Biology (with good computational skills) or equivalent

Competences

• You are eager to learn
• You are creative
• You have good communication skills
• You want to work as part of a collaborative team

Languages

You have French or English fluency (at least B2 on the CEFR)

The Offer

• Contract duration: 3-year position, extension possible
• Target start date: from July 2021
• The salary will be based on Aix-Marseille University’s salary scale, depending on the candidate’s profile and experience

Application Procedure

All applications must include:

1. A motivation letter addressed to Léo Guignard.
2. A complete CV including contact details.
3. Contact details of at least one (for Ph.D. candidates) or two (for postdoc candidates) referee(s).

All applications must be sent to Léo Guignard by email with the mention [Job-2021] in the subject at the address leo.guignard+lab[at]gmail.com.

Selection Process

Pre-selection: The pre-selection process will be based on qualifications and expertise reflected in the candidates CV and motivation letter. It will be merit-based. All candidates will be informed whether they have been pre-selected or not.

Interview: Pre-selected candidates will be contacted to coordinate a set of interviews with a set of selected members of CENTURI (including Léo) and a seminar. The interview will include a computational skill test (no specific coding language is required).

Relevant publications

• Guignard L.*, Fiuza U.-M.*, et al., Contact area-dependent cell communication and the morphological invariance of ascidian embryogenesis, Science, 369(6500):eaar5663, (2020)
• McDole K.†, Guignard L.†, et al., In Toto Imaging and Reconstruction of Post-Implantation Mouse Development at the Single-Cell Level, Cell, 175(3):859-876, (2018)
• Amat F., et al., Fast, accurate reconstruction of cell lineages from large-scale fluorescence microscopy data, Nature Methods 11, 951 (2014)

About the team

We are a group of computer scientists with a strong interest in biology in general and more specifically in embryonic development. We develop novel computational methods and models that allow the analysis of very large 3D movies of animal embryonic development (up to 2TB per movie). We work closely with biologists to tailor our methods so that they help to address fundamental biological questions.

The developmental biology question that mainly animates us is to better understand the mechanisms driving the reproducibility of embryogenesis.

For further information about the lab you can visit our website guignardlab.com, our twitter @guignardlab or contact directly Léo Guignard via email: leo.guignard+lab[at]gmail.com

The Institute

The Turing Centre for Living Systems (CENTURI) is an interdisciplinary project located in Marseille (France).

CENTURI aims at developing an integrated interdisciplinary community, to decipher the complexity of biological systems through the understanding of how biological function emerges from the organization and dynamics of living systems.

The project federates 15 teaching and research institutes in biology, physics, mathematics, computer science, engineering and focuses on Research, Education and Engineering, 3 missions that hold interdisciplinary as their core principle.

The research and training programmes implemented under the auspices of CENTURI will foster new collaborations, transform practices, attract new talents and thereby contribute to making the Luminy campus a leading site for the ​​interdisciplinary study of biological systems.

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We’ll soon be launching a newly designed Node homepage to help make our historical content easier to find and improve navigation through the various parts of the site. To accompany this change we’re going to refresh our header image – that’s the letterbox-shaped image you see above the menu bar. Currently we circulate between these four images:

…and now we need four more. And where better to source beautiful developmental biology than the community?

So, do you have a developmental biology image that would be a good replacement? Winning images will be seen by thousands of readers a month from all over the world (better, surely, than languishing unseen in a folder within a folder on your desktop!).

Competition details

• The image must be croppable to 1140×190 pixels (that’s 6:1), or be submitted at those dimensions.

• The higher quality the better – if cropping leads to pixellation, we won’t pick it
• Subject can be anything related to developmental biology – any organism, any system, any imaging platform.
• As you see above, the image could be a striking image, a close up of an embryo, or a repeated pattern
• If there is a background to your image, please make it black
• Colour blind friendly images are preferable
• Feel free to send more than one entry
• Please send your entry to thenode@biologists.com
• Winning entries will be chosen by the Node & Development team
• Please enter by Monday 1 February

We look forward to seeing your beautiful #devbio

(1 votes)

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During their journey from zygote to adult, embryos experience several symmetry breaking processes. Structures which are not isotropic (equal in all directions) are formed, creating the inside-out axis, forward-backwards axis, etc. Each of these patterns increases the information required to describe a multicellular system. As Maynard Smith put it: sometimes the “extra” information is stamped by maternal cues (gradients) and other times it emerges from self-organized processes. Decades of research have accrued a lot evidence for self-organized processes in development, from the theoretical to the experimental. More recently, synthetic biology has provided an avenue for enquiry by allowing us to create in vivo and de novo patterning mechanisms.

In our recent publication we take an engineering approach by inducing a symmetry breaking process in growing bacterial colonies. Without external factors like lack of nutrients or chemoattractants, E. coli colonies develop with remarkable symmetry into circular shapes. Their propagation front is isotropic and homogenizing diffusion is the leading morphogenetic drive, erasing any patterns in cellular density.

We induced pattern formation using four synthetic genes relating to adhesion, signaling and growth inhibition. These would make cells stop dividing and attach to one another, but only once a certain local cellular density threshold had been surpassed. With this we hoped that differences in cell density would be amplified with short range activation and long range inhibition, and that the patterns in space would be preserved from diffusion through adhesion.

When we put these elements together in growing colonies, we observe a remarkable symmetry breaking process. Colonies now develop into flower-like shapes with “petals” forming at a characteristic scale (constant wavelength). Regions with increased cell density inhibit the growth of neighboring cells and delay front propagation. This emergent pattern is not found in any other possible combination of our synthetic genes.

We believe these is just a first step into developing an engineering research program of artificial developmental processes. Using mechanical processes inherent to cellular embodiment allows us to make robust patterns that emerge from many interacting agents. Hopefully, armed with bioengineering tools we will gain a better grasp on the sometimes counter intuitive emergent interactions that create order in real developing embryos.

(5 votes)

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We are looking for two postdoctoral researchers (3 or 5 years) to work in Roberto Mayor laboratory at University College London, UK.

The scope of the positions is quite open and the project will be agreed with the candidate according to background and research interests. The general aims of the project is to study the interplay of mechanicaland chemical cues on cell migration and differentiation in vivo, using zebrafish and Xenopus embryos and cells cultured in vitro.

Project will involve tools to:

• measure and modify mechanic properties of tissues in the embryo and ex vivo, such as AFM nanoindentation, optogenetics, traction force microscope (Nature. 2018, 554, 523; Science. 2018, 362, 339; Nat Commun. 2020, 11, 472; Dev Cell. 2018, 45, 565)
• Analyse cell migration and differentiation in vivo such as 4D live imagining, transgenesis (J Cell Bol.204, 206, 113)
• Study cell shape, migration and differentiation in vitro using micropatterning (Dev Cell. 2015, 34, 421)
• Simulate cell behaviour using computational modelling (PLoS Comput Biol. 2019, 15, e1007002)
• Characterize cell differentiation using scRNAseq

The selected candidate will join an interdisciplinary group with possibility of multiple collaborations in a stimulating and high quality international scientific environment. Salary will be determined upon experience and scientific background. There is flexibility in the start date of the position. Candidates interested could contact Roberto Mayor (r.mayor@ucl.ac.uk) for more details.

(1 votes)

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In December, The Company of Biologists hosted its first virtual workshop on Cell State Transitions: Approaches, Experimental Systems and Models. Ten early-career researchers were given the opportunity to participate along with several invited senior scientists. Instead of meeting in-person at the Wiston House, we used the Remo platform to convene online, utilizing a virtual stage for presentations and individual tables to facilitate smaller discussions. The variety of model systems represented, from cell culture to organoids to embryos, was only rivaled by the areas of expertise of the speakers, which included mathematicians, physicists, and cell biologists. Some key themes of discussion included defining cell identity and heterogeneity, autonomous and non-autonomous regulation of cell behavior, as well as advancements and limitations of current technologies. As some of the early-career researchers invited to participate, we each provide our perspectives on this incredible workshop below and collectively express our gratitude to the workshop organizers, Kevin Chalut and Austin Smith, as well as the Company of Biologists, for this experience.

Taylor Medwig-Kinney

PhD student, Stony Brook University, USA

This workshop could not have come at a better time for me, as my research has recently become more focused on cell fate acquisition and maintenance. I feel very fortunate to have been selected to participate alongside this impressive cohort of junior and senior scientists. From the very start of the workshop, we began collectively thinking about difficult, perhaps philosophical, questions related to our field, including “how does one define a cell state?”. Each presentation spawned inspiration, including different tools and analyses to utilize and new experimental questions and approaches to explore. At the conclusion of each day I was excited to return to the laboratory to apply what I had learned. Finally, the workshop ended with lively themed discussions surrounding open questions in our field. The result of these, as Sally Lowell put, is that “we still don’t really understand cell state transitions, but we now understand more about why we don’t understand them.”

In addition to the content of the workshop, I really enjoyed the format. Unlike most conferences, where junior scientists can feel like small fish in a large pond, early-career researchers like myself made up about a third of the group and were given priority to encourage our active participation. In fact, the topics of the themed discussions at the conclusion of the workshop were decided based on our suggestions. Additionally, there were plenty of opportunities for intimate discussions during breaks and “meet the speakers” sessions. I had the opportunity to have one-on-one chats with several brilliant scientists from across the world from the comfort of my own home. While I certainly can appreciate the benefits of in-person meetings, the virtual format was convenient for me personally as the mother of a young child. Thus, I hope that, even post-COVID, organizers of conferences and workshops will consider the benefit of a virtual option for parents and caretakers.

Merrit Romeike

PhD student, Max Perutz Labs, Austria

When the application deadline arrived in spring of 2020, I never imagined how this year would play out. I was still naively optimistic, that by fall we would be “back to normal”. However, it quickly became clear that a pandemic lasts longer than just a couple of weeks and that the workshop could not take place in the original in-person format. There was the perspective to postpone it for two years, but especially as an early career researcher this was only little comfort. Therefore, I was happy that the workshop was moved to a virtual format at the end of a turbulent year. I do not think that a virtual setting can fully replace face-to-face interactions and especially informal conversations, but the way this workshop was organized was the best proxy I have experienced so far. 

Even though the workshop was called “Cell State Transitions”, one fundamental question came up repeatedly and was even one focus during the themed discussions at the end of the workshop: How do we define a cell state? And, maybe even more important: How can such a definition not be just semantics, but aid our understanding of biology in development and disease?

It is clear that the last years have seen fantastic advances in single cell methods, which have changed the traditional concept of cell state based on characteristics like function or morphology to the consideration of multiple modalities. However, my biggest take away message from this workshop is the need to place this single cell knowledge back into the broader perspective: To understand dynamic cell fate transitions, we have to consider the spatial and temporal context of each cell. Can there be the same cell state in different contexts? Can we distinguish cell autonomous from non-autonomous effects? How can we integrate our generated knowledge across experimental scales? 

These questions will surely drive the field for several years to come, and I am grateful for the opportunity to be part of the discussion.

Ani Amar

Postdoctoral research fellow, Bar-Ilan University, Israel

As an early-career researcher, I was excited to be offered a place at this great workshop. For me, it was the first opportunity to present my recent unpublished research, which was one of the bright sides of 2020. Looking at the smiling face of my 3-month-old baby, I can say that last year I took “cell state transitions” research one step ahead ?. 

I have always dreamed of visiting the south coast of England. Picturesque villages, greenery and sweeping valleys, and iconic landscapes – I didn’t get to see them this time. What I got was a chance to meet a group of exceptional senior and early-career scientists in a fruitful and mutually advantageous virtual environment, which encouraged them to share their distinct experiences and provide honest feedback to each other. The format of the pre-recorded presentations allowed me to reconsider each slide in order to make it more relevant, concise, and tailored for the audience. 

While I looked forward to hearing the talks on stem cell decision-making, which is one of my research interests, it was exciting to see how other computational scientists like me present their research. I really enjoyed the research topics that, to some extent, were new to me, for instance inspiring synthetic biology approaches for reconstituting developmental mechanisms, as presented by Miki Ebisuya. On the other hand, I learned a lot of new aspects of mechanical signaling in controlling cell fate choice from a highly interesting talk by Kevin Chalut, who described a computational approach to explain the spatial segregation of embryonic cell lineages. Lastly, I was more than glad to hear about the new experimental model of signal transduction pathways responsible for cell fate decisions during gastrulation in human ES cells, presented by Aryeh Warmflash. These pathways are very well conserved and operative in mouse, and can hence be used for the construction of genetic regulatory networks and further in silico analyses in my current project. 

I truly believe that the combination of experimental knowledge and computational models can provide important clues about the dynamics of cell state transitions or can reveal missing regulatory interactions that control them. Using gaps between sessions, I raised this discussion with experimentalists, encouraging them to consider multidisciplinary partnerships. This workshop was a real opportunity to broaden my network of scientific collaborators. I would like to express my sincere thanks to the organisers, Austin Smith and Kevin Chalut.

(8 votes)

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PhD student position in neurobiology at Stockholm University at the Department of Molecular Biosciences, The Wenner-Gren Institute. 

Research at the Department of Molecular Biosciences, The Wenner-Gren Institute (MBW) experimentally addresses fundamental problems in molecular cell biology, integrative biology, and infection and immunobiology. State-of-the art and advanced methodologies are applied in a professional research environment characterized by its well-established international profile. The institute has 30 research groups with a research staff of 170, of which 60 are PhD students. Read more about MBW at www.su.se/mbw.

Project description

This doctoral student position is available in the laboratory headed by Associate Professor Qi Dai. The Dai lab exploits the combination of molecular, genetic and genomic approaches to gain mechanistic insights on how cell fates are specified. The project aims to uncover novel regulatory mechanisms controlled by chromatin and transcription factors during neural cell fate decisions in the developing mouse brain. Candidates with strong background at molecular genetics, developmental biology and biochemistry are welcome to apply.

Qualification requirements
Graduate studies in molecular biosciences requires a completed university degree at an advanced level or at least 240 credits of university education (240 hp in the Swedish universities), including at least 120 hp at the bachelor level in molecular biology, biology, chemistry or similar subject. Candidates should have successfully completed courses at the advanced level in molecular biosciences or equivalent subject (at least 60 hp), of which at least 30 hp represent independent research project work. Candidates who have other documented qualifications, obtained in Sweden or elsewhere, that are judged to provide equivalent knowledge are also qualified.

Selection
The selection among the eligible candidates will primarily be based on the ability to obtain education at the research level. The following criteria will be used to assess this capacity: the candidates’ documented knowledge in a relevant field of research, written and oral proficiency in English, the capacity for analytical thinking, the ability to collaborate, as well as creativity, initiative, and independence. Experience in mouse genetics, biochemical and genomic approaches will be an asset. The assessment will be based on previous experience, grades and publication record, the quality of the degree project, references, relevant experience, interviews, and the candidate’s written motivation for seeking the position.

Terms of employment

The term of the initial contract may not exceed one year. The employment may be extended for a maximum of two years at a time. However, the total period of employment may not exceed the equivalent of four years of full-time study.

Doctoral students should primarily devote themselves to their own education, but may engage in teaching, research, and administration corresponding to a maximum of 20 % of a full-time position.

Please note that admission decisions cannot be appealed.

Stockholm University strives to be a workplace free from discrimination and with equal opportunities for all.

Contact

Further information about the position can be obtained from Qi Dai, telephone: +46 8 16 4149, qi.dai@su.se

Application
This is a non-official advertisement. The documents for initial application should be sent directly to qi.dai@su.se.

Please include the following information with your application

• Your contact details
• Your highest degree
• Your English language skills
• Contact details for 3 references

and, in addition, please include the following documents

• Cover letter in which you explain why you are interested in the project described in the advertisement and what makes you suitable for the project in question
• CV – degrees and other completed courses, work experience and a list of degree projects/theses
• Degree certificates and grades confirming that you meet the general and specific entry requirements (no more than 6 files)
• Letters of recommendation (optional, referees’ contact details are required instead)
• Degree projects/theses (no more than 3 files).

You are welcome to apply!

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