Postdoctoral Scientist – Marine Biological Laboratory

Posted by Kristin Gribble, on 30 October 2017

Closing Date: 15 March 2021

The Marine Biological Laboratory seeks a motivated Postdoctoral Scientist to join the laboratories of Kristin Gribble and David Mark Welch in the Josephine Bay Paul Center. The successful candidate will develop genome editing techniques, including CRISPR/Cas9, in rotifers, a novel aquatic invertebrate model system for studies of aging, neurobiology, developmental biology, ecology, and evolution. Specific goals of the project include designing guide RNAs, optimizing microinjection methodologies, phenotyping and genotyping mutant strains, and screening genes of interest.

Basic Qualifications:

Applicants should have a Ph.D. in biology, cell/molecular biology, biochemistry, or a related field. This position requires proficiency in basic molecular biology techniques, microscopy, microinjection, and CRISPR/Cas9 methodology. We are seeking an independent, organized, enthusiastic, and productive individual with robust problem solving skills. Excellent written, verbal and interpersonal skills, attention to detail, and a strong work ethic are essential. Position level and salary will depend upon education and experience.

Preferred Qualifications:

The ideal candidate will have working familiarity with RNAi techniques, transgenic protocols, and confocal microscopy. Proficiency in bioinformatics is a plus. Previous experience in established animal model or in non-model systems is preferred.

Special Instructions to Applicants:

Please submit the following three items with your application:

Cover letter describing your research goals, specific interest in joining our group, and what you would contribute to the project
CV
Contact information for 3-4 references

Please apply at: https://mbl.simplehire.com/postings/3824

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BSDB Gurdon Summer Studentship Report (13)

Posted by BSDB, on 30 October 2017

Established by the British Society for Developmental Biology in 2014, The Gurdon/The Company of Biologists Summer Studentship scheme provides financial support to allow highly motivated undergraduate students an opportunity to engage in practical research during their summer vacation. Each year, ten successful applicants spend eight weeks in the research laboratories of their choices, and the feedback we receive is outstanding. Our second report from the 2017 group of student awardees comes from Jack O’Shea (student at University College London), who undertook his studentship with Richard Poole at the Division of Biosciences in UCL.

glia to neuron transitions occurring simultaneously in the MCM (top)and PHDs (bottom) of a single animal

When I tell my friends that I spent my summer looking down a microscope at worms they often give a snigger. My enthusiasm on the subject quickly earned me the affectionate (I hope) nickname, ‘Wormboy’. Yet the Wormboys and girls of Richard Poole’s lab instilled in me a great thirst for scientific study over the 8 weeks I spent with them, which I will certainly carry forward in my career. The lab studies the nematode worm C. elegans, and my job was to help characterise a glia-to-neuron transition they discovered in the male tail that occurs during sexual maturation. During my time, I learned how to handle worms, keep them healthy, perform crosses, use a fluorescent microscope and present my data to an audience. All of this as part of my first lab experience was not only invaluable, but very enjoyable, and I came away wanting more.

Worm death was a regular part of lab life. Saving them from starvation and disease was a constant uphill battle, one that at first I found insurmountable. Along with those natural causes of death, they also had to contend me, often crushing them clumsily under my pick and purging potentially contaminative stragglers on said pick in the Bunsen. Happily for the worms, such fates became less and less frequent, and I was eventually able to sustain healthy populations from which I selected young males to dunk in the intensely toxic chemical sodium azide, all the better to view them under fluorescent microscopy. A necessary sacrifice.

This microscopy work was the first step in characterising the glia-to-neuron transition of phasmid socket 1 (PhSo1) into the neuron PHD, which occurs in the male tail during sexual maturation. The lab had previously identified a similar transition of the amphid socket to MCM neuron in the head of the male (Sammut et al., 2015), though the PHD transition differs in how the neuron is formed. Where the amphid socket divides asymmetrically to generate the MCM, the PHD derives from PHso1 by direct trans-differentiation, without a division, while its sister- PHso2- remains glial. This new neuron’s activity was found to be linked to initiation of a novel behaviour employed by males during mating thought to improve their chance of spicule insertion. To track the changing identity of PHso1, I compared its expression of glial and neuronal markers linked to GFP and RFP respectively with that of PHso2. The two glial markers I used were grl-2 (socket specific protein) and mir-228 (pan-glial microRNA), and the neuronal marker a nuclear synaptic fusion protein, rab-3.

The glia-to-neuron transition appears to start in males of larval instar 4 (L4), while the gonad is taking shape. Through picking many, many worms, I showed a clear gradient of change of marker expression in PhSo1 compared with PhSo2:

In late L3/early L4 GFP brightness is equal in the two sockets
By mid/late L4, GFP is dimmer in PHso1
The PHso1 of day 1 adults is beginning to express neuronal marker, displaying coexpression of GFP and RFP
By day 2, all GFP has dissipated from the newly formed PHD
Both glial markers displayed the same trend (fi g.1 and 2)
Some animals classified mid/late L4 displayed coexpression of markers, but these were all on the cusp of adulthood, undergoing moult at the at the time of imaging (fig. 3)

Of course, fluorescent proteins do not perfectly match levels of the markers they represent, rather they give a general overview of the transformation. At the very least, this result shows PhSo1 might partially dedifferentiate before it eventually acquires neuronal characteristics when the worm becomes an adult. Understanding trans-differentiation events such as this is key to understanding how nature itself reassigns cell fate. And if you’re trying to do something yourself in cell biology, it often pays to learn how nature beat you to it. To determine the mechanics of this trans-differentiation would require a more quantitative technique: single molecule fluorescent in situ hybridisation (smFISH).

SmFISH employs fluorescently tagged RNA oligomers, antisense to an mRNA (or miRNA) of interest. Combined, these oligos fluoresce strongly enough that individual RNAs can be resolved and counted within PHso1. Tracking change in RNA quantity rather than GFP fluorescence would tell you whether or not glial expression stops before neuronal expression begins. Does the cell become completely naive? Perhaps only partially? Or maybe there’s no dedifferentiation at all, and the cell passes through a totally novel identity- part glia, part neuron. Though I didn’t have time to perform these experiments, I did create the necessary strains. By crossing a markerless strain with my GFP/RFP animals, and then selecting against RFP over a couple of generations I rendered worms expressing only one of the two GFP markers so that the RFP reporter used in smFISH would be visible.

Though the work I was doing represented a project in its early stages and was at times very laborious, I quickly got an appetite for it. There was a thrill to it, knowing that no one had ever done what I was doing. I felt that buzz again when I arranged the prettiest pictures I could muster into figures to show to the lab, and then again when they ceremoniously scoured my findings with the same level of scrutiny I had seen them exact on each other. Alongside my data, I showed off a particularly pretty picture of both the worm’s glia-to-neuron transitions occurring at once in the same animal, which I think will remain my crowning achievement in science for a long time (Richard even kindly offered to steal it for his presentations). The BSDB’s grant has allowed me a taste of what a career in academia can offer. Straightforward experiments fraught with unforeseen difficulties. Working on weekends when, infuriatingly, age-specific experiments simply weren’t possible on Friday. Enough money to live off (just). But above all, the enormous reward in discovering something new. And getting to work with some really, really great people. Thanks guys.

Fig 1.1 – Percentages of observed expression patterns of grl-2 and rab-3 in PHD neurons

Fig. 1.2 – progression of grl-2 and rab-3 expression in the PHD and PHso2

Fig 2.1 – Percentages of observed expression patterns of mir-228 and rab-3 in PHD neurons

Fig. 2.2 – progression of mir-228 and rab-3 expression in the PHD and PHso2

Fig. 3 – examples of maulting animals with glial and neuronal marker coexpression

References

Sammut, M., Cook, S., Nguyen, K., Felton, T., Hall, D., Emmons, S., Poole, R. and Barrios, A. (2015). Glia-derived neurons are required for sex-specific learning in C. elegans. Nature, 526(7573), pp.385-390.

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Tags: Awards, BSDB, Gurdon Studentship
Categories: Discussion, Education, Funding, Lab Life, Research

Postdoctoral position in Neurobiology – Lyon, France

Posted by Julien Courchet, on 30 October 2017

Closing Date: 15 March 2021

A ERC funded postdoctoral position is available in the laboratory of Julien Courchet at the NeuroMyoGene Institute within the University of Lyon, France.

Our group studies the molecular mechanisms underlying axon outgrowth and neural circuits formation in the mouse cerebral cortex. Our current research is supported by an ERC Starting Grant and funds from AFM-telethon to explore how a dynamic regulation of the energy metabolism is involved in axon morphogenesis and cortex development. We focus on a previously identified kinase pathway controlling terminal axon branching through the regulation of mitochondria trafficking and distributing in developing axons (Cell 2013). Building on this previous research, the proposed project will use a combination of whole cell metabolomics, real-time fluorescent videomicroscopy and live 2-photon imaging to characterize some of the molecular mechanisms involved in the local regulation of mitochondria function in developing axon in vivo.

The selected candidate will join a young research team within a dynamic and collaborative scientific environment at the newly created NeuroMyoGene Institute (INMG). The candidate will have access to state-of-the-art facilities for imaging and metabolic analyses, including high quality confocal and 2-photon microscopes, animal phenotyping centers and a seahorse analyzer. Our institute is located in a newly renovated laboratory space in the Rockefeller faculty of Medicine in close proximity to the Neuroscience and the Cancer Research Centers.

Applicants should have a PhD degree or equivalent with a strong background and practical experience in neurobiology, confocal microscopy and/or real-time imaging. Previous experience working with rodent models is required. Training in techniques relevant to cell signaling, metabolic regulation and optogenetics would be an asset. We are looking for a highly motivated candidate with a strong attitude towards independent work and good interpersonal and communication skills. Excellent written and spoken English skills are essential. Ability to speak French in not mandatory.

The initial appointment is one year and can be renewed for 2 additional years. Salary including benefits will depend on previous experience according to guidelines at the University of Lyon. Applications will be reviewed on a rolling basis until position is filled. Selected candidates will be invited for an interview early 2018. Project start date is expected during the first semester of 2018.

Interested candidates should contact Dr Julien Courchet (julien.courchet@inserm.fr) with their CV, a summary of their previous research (< 1 page), a brief statement of their research interests and career goals, as well as the contact information for at least 3 references.

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MRC WIMM Prize PhD Studentships 2018

Posted by ecloke, on 30 October 2017

Closing Date: 15 March 2021

The MRC Weatherall Institute of Molecular Medicine (WIMM) has fully funded 4-year Prize PhD (DPhil) Studentships available to start in October 2018. These Studentships are open to outstanding students of any nationality who wish to train in experimental and/or computational biology.

The Institute is a world leading molecular and cell biology centre that focuses on research with application to human disease. It includes the recently opened MRC WIMM Centre for Computational Biology and houses over 500 research and support staff in 50 research groups working on a range of fields in Haematology, Gene Regulation & Epigenetics, Stem Cell Biology, Computational Biology, Cancer Biology, Human Genetics, Infection & Immunity. The Institute is committed to training the next generation of scientists in these fields through its Prize PhD Studentship Programme.

The fully funded studentships include a stipend of £18,000 per annum and cover University and College fees.

Further information on the studentships, how to apply, and the projects available can be found at:

http://www.imm.ox.ac.uk/wimm-prize-studentships-2018

Closing date for submission of applications: Monday, 8 January 2018, 12 noon UK time.

Interviews will take place the week commencing 22 January 2018.

Pure Computational Biology Project Leaders

Hashem Koohy – Machine-learning in gene function, transcription regulation and immunology

Ed Morrissey – Quantitative biology of cell fate

Aleksandr Sahakyan – Regulatory chromosomal domains and genome architecture

Supat Thongjuea – Computational biology of single-cell transcription and gene regulation

Molecular and Cell Biology Project Leaders

Ahmed Ahmed – Experimental therapeutics

Chris Babbs – Causes of congenital anaemia

Oliver Bannard – B cell biology

Andrew Blackford – DNA damage and disease

Walter Bodmer – Colorectal cancer, stem cells, differentiation & drug response

Marella De Bruijn – Developmental haematopoiesis

Zam Cader – Stem cell neurological disease models

Vincenzo Cerundolo – Tumour immunology, vaccine strategies

David Clynes – DNA damage, repair and cancer

Simon Davis – T-cell biology

Hal Drakesmith – Iron and infection

Christian Eggeling – Super-resolution microscopy in immunology

Ben Fairfax – Inflammation, genetics and cancer therapeutics

Marco Fritzsche – Biophysical immunology

Lars Fugger – Multiple sclerosis

Tudor Fulga – MicroRNAs in development and disease

Richard Gibbons – Chromatin, epigenetics & transcription

Anne Goriely – De novo mutations and human disease

Doug Higgs – Gene regulation and epigenetics

Ling-Pei Ho – Lung immunology

Georg Hollander – T cell development and thymus organogenesis

David Jackson – Lymphatic trafficking in inflammation and cancer

Peter McHugh – DNA repair

Adam Mead – Normal and leukaemic haematopoietic stem cell biology

Claus Nerlov – Tissue stem cell genetics

Graham Ogg – Translational skin research

Catherine Porcher – Transcription factors and blood development

Jan Rehwinkel – Innate detection of viruses

Irene Roberts – Trisomy 21, haematopoiesis and leukaemia

Tatjana Sauka-Spengler – Neural crest gene regulatory networks

Alison Simmons – Innate immunity & Crohn’s disease

Alain Townsend – Influenza and ebola, vaccination and treatment

Paresh Vyas – Leukaemic stem cells

Andrew Wilkie – Sperm and craniofacial mutations

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Postdoctoral Position in Germline Stem Cell Biology – University of Cambridge

Posted by Felipe Karam Teixeira, on 27 October 2017

Closing Date: 15 March 2021

The Karam Teixeira laboratory (https://www.gen.cam.ac.uk/research-groups/karam-teixeira) at the University of Cambridge (Department of Genetics) is looking to recruit an outstanding Postdoctoral scientist to investigate the molecular mechanisms sheltering totipotency and controlling germline stem cell behavior in vivo. Using the Drosophila germline as a model for studying stem cells, we employ an integrated approach, combining high-throughput molecular analysis (next-generation sequencing) and computational investigation with developmental, microscopy, and genetic analyses (including CRISPR-Cas9 gene editing, tissue-specific RNAi knockdown, etc). We were previously able to assemble the complete genetic framework controlling germline stem cell self-renewal and differentiation in vivo, revealing conserved new aspects of stem cell biology (Teixeira et al, Nature Cell Biology, 2015; Sanchez et al, Cell Stem Cell, 2016). Moving forward, our goal is to build a refined molecular understanding of how protein synthesis control – a new frontier in gene regulation – governs stem cell fate transitions in vivo. Our lab is generously funded by the Wellcome Trust.

Candidates must have experience in a wide range of molecular biology techniques, and prior expertise in next generation sequencing would be an advantage. Experience working with fly genetics is a plus but not required. The successful candidate will be highly motivated, willing to join a young and dynamic research group, have good communication skills, and possess strong problem solving capacities.

How to apply:

To apply online, please follow the link: http://www.jobs.cam.ac.uk/job/15379/

Applications should include a cover letter, Curriculum Vitae, and the contact information of at least two references.

The position start date is flexible. Application deadline: November 17^th, 2017.

For an informal discussion about this position, please contact Dr. Felipe Karam Teixeira (fk319@cam.ac.uk).

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A glimpse of a dynamic cell fate decision

Posted by Andras, on 27 October 2017

Andras Paldi, Daniel Stockholm, Alice Moussy

How do phenotypic differences between cells of the same clonal origin emerge? How exactly does the transition between the initial and final phenotypes occur? What happens in the cell during the transition? When there are two or more options, how is the choice made between them? How long does it take to acquire a new phenotype? What is the minimal difference required to consider two cells as phenotypically different? To define a cell type, should we consider only morphological, molecular differences or both simultaneously?

Despite the plethora of studies, these simple questions remain unanswered. Most of the studies focus on identifying the essential genes or environmental factors usually at the level of cell populations. The huge amount of molecular data accumulated over the past decades gave us the illusion of knowledge. Knowing the players is obviously essential, but this is only the starting point for the understanding. Unfortunately, our understanding of the process of differentiation remains desperately scarce, as the lack of clear responses to the above listed simple questions shows.

Recently, two important challenges came to modify the perception of differentiation. The first comes from the spectacular development of single-cell technologies. The second is that we have to come to realize how much phenotypic plasticity is a genuine characteristic of cells. The main lesson from the rapid development of single-cell detection techniques is the unambiguous demonstration of how different individual cells are and how poorly population-level averages represent them. The bulk of our knowledge on differentiation comes from studies of cell populations. Perhaps unconsciously, we took for granted that individual cells all follow with small variation the same sequence of events as what we could see at the level of cell populations. The unexpectedly high variation of individual cell phenotypes in populations that were believed to be homogenous (because of the morphological similarity of the cells, their clonal origin, their expression of some markers etc.) draw the attention to the phenotypic plasticity of the cells and to the fact that fate decisions are “taken” by individual cells.

Clearly, a coherent, systemic level explicative frame is needed that can account for the coherent population-level behaviour emerging from highly variable individual cell phenotypes and behaviour.

Our recently published work [1] was motivated by the wish to contribute to this effort. Although we used the extensively studied hematopoietic stem cell model, we were surprised how much these general questions fit to the model. The definition of the hematopoietic stem cell is widely debated, no precise description of the earliest events of differentiation and only very scarce information on the morphological changes during the same period were available. The study of hematopoietic stem cells is made difficult by the lack of exact criteria to identify them. Nonetheless, there is a consensus that CD34+ cell fraction in the umbilical cord blood contains high number of these cells. We decided therefore to privilege an integrated view and work on the whole population of CD34+ cells. Individual cells were randomly sorted from the population at different fixed time-points and their gene expression profile was analysed by single-cell RT-PCR. The structure of the population and its components were identified on the basis of the collected single-cell gene expression data. Parallelly, we set up a time-lapse system that allowed the continuous monitoring of the cells and their progeny during the first 96hrs after stimulation. Adding the continuous observations of the morphological changes and cell division timing of individual cells to the single time-point single-cell molecular analysis sampling of the same population provided a glimpse of the true dynamic nature of cellular fate decision.

The CD34+ cell fraction is traditionally considered as heterogeneous. Indeed, before cytokine stimulation every cell displayed a unique gene expression profile. However, no groups could be identified on the basis of their statistical similarity, this population is not a mixture of a limited number of “cell types”. When cytokines were added to the culture, every cell responded in a unique way. Again, every cell displayed a unique gene expression pattern that was different of the previous seen at t=0 hours. It was characterized by the simultaneous expression of different lineage-specific genes. This state is known as a multi-lineage primed pattern [2, 3]. A second round of change occurred during the second 24 hours. Two days after the stimulation of the cells two distinct transcription patterns emerged. One pattern was typical for myelo-erythroid progenitors, while the second was reminiscent of multipotent cells. Until now, the results overall confirmed the previous studies; the main novelty was the apparent rapidity of transition from the initial to a multilineage primed gene expression pattern and, just 24 hours later, to two distinct profiles. However, these snapshots did not allow us to deduce on the dynamics of the changes.

Time-lapse video of a cell clone with cells conserving polarized morphologies. GIF made from from Movie S1 in the paper

The real surprise came from the analysis of the time-lapse records. Individual CD34+ cells were placed in microwells and imaged for a week at 1 image/min. The resulting time-lapse records allowed us to record cell cycle lengths and morphological changes of each individual cell within individual clones. After stimulation, the cells usually displayed a polarized shape with a strong protrusion on one side called uropod. The first unexpected observation was to see that the unusual length of the first cell cycle. The cells made more than 50 hours on average to divide. This means, that the first major transcriptional change occurred during the first cell cycle and the second around the end of the first or the very beginning of the second cell cycle. After the first division, we could see two different morphologies; one was strongly polarized with a uropod, the second is spherical. The daughter cells usually inherited the morphology of their mothers. Polarized cells gave two polarized and round cells two round daughters. However, we were surprised to observe that a significant proportion of the cells did not conserve a stable morphology; they switched from one morphology to another and back many times during the cell cycle. The majority of their daughter cells also conserved the fluctuating phenotype

Red color: CD133; Green: actin; Blue: DNA

We called these cells “hesitant”. The overall picture suggest that stimulated CD34+ cells, after a brief passage through a multilineage primed state reach (without cell division!) one of the two alternative states characterized by a typical transcription pattern and cellular morphology. However, a significant proportion of cells fluctuate between the two morphologies. Does this morphological instability reflect transcriptome fluctuations? To answer this question, we have isolated individual cells with the three different – stable round, polarized or “hesitant” – behaviours and analysed their gene expression pattern. It appeared that the cells with stable morphology displayed one of the two expression patterns first observed at the 48 hors time point. The “hesitant” cells were characterized by an intermediate profile. The molecular analysis correlated to the time-lapse data suggests therefore that these cells are in an unstable state; their transcriptome undergoes fluctuations that are reflected in their fluctuating morphology also.

These are the key observations and the immediate conclusions of this work. However, these observations may contribute to the current tendency to reframe the issue of cell differentiation and stem cells in general. Cell differentiation can be approached using the concepts of stability and change – two complementary concepts widely used in biology. Stem cells may represent a highly unstable cell fraction contrary to the cells with stable differentiated phenotype. Unstable stem cells are actively exploring the space of available phenotypes before getting trapped by one of them. This is a kind of trial-and-error process. Under normal conditions, the unstable period is relatively short lasting; this is why the unstable cells we consider as stem cells are so rare in a normal tissue. However, a substantial change in the environment can destabilize many cells at the same time. This is what we see when CD34+ cells are stressed by the sudden addition of a cytokine cocktail. Due to the progressive adaptation to the new environment, the proportion of the “hesitant” stem cells decreases gradually as they attracted to the more adapted phenotypes. Importantly, this process seems to depend only indirectly on cell divisions. This interpretation is in remarkable agreement with earlier theoretical predictions and experimental work [4-8] and supported by recent experimental observations also [9-12].

Our paper was initially submitted to a well-known journal in stem cell biology. Beyond the disappointment of the rejections (every scientist is used to that), we were surprised by the poor quality of the reviews. The referees raised some technical concerns about the single-cell RT-PCR versus single-cell RNA sequencing, but not a single word about the time-lapse experiments that represented the major part of the paper, nor about the coupling the molecular and cellular scales, which is the true originality of the work. The reviews were very different when the manuscript was submitted to PloS Biology. The comments concerned all aspects of the work and the suggestions truly helped to improve the final version.

It would be naïve to think that a single paper can answer the fundamental questions raised at the beginning of this text. Clearly, we need a fresh view on cell differentiation that goes beyond the simple gathering and classification of molecular data and takes into account the true dynamics.

References

Moussy A, Cosette J, Parmentier R, da Silva C, Corre G, Richard A, et al. Integrated time-lapse and single-cell transcription studies highlight the variable and dynamic nature of human hematopoietic cell fate commitment. PLoS Biol. 2017;15(7):e2001867. doi: 10.1371/journal.pbio.2001867. PubMed PMID: 28749943; PubMed Central PMCID: PMC5531424.
Hu M, Krause D, Greaves M, Sharkis S, Dexter M, Heyworth C, et al. Multilineage gene expression precedes commitment in the hemopoietic system. Genes & development. 1997;11(6):774-85. PubMed PMID: 9087431.
Pina C, Fugazza C, Tipping AJ, Brown J, Soneji S, Teles J, et al. Inferring rules of lineage commitment in haematopoiesis. Nature cell biology. 2012;14(3):287-94. doi: 10.1038/ncb2442. PubMed PMID: 22344032.
Furusawa C, Kaneko K. A dynamical-systems view of stem cell biology. Science. 2012;338(6104):215-7. doi: 10.1126/science.1224311. PubMed PMID: 23066073.
Huang S. Non-genetic heterogeneity of cells in development: more than just noise. Development. 2009;136(23):3853-62. doi: 10.1242/dev.035139. PubMed PMID: 19906852; PubMed Central PMCID: PMC2778736.
Kupiec JJ. A chance-selection model for cell differentiation. Cell death and differentiation. 1996;3(4):385-90. PubMed PMID: 17180108.
Kupiec JJ. A Darwinian theory for the origin of cellular differentiation. Molecular & general genetics : MGG. 1997;255(2):201-8. PubMed PMID: 9236778.
Paldi A. Stochastic gene expression during cell differentiation: order from disorder? Cellular and molecular life sciences : CMLS. 2003;60(9):1775-8. doi: 10.1007/s00018-003-23147-z. PubMed PMID: 14523542.
Mojtahedi M, Skupin A, Zhou J, Castano IG, Leong-Quong RY, Chang H, et al. Cell Fate Decision as High-Dimensional Critical State Transition. PLoS Biol. 2016;14(12):e2000640. doi: 10.1371/journal.pbio.2000640. PubMed PMID: 28027308; PubMed Central PMCID: PMC5189937.
Notta F, Zandi S, Takayama N, Dobson S, Gan OI, Wilson G, et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science. 2016;351(6269):aab2116. doi: 10.1126/science.aab2116. PubMed PMID: 26541609; PubMed Central PMCID: PMC4816201.
Richard A, Boullu L, Herbach U, Bonnafoux A, Morin V, Vallin E, et al. Single-cell-based analysis highlights a surge in cell-to-cell molecular variability preceding irreversible commitment in a differentiation process. . Plos Biology. 2016;(14):e1002585. doi: doi.org/10.1371/journal.pbio.1002585.
Velten L, Haas SF, Raffel S, Blaszkiewicz S, Islam S, Hennig BP, et al. Human haematopoietic stem cell lineage commitment is a continuous process. Nature cell biology. 2017;19(4):271-81. doi: 10.1038/ncb3493. PubMed PMID: 28319093.

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Tags: cell dynamics, cell fate, hematopoiesis, stem cells
Categories: Discussion, Research

PhD Advice From the Twitter Hive Mind

Posted by the Node, on 26 October 2017

Doing a PhD is tough, the data from surveys supports that. However it is not insurmountable, and here we have a collection of some guidance from the Twitter community. Let us know in the comments if you have any thoughts to add.

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Tags: phdcareer, Phdchat
Categories: Careers, Discussion, Lab Life

Assistant Professor of Biology (Developmental Biologist)

Posted by the Node, on 25 October 2017

Closing Date: 15 March 2021

The Department of Biology within the College of Natural and Health Sciences at The University of Tampa invites applications for a tenure track position in developmental biology at the rank of Assistant Professor starting in August 2018.

The University of Tampa is a medium-sized, comprehensive, residentially-based private institution of 8,913 undergraduate and graduate students. The University is ideally situated on a beautiful 110-acre campus next to the Hillsborough River, adjacent to Tampa’s dynamic central business district, which is a growing, vibrant, diverse metropolitan area. UT reflects this vibrancy; with 20 consecutive years of enrollment growth UT boasts 229 student organizations, a multicultural student body from 50 states and 140 countries, and “Top Tier” ranking in U.S. News and World Report.

Primary responsibilities will include an undergraduate teaching load of 12 contact hours per semester. The candidate is expected to teach introductory biology for majors, an upper division course in developmental biology, and other courses as needed.
Secondarily, the candidate is expected to engage in scholarly and research activity that involves undergraduates, advise students, and provide service to the department, college, university and broader community. Research activities must yield peer-reviewed publications.
PhD preferred (advanced ABD candidates considered), prior teaching and research experience with undergraduates is desirable.

Salary for this position is competitive and commensurate with experience.
Review of applications will begin January 2, 2018, and continue until the position is filled. Limited start-up packages and modest research space are available for tenure-track positions.

For application details please visit

https://utampa.wd1.myworkdayjobs.com/en-US/Faculty/job/Tampa/Assistant-Professor-of-Biology–Developmental-Biologist-_R0001530

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Christiana Ruhrberg, winner of the BSDB Cheryll Tickle Medal 2018

Posted by BSDB, on 24 October 2017

In 2016, the BSDB introduced the Cheryll Tickle Medal, which is being awarded annually to a mid-career, female scientist for her outstanding achievements in the field of Developmental Biology. The BSDB is proud to announce the 2018 awardee Christiana Ruhrberg. The medal will be presented at next year’s Spring Meeting where Christiana will give the Cheryll Tickle Award Lecture.

Christiana Ruhrberg studied Biology at the Justus Liebig University (Giessen, Germany), and obtained her first class Diploma/MSc degree in 1992. After taking on an MSc/research assistant position at the University of Sussex for two years to elucidate genetic changes in ovarian cancer, she moved to Imperial College London to work for another two years to study the genomic organisation of the gene-rich human ‘surfeit’ locus. She then carried out her PhD project in the laboratory of Fiona Watt at the Imperial Cancer Research Fund (1994-97) where she identified and described the function of the envoplakin and periplakin genes. Her postdoctoral research in the laboratories of Robb Krumlauf at the National Institute for Medical Research in London (1997-1999) was funded by a MRC postdoctoral training fellowship and dedicated to studying the role of Hoxa1, Hoxb1 and Hoxb2 during hindbrain development. During her second postdoc with David Shima at the Imperial Cancer Research Fund in London (2000-2002), she was funded by a ICRF fellowship and worked on VEGF-A-mediated blood vessel branching. Having received an MRC Career Development Award in 2003, she became an independent investigator at University College London’s Institute of Ophthalmology studying links between vascular and neuronal development, with particular focus on the roles of VEGF and SEMA3A signalling during facial nerve and blood vessel formation. Staying at that same institute, she was appointed Lecturer in 2007, promoted to Reader in 2008 and then full Professor in 2011. Christiana has an excellent record in obtaining research funding, as illustrated by a Wellcome Trust Junior Investigator Award in 2011 and a Wellcome Trust Investigator Award in 2016 for her research on vascular biology and neurovascular interactions.

Figure: Using the mouse embryo hindbrain to elucidate neuronal and vascular development. (A) The hindbrain from an embryonic day (E) 10.5 mouse was dissected to perform visualise the expression of Hoxb1 in rhombomere 4 (A), the origin of the Isl1-positive facial branchiomotor (FBM) neurons, which can be observed during their caudal migration by Isl1 at E12.5 (B). (B-F) Main cell types (B) and cell interactions (C-F) in the developing mouse hindbrain. In (C-F), dissected hindbrains were stained with the vascular endothelial marker IB4 (red) and markers for mitotic neural progenitors, microglia or neural progenitor processes, shown in green in C-E, respectively). Note that neural progenitors attract sprouting blood vessels (C), the physical contact between microglial and endothelial processes (D) and that neural progenitor processes contact vasculature (E).

Christiana has been a mentor to 11 PhD students and 6 postdocs, 3 of whom have now established themselves as independent investigators. She has published many influential papers in the fields of vascular, neuronal and neural crest cell development, including primary research articles and reviews, methods papers and book chapters. Twelve of her research papers have been listed as recommended reads by the Faculty of 1000, five have been featured with cover images and six have been featured in editorials in influential journals such as JCB, PNAS, Nature, Science, Neuron and JCI.

Christiana received an impressive amount of honours, including the title ‘Young Cell Biologist of the Year’ (BSCB, 1996), the ‘Werner-Risau-Prize’ (German Society for Cell Biology, 2003), the MRC’s ‘Science Heirloom’ (Suffrage Science, 2011). She was also named an ‘Academic Role Model’ (UCL, 2013) and is listed in EMBO’s ‘Expert Women in Life Sciences’ (2013) and ‘AcademiaNet’ (Robert Bosch Stiftung, Germany, 2014). Besides all these achievements, Christiana takes on regular institutional responsibilities, is a member of various grant committees and a contributing member of the Faculty 1000, editor for PLoS One, and serves on programme committees of a number of scientific meetings.

The BSDB makes it a tradition to ask the Cheryll Tickle Medal awardees a number of questions concerning our field and its future. Please, read Christiana’s answers below.

What were the questions that inspired you to work in the field of Developmental Biology?

I was initially attracted to working in the field of developmental biology when the first mouse knockouts became available. Many of them had lethal phenotypes, making embryological studies imperative to determine the physiological functions of the ablated genes. I initially examined mouse knockout models to identify molecules that regulate the migration of facial branchiomotor neurons and subsequently to determine how the growth factor VEGF orchestrates blood vessel morphogenesis. By answering two different biological questions with the mouse embryo hindbrain as a model system, I serendipitously identified VEGF as the elusive migratory cue for facial branchiomotor neurons. This finding inspired me to continue investigating VEGF functions in neuronal and vascular development, with a more recent strive to apply knowledge gained through developmental studies also to further our understanding of disease processes in the adult.

Why should young researchers continue to engage in Developmental Biology?

Personally, I have always been fascinated by how the vertebrate body develops to enable postnatal life. Developmental studies also yield striking images of a multitude of diverse cellular processes that coordinate organ morphogenesis, making this type of research not only exciting, but also aesthetically pleasing. The PhD students, postdocs and technicians who train in my laboratory share these sentiments and have gained much deserved appreciation for their developmental biology research work through journal cover images and when winning presentation prizes at conferences. Developmental biology research also impacts on public health, because understanding how embryonic processes yield functional organs informs regenerative medicine. In particular, knowing how functional tissues are built normally might one day soon provide a gold standard for designing therapeutic strategies to recreate or repair dysfunctional tissues. That said, the developmental biology community is increasingly faced with the challenge of having to convince funding agencies that developmental biology research can underpin research into tissue repair and regeneration!

Which were the key events or experiences in your life that influenced your career decisions and paved your path to success?

My career path has not been straightforward, but encompassed a series of obstacles and opportunities. For example, the failure to appoint a successor for our retiring genetics professor at my home university in Germany could have persuaded me to switch subjects from molecular biology and genetics to a different one to avoid a significant delay to graduation, but I took this challenge as an opportunity to study for a year in the UK, being the first student on my course to embark on such an overseas placement. I ended up staying at the University of Sussex for almost 2 years to complete a research project all the way to publication, returning to Germany only to submit my thesis. Incredibly, after all the long hard work, I almost did not graduate, because those in charge at my German University deemed an English-written thesis unacceptable! This experience encouraged me to return to the UK to continue academic research in an English-speaking environment. Unfortunately, I initially chose a PhD supervisor at the Imperial Cancer Research Fund who turned out to be rather unsupportive of my endeavours; yet, I was able to make a ‘lateral’ move within the same organisation to re-start my PhD with Fiona Watt. She was a most inspirational PhD supervisor and mentor, and later matched me with an ideal postdoc supervisor in Robb Krumlauf at the National Institute of Medical Research. In Robb’s lab, I discovered both my love for developmental biology and the inspirational community of scientists working in this area. In a nutshell, it was not careful planning that allowed me to get to my current career stage, but my unwavering enthusiasm for research combined with resilience when faced with adversity and the will to take advice and encouragement from my fabulous mentors Fiona and Robb.

What advice do you give young researchers towards a successful career?

Whether you choose to continue on an academic career or embark on an alternative career, I recommend everyone to take advantage of transferable skills training to complement the technical training gained in the research environment. Strengthening your verbal and written communication skills, learning about project and team management and developing effective networking skills will provide a strong foundation to equip you for success in a diverse range of career options.

(2 votes)

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Tags: Awards, BSDB, Cheryll Tickle Medal, Prizes
Categories: Careers, Societies

BSDB Gurdon Summer Studentship Report (12)

Posted by BSDB, on 24 October 2017

Established by the British Society for Developmental Biology in 2014, The Gurdon/The Company of Biologists Summer Studentship scheme provides financial support to allow highly motivated undergraduate students an opportunity to engage in practical research during their summer vacation. Each year, ten successful applicants spend eight weeks in the research laboratories of their choices, and the feedback we receive is outstanding.

Our first report from the 2017 group of student awardees comes from Josie Elliott (student at University of Oxford), who undertook her studentship with Alison Woollard at the Dept. of Biochemistry in Oxford.

**What is the role of wrt-2 and wrt-4 in left-right asymmetry in C.elegans?**

Once upon a time a genetic screen identified a signalling pathway that caused Drosophila melanogaster embryos to develop a ‘lawn’ of denticles rather than forming them only at parasegment boundaries. Thus the so-called Hedgehog signaling pathway was born (Nusslein-Volhard & Wieschaus, 1980). This pathway has revealed itself to be one of the core signal transduction pathways in regulating animal development. Through gene duplication and diversification events, different types of hedgehog proteins have been found across vertebrates. The brilliantly named Sonic Hedgehog ligand is the best studied ligand present in mammals. Loss of expression of Sonic Hedgehog in mice causes defects in left right asymmetry (Levin et al., 1995).

The story was expanded into C.elegans by bioinformatics (Burglin, 1996). A search of the C.elegans genome for homologues of the carboxyl terminal ‘hog’ domain revealed a family of proteins which did not contain the amino terminal ‘Hedge’ domain but instead a novel domain dubbed ‘Wart’. Thus the warthog (wrt) genes were named. Further genome analysis revealed genes which contained the amino wart domain but lacked the carboxy hog domain. Together this made a family of ten warthog genes.

Previous research in my lab (the Woollard lab in the Biochemistry department at the University of Oxford) had linked the wrt-2 branch of the warthog family (figure 2) to defects in left right asymmetry, with wrt-2 and wrt-4 giving the highest penetrance phenotypes. However it was found that the GFP marker used in the previous strains to help quantify another phenotype (related to vulval development) caused defects of its own. This is where I come in. My project was to cross and create strains of worms without this GFP background and then requantify the left right asymmetry defects. I studied the single mutants wrt-2, wrt-4, wrt-8, as well as the double mutants wrt-4;wrt-2, wrt-8;wrt-2, wrt-8;wrt-4 and the triple mutant wrt-8;wrt-4;wrt-2. The double and triple mutant strains I created myself. The combined mutations allow investigation into redundancy between the genes, giving a glimpse into their evolutionary history. The wrt-7 gene has been shown to have no expression pattern and is likely a pseudogene, so due to my limited time in the lab I didn’t quantify the wrt-7 mutations.

**Fig. 2** The tree presents the origin of the ‘Wart’ domain in *C. elegans*’ most distant relative in the Rhabditiada order, Brugia malayi, as well as its two closet relatives in the Caenorhabditis genus, C. briggsae and C. remanei. A multiple sequence alignment of Wart domains was used to generate this unrooted Neighbour Joining tree (default setting Clustal_X). Results of 1000 bootstrap trials are shown. Figure from Emily Baker’s dissertation.

On a side note: the C.elegans species is great. They’re heamaphrodites so you can just leave them on an agar plate to reproduce by themselves. Males do exist – enabling you to perform genetic crosses. They’re transparent, so no need to dissect anything. You can even freeze them and they’ll be alright in liquid nitrogen until someone needs them!

At first glance C.elegans may not seem very asymmetric. However one source of left right asymmetry is the relative positioning of the gonads and intestine either side of the vulva in the worm. This is best shown through pictures. In the wildtype worm (figure 3d) the picture in the lefthand plane shows that in the anterior part of the worm one can see intestinal cells and the intestinal lumen going down the centre. In the posterior part of the worm one can see the U shaped gonad that migrates away from the vulva (just visible in the bottom left hand corner of that picture) along the body, turns twice then travels back along the body (schematic figure 3c). The top picture of a whole worm (figure 3d) shows the opposite situation (the worm is laying on its other side) where the gonad can be seen at the anterior part of the body and the intestine at the posterior.

**Fig. 3** a) L1 stage animal. b) L4 stage animal. The gonad turns twice due to the migration of the distal tip cell (DTC). c) Commencement sees the gonad arms depart from the ventral midpoint and travel along the ventral sides of the worm (red arrow); firstly turning to the dorsal side of the animal and secondly along the anteroposterior axis (yellow arrow) until they meet again, this time at the dorsal midpoint (blue arrow). The gonad migration at the anterior end of the worm is the mirror-image. Furthermore, the anterior gonad is located on the right-hand lateral side of the worm (shown as the bottom plane), whereas the posterior gonad lies along the left-hand lateral side (top plane); however, this is not shown in the image. d) Arrowhead points to vulva. The right-hand lateral side is shown and therefore the anterior, but not the posterior, gonad arm is visible. The alternate scenario in which the posterior gonad is visible in the top plane of view is hypothetically depicted; in which instance, the anterior gonad would be hidden from view by the intestine. Scale bar = 25μm. Figure taken from Emily Baker’s dissertation.

Thus the anterior/posterior distribution of gonad and intestine gives us a tool to study and quantify left right asymmetry in worms. After discussions with Emily (a recent biology graduate who had been working on the project before me) we decided to only quantify worms in which the posterior gonad was visible down the microscope. Thus, worms which I counted looked like those in the two lefthand plane pictures in figure 3d. This decision, although arbitrary in itself, allows our results when published to be more understandable and easier to replicate.

The pictures shown in figure 4 demonstrate some of the mutant phenotypes scored in this project. Basically I was looking for gonad tissue poking through anterior intestine tissue and intestine tissue poking through posterior gonad tissue. Worms with this phenotype were scored as mutant and were also further divided into anterior or posterior defects.

**Fig. 4** **Top left** shows the anterior gonad of a wrt-2;wrt-4 worm in which gonad tissue can be seen as well as intestine. **Bottom left** shows the anterior gonad of a wrt-8 worm in which gonad can be seen above and below the intestine cells. **Top right** shows the posterior gonad of a wrt-2;wrt-4 worm in which the gonad has migrated unsuually thus intestine tissue can be seen. **Bottom right** shows the posterior gonad of a wrt-2;wrt-4 worm in which half the gonad has disappeared to the other side of the worm. Photos taken by me on a Zeiss microscope.

One of the most enjoyable parts of this project has been pipetting alongside Emily, who worked on this project before me and is continuing to develop it. In my 8 weeks I have seen first hand a small portion of the amount of research that has gone into studying the warthog genes. However chatting with Emily I have seen how my short project may in future count towards producing a scientific paper. At the moment Emily is taking the story of warthog genes in C.elegans back to its bioinformatics heart, producing a phylogenetic tree of all the warthog genes across the nematode family – trying to link evolution with phenotype. She is also expanding from the wrt-2 branch of the gene family into as many other members as she can get her hands on.

The highlight of my time in the project has been having so much independence in the lab, deciding day to day, week to week how I wanted to spend my time. This has been a fantastic insight into the life of a researcher and totally different to undergraduate labs. The lowlight would have to be the Saturday when I broke a pipette and in the process spilled a box of pipette tips all over my desk…

Thank you so much to everyone in the Woollard lab for being more friendly and welcoming than I could have hoped for.

Josie Elliott

(6 votes)

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Tags: Awards, BSDB, Gurdon Studentship
Categories: Societies