Applications are invited for postdoctoral positions in the laboratory “Epigenetic Regulation of Cell Identity” headed by Dr. Michael WEBER at the CNRS in Strasbourg (France). The positions are funded for up to three years by an ERC Consolidator grant and the INCa (National Cancer Institute).

The research in our laboratory aims at better understanding the function and regulation of DNA methylation in mammalian development by combining molecular biology, high-throughput sequencing, bioinformatics and mouse genetics (Auclair G et al Genome Biol 2014; Guibert S et al Genome Res 2012; Borgel J et al Nature Genet 2010). The successful applicants will uncover and study novel regulatory pathways of DNA methylation in normal and malignant cells.

Our Institute is located on the Illkirch research campus in Strasbourg. The campus offers an international environment with access to state-of-the-art facilities (NGS sequencing, animal housing, proteomics, imaging). The successful candidates will join a young and dynamic team. For more information see our website: http://irebs.u-strasbg.fr/spip.php?rubrique186&lang=en.

We are looking for candidates with a Ph.D. in Molecular or Developmental Biology. Prior experience with epigenetics, NGS datasets or mouse embryology will be positively considered. We expect the candidates to be motivated, creative, excellent team players, and preferably with at least one publication as first author. Applicants with less than two years after obtaining their PhD will be favored.

Starting date: end 2015 or early 2016

Salary: Competitive salary following the CNRS guidelines (> 2,500 € brut / month)

Please send a CV, letter of motivation, and at least one letter of recommendation to Dr Michael Weber (michael.weber@unistra.fr).

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We are seeking outstanding and highly motivated postdoctoral candidates to join an interdisciplinary collaboration between the Gros lab (“Imaging and Regulation of
Morphogenesis in Higher Vertebrates” lab) at the Pasteur Institute in Paris, France, and the Campas lab (“Morphogenesis and Self-Organization of Living Matter” lab) at the University of California, Santa Barbara. This specific position would be based at the Pasteur Institute in Paris, with occasional stays at the University of California, Santa Barbara.

The overall aims of this collaborative project are to (1) quantify the spatial and temporal distributions of physical forces in developing mouse limb buds using novel force transducers developed recently by the Campas lab and, (2) elucidate their role in maintaining skeletal progenitor differentiation/maintenance balance. For more information about projects and the labs please visit:
www.jgroslab.com ,
https://research.pasteur.fr/en/team/morphogenesis-regulation-in-higher-vertebrates/
and http://www.engineering.ucsb.edu/~campas/.

The position is a 3-year postdoctoral position funded by the Human Frontier Science Program (HFSP), available December 1st, although the starting date is flexible. Candidates should have expertise in developmental and/or cellular biology, be willing to extend their knowledge to quantitative biophysics approaches and collaborate with biophysicists and engineers. Experience in live imaging, mouse development, biophysics and/or quantitative biology will be positively considered.

The Pasteur Institute, located in the vibrant city of Paris, has a longstanding history of excellence in developmental biology and in science in general, with access to excellent core facilities.

Applicants should send a cover letter (describing briefly research interests), a C.V and contact information for up to 3 academic references to jgros@pasteur.fr and
campas@engineering.ucsb.edu.

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There is an increased awareness that only a small fraction of PhD students will ultimately secure a tenure-track position in academia. This has led to a discussion on whether graduate schools have a responsibility to help PhD students prepare for a career outside academia, either by providing training on a broader range of transferable skills, or simply by increasing awareness of the various career paths available.

One of the ways PhD programmes have started to support students in this way is by providing access to internship opportunities during their PhDs. A recent article in Nature Jobs discussed the efforts in this direction in the US, where internship options are available for PhD students and postdocs. In the UK, 3 month internships are now part of the compulsory training of PhD students in certain graduate programs (most notably the PIPS scheme, part of the BBSRC PhD studentships). So this month we are asking:

Are PhD internships a valuable exposure to careers outside academia or a harmful distraction from research?

Share your thoughts by leaving a comment below! You can comment anonymously if you prefer. We are also collating answers on social media via this Storify. And if you have any ideas for future questions please drop us an email!

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Here is some developmental biology related content from other journals published by The Company of Biologists.

Auditory hair cell defects in Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome (WHS) is a rare genetic disorder associated with sensorineural deafness. In this study, Andrea Streit and colleagues show that, although cochlear hair cells are specified normally in a WHS mouse model, they are disorganised and display sterocilia defects. Read the paper here [OPEN ACCESS].

Studying Huntington disease using iPSCs

Figiel and colleagues examined putative signaling pathways and processes involved in Hutington disease pathogenesis in pluripotent cells. They show that dysregulation of signaling pathways is a very early event in the pathogenesis of Huntington disease and that these pathways are already dysregulated in cells at the stage of pluripotency. Read the paper here [OPEN ACCESS].

Sequential mutagenesis in the mouse

Zhang and Kirsch generated two mouse strains expressing Cre-ER^T2 under Flp-FRT regulation. These tools enable sequential mutagenesis in the same or different cells to study development, tissue homeostasis and diseases such as cancer. Read the paper here [OPEN ACCESS].

KCNK1 on osteoclastogenesis

KCNK1 (K⁺ channel, subfamily K, member 1) is a member of the inwardly rectifying K⁺ channel family, which drives the membrane potential towards the K⁺ balance potential. Kim, Choi and colleagues show that KCNK1 negatively regulates osteoclast differentiation. Read the paper here.

A role for periostin on Schwann cell migration

Riethmacher and colleagues performed comparative gene expression analysis of dorsal root ganglia explant cultures from ErbB3-deficient and wild-type mice, in order to identify genes that are involved in Schwann cell development and migration. Their results demonstrate that the expression of periostin is stimulated by the ErbB ligand NRG1 and promotes the migration of Schwann cell precursors. Read the paper here.

Daphnia sniff out doom with first antennae

Weiss and colleagues analysed the developmental characteristics of the inducible defences formed by Daphnia in response to the warning odours (kairmones) exuded by predators. Read the paper here [OPEN ACCESS].

Developmental remodeling in response to hypoxia/anoxia

Harrison and colleagues observe that Drosophila larvae, which live and feed in severely hypoxic conditions under normal laboratory conditions, show strikingly different behavioral and physiological responses to anoxia from those of adults. Read the paper here.

Toadfish hearing improves with age

Vocal differentiation is widely documented in birds and mammals but has been poorly investigated in other vertebrates, including fish. Vasconcelos and colleagues examined how closely hearing development in the toadfish matches the development of their vocal repertoire. Read the paper here.

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This week, Cambridge (UK) hosted the 10th Symposium on the Physics of Living Matter (PLM10) (http://www.plm-symposium.org/). For those of us who were at PLM1, it is surprising to see that what was (and remains) a grass roots organized event, persists. In some ways it is a tribute and an example that a community can be created by nurturing a common set of interests; in this case how the physical sciences can shed light onto biological problems (NB this is different from Biophysics which looks for biological examples of physical phenomena).

The symposia started with the view of making the local community aware of developments at the interface of Physics and Biology. In the early 00s there were a few pockets of activity cradling this interest. In particular, the legendary Physiology course of Woods Hole (this year’s Bragg lecture was given by Julie Theriot, who has been a pioneer in the field and an active participant in Woods Hole), Eric Karsenti’s division in EMBL, Dresden CBG/PKS was starting and Stan Leibler in Rockefeller was breeding a group of interesting scientists, while individuals like Dennis Bray, were making significant contributions from ‘the side”. Things have changed and ten years on, the interactions between Physics and Biology are on a solid ground. This year’s Symposium bore witness to this and left the message that the future of Biology lies in the quantitative analysis of biological problems and on the use of the reasoning and methods of the physical sciences. It has taken a long time to come but many of us got the feeling at the meeting that the Physics of Living Matter is coming of age.

In his book “What a mad pursuit”, F Crick comments on how Max Delbruck was driven into Biology to search for new Physics to explain living systems (see http://amapress.gen.cam.ac.uk/?p=1489 if you want to learn a bit more) and contrasts this with the belief of Linus Pauling in Chemistry to understand the same problem. Crick makes the point that, as he sees it, history shows that Pauling was right and Delbruck was wrong. However, he puts it in an interesting manner by stating that “time has shown that, SO FAR, Pauling was right and Delbruck was wrong……”. It is the ‘so far’ that reveals Crick’s caution and belief that the story had a second part. This second part is emerging now. With hindsight one can say that the reason why Chemistry rather than Physics provided the insights into Biology during the XX century was, simply, that the problem then was the structure of living matter, not its function. And the structure was, and remains, a problem of Chemistry. Surely one uses physical methods to understand it e.g crystallography and the different flavours of microscopy, but the answers lie in Chemistry. However, when we want to understand how the elements of living matter combine and interact to make WORKING cells, tissues and organs, we have to recur to physics. Herein we find the ways in which biological systems ‘cheat’ the laws of equilibrium thermodynamics and statistical mechanics and, in probing the HOW we learn about how Physics helps explain Biology and about how Biology extends Physics. The XXI century proves that both Pauling and Delbruck were right and PLM10 was a great tribute to this statement with talks on experimental approaches to the origin of life, top notch cell biology and statistical approaches to the behaviour, and output, of cell populations.

The change in the field has been remarkable. Daniel St Johnston commented to me during the meetinh how we can now see that cell biology is Physics. Well, actually, cell biology has always been close to Physics, what has happened in the last few years is that looking at real cells, cells in ensembles or organisms, poses much more interesting questions and problems than when we look at them in isolation. That when we ask questions about their Biology rather than their Physics, we do get interesting answers. An approach to cell (and developmental) biology, which sees tissues and organs as ‘living matter’ is important and harbours the future of the biological sciences. A future in which genetics is not only a tool for the discovery of parts but a tool to perturb systems, to test hypotheses posed in the form of detailed models which, as J Skotheim said, need to be taken seriously i.e. building them to make quantitative predictions and testing these predictions in the terms dictated by the models. And this is another of the issues raised by the Physics of Living Matters: models are the path to mechanisms. But models, not as cartoons of a process but in the sense that an engineer uses them, as ways to test the functioning of a system through a mechanism. There was much of this at PLM10.

PLM10 was the annual gathering of a community that is growing, a community that breaks the disciplinary barriers to solve interesting problems. Surely there are many meetings on this topic but with its 10th anniversary (duly celebrated with a great party which included cells and tissues dancing in the background to the tunes of a great band) but PLM continues to be a unique one because of its grass roots origin, the breadth of its content and its emphasis on the meat of the topic: biological systems, living matter a way of doing Biology which sees tissues and organs as a matter of Genes, Cells and Numbers.

PLM10 was a tribute to all this and it was good to see that the future is being built on a solid basis. Importantly I want to highlight here the interactions constructive interactions between UCL and Cambridge on PLM which continue to build a community and, in particular my colleagues Ewa Paluch, Buzz Baum,. Kristian Franze, Alexander Kabla and specially An Tyrrell for organizing a meeting that seems to go from strength to strength. PLM11, September 2016, is on the horizon; keep it as a date in your diaries!

(7 votes)

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In a world first, Phil Day presents a complete summary of a peer-reviewed scientific paper in the medium of rap: The Rapstract.

Original paper: Dr. Carolina Barcellos-Machado et al., Reconstruction of Phrenic Identity in Embryonic Stem Cell-Derived Motor Neurons (2014)

http://dev.biologists.org/content/141/4/784.abstract

Interpretation in Rap by Phil Day presented here. Subtitles available.

Phil Day is the author of the Rap History of the World www.raphistoryoftheworld.com

(7 votes)

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We seek to fill two tenure-track faculty positions at the Assistant or Associate Professor level. Both positions will have 70% research and 30% either teaching or extension responsibilities, depending on the successful candidates’ interests. For appointment as an assistant professor, the selected candidates will be expected to establish an extramurally funded research program, and for appointment as an associate, the individual is expected to have demonstrated success at supporting their research through extramural funding. Candidates interested in a research/teaching appointment will be required to establish an independent, extramurally funded research program and contribute to the educational mission of the department through teaching of undergraduate and/or graduate courses. Candidates seeking a research/extension appointment will be expected to develop and maintain an independent, extramurally funded research and extension program. All candidates must have the interest and ability to conduct research in agriculturally-relevant animal models. The successful candidates will be expected to collaborate with existing faculty members, and to develop a strong graduate student research and educational program. Familiarity with the commercial production system of their model species is greatly desired.

Position Title: Animal Biologist #103156

This faculty member will be expected to investigate fundamental aspects of biology with the goal of identifying novel approaches to improve the quality and efficiency of producing meat, milk, eggs, or animal fiber. We seek a scientist who will create new knowledge relating to the biological and physiological mechanisms underlying nutrition, growth, reproduction, or health in livestock, poultry, equine, and/or aquaculture species.

Position Title: Gastrointestinal Health/Physiology #103160

This faculty member will be expected to investigate aspects of gastrointestinal and digestive physiology of agriculturally relevant species. Gastrointestinal health plays a critical role in the sustainability and competitiveness of U.S. agriculture. We seek a scientist who will create new knowledge that will ultimately reduce animal production and health costs. Candidates examining intestinal physiology and those examining host-microbe interactions will receive equal consideration.

The College Park campus is located in suburban Maryland about 8 miles northeast of Washington, D.C. and 3 miles south of the USDA-ARS campus in Beltsville, MD. The Department of Animal and Avian Sciences primary offices, classrooms and laboratories are all located centrally on campus. The Department includes 23 faculty members and more than 30 support personnel. The candidates will be expected to develop and maintain independent, extramurally funded research programs in their respective areas. Facilities to support a research program are operated by the department and by the Maryland Agricultural Experiment Station (http://www.ansc.umd.edu/research/research-facilities). In addition to 30,000 square feet of laboratory space and 54,000 square feet of support facilities for various on-campus animal research activities, the Maryland Agricultural Experiment Station operates animal research facilities at the Central Maryland Research and Education Center for dairy cattle, the Wye Research and Education Center for beef cattle, and the Upper Marlboro Poultry Research Facility. In addition, our location in the Washington DC metropolitan area offers a wealth of opportunities for collaborations with government agencies such as the USDA, EPA, FDA, and NIH. Additional information about the Department can be obtained at www.ansc.umd.edu/

Salary & Benefits:

The University offers a comprehensive benefits package. The position is a full time 9-month academic year appointment. The opportunity exists to supplement salary through summer salary support from extramural funding.

Applications:

All interested individuals are encouraged to apply. Applications must be submitted through eTerp2 at https://ejobs.umd.edu/. Completed applications must have a letter of application addressed to the Search Chair, Department of Animal and Avian Sciences, University of Maryland. The position must be indicated in the application letter as the Animal Biologist or the Gastrointestinal Health position. Applications must include a description of research and either teaching or extension accomplishments, a proposed research/teaching or research/extension program, a curriculum vitae, unofficial transcript, and contact information for three professional references. The request for professional letters of reference will be generated by the eTerp2 system. Letters of reference must be submitted through eTerp2 prior to review of applications.

Closing Date:

For best consideration, applications will be accepted until November 23, 2015 or until a suitable candidate is identified.

The University of Maryland, College Park, actively subscribes to a policy of equal employment opportunity, and will not discriminate against any employee or applicant because of race, age, sex, color, sexual orientation, physical or mental disability, religion, ancestry or national origin, marital status, genetic information, or political affiliation. Minorities and women are encouraged to apply.

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This Spotlight article was written by Dianne Gerrelli, Steven Lisgo, Andrew J. Copp and Susan Lindsay, and was first published in Development.

Congenital anomalies are a significant burden on human health. Understanding the developmental origins of such anomalies is key to developing potential therapies. The Human Developmental Biology Resource (HDBR), based in London and Newcastle, UK, was established to provide embryonic and fetal material for a variety of human studies ranging from single gene expression analysis to large-scale genomic/transcriptomic studies. Increasingly, HDBR material is enabling the derivation of stem cell lines and contributing towards developments in tissue engineering. Use of the HDBR and other fetal tissue resources discussed here will contribute to the long-term aims of understanding the causation and pathogenesis of congenital anomalies, and developing new methods for their treatment and prevention.

Introduction

An important goal of developmental biology is to understand human embryonic/fetal development and the causes of congenital anomalies. A better understanding of the gene pathways that lead to developmental anomalies will aid new medical approaches for disease treatment and prevention. The causes of congenital anomalies include a variety of genetic and environmental factors, with the majority probably involving multifactorial aetiology. In Europe the recorded prevalence of major congenital anomalies is 23.9 per 1000 pregnancies, of which 80% were live births and 20% resulted in termination, fetal death or stillbirth (Dolk et al., 2010). Children who survive with congenital anomalies frequently experience long-term disability. For example, patients with congenital heart defects (the commonest group of anomalies) may develop severe disability in the first few days after birth (e.g. transposition of the great vessels), often requiring early surgery. In economic terms, the lifetime cost of caring for someone with a severe birth defect, like spina bifida, is estimated at over $0.5 million (Yi et al., 2011). This represents a challenge not only for individuals and families, but also for healthcare systems. In recent decades it has become possible to prevent some congenital anomalies. Two notable examples are vaccination of women against rubella to reduce the number of newborn babies with congenital rubella syndrome (Tookey and Peckham, 1999), and supplementation with folic acid in early pregnancy to decrease the prevalence of neural tube defects (Eichholzer et al., 2006).

Animal models are widely used to test hypotheses about the development of the embryo and fetus. Over the last 10 years there have been huge advances in the understanding of model organisms, in terms of whole-genome sequencing, identifying gene regulatory networks and determining developmental mechanisms. A striking finding is that the majority of protein-coding genes are shared between mouse and human (Yue et al., 2014). Therefore, the differences between the species are unlikely to be due to gene diversity but mainly to modifications in regulatory programmes controlling where and when genes are expressed. The spatial and temporal control of gene expression is therefore extremely important and might help to explain what makes us human.

As well as similarities, there are many established differences between the development of humans and model organisms such as the mouse. Most notably, during evolution the brain has changed in size and shape. Differences are particularly evident in the development of the human cerebral cortex (Bae et al., 2015), with huge increases in the number of cells and in the complexity of cell types. The cortex of the human brain also undergoes a process of folding known as gyrification, which increases the number of cortical neurons. This gyrification is thought to correlate with increased cognitive abilities (Gautam et al., 2015). The mouse brain does not undergo gyrification.

As another example, the eyes of humans are also more complex: they contain three types of cone cells as opposed to only two in mice; while the macula – a highly pigmented area at the back of the human retina – is absent in mice. A number of genes whose mutation is associated with human congenital syndromes, such as KAL1 (ANOS1) (Cadman et al., 2007) and SHOX (Blaschke and Rappold, 2006), are not found in the mouse genome. Thus, although model organisms have proved hugely valuable in understanding developmental processes, there is also a need to study human tissue directly.

Here, we present an overview of the resources available to the research community for analysing human development, with a particular focus on the Human Developmental Biology Resource (HDBR). Resources such as tissue banks, bioinformatics portals and archive collections provide researchers with crucial information and material for the analysis of human development and associated congenital abnormalities.

Research tissue banks

Several research tissue banks have been created in the UK and elsewhere to enable researchers to gain access to human embryonic and fetal samples. These banks collect tissue in a systematic fashion and conform to the highest ethical standards and research governance.

The Human Developmental Biology Resource (HDBR)

The HDBR (www.hdbr.org; with whom the authors are associated) was established in 1999 and is funded by the Medical Research Council and Wellcome Trust. It has National Research Ethics Service approval and is licensed by the UK Human Tissue Authority (https://www.hta.gov.uk/). The collection of material from elective terminations of pregnancy currently comprises over 4000 specimens aged between 3 and 20 post-conception weeks (pcw). The resource continues to collect material, with 400 new specimens added each year. All specimens are karyotyped, with 4% having chromosomal abnormalities (most commonly trisomy 21 and monosomy X) and 9% displaying some form of phenotypic abnormality.

Various types of sample are available from the HDBR (Fig. 1). The majority of tissue provided by the resource is from chromosomally normal samples but material can also be provided from specimens with chromosomal abnormalities. Fresh tissue from specific organs and developmental ages can be used in a range of scientific procedures, such as fluorescence-activated cell sorting of live cells to purify specific human fetal cell populations in order to derive primary cell lines or stem cells. Frozen tissue can be used for the production of mRNA, genomic DNA or protein. These samples are being used in large-scale transcriptome analyses to compare human and animal models and across specific tissues, sexes and between normal and karyotypically abnormal samples.

Fig. 1 Examples of resources available from the HDBR. (A) Images of embryos at (from left to right) CS12 [∼26 days post conception (dpc)], CS16 (∼37 dpc) and CS19 (∼47 dpc). (B) A CS17 (∼41 dpc) embryo with trisomy 21. (C) CS12-CS21 series of 3D models, generated using optical projection tomography (OPT) from embryos in the HDBR collection, displayed at their relative sizes. Movies and images of the models can be viewed or the full models requested via the HuDSeN website (www.hudsen.org). (D) The HDBR provides access to curated gene expression data. The upper image shows a section through a CS17 embryo stained with anti-GAP43 antibody (brown); the lower image is of the corresponding section in the CS17 OPT model onto which the GAP43 expression data have been mapped (red, strong expression; yellow, moderate expression). Expression data were mapped from experimental sections to digital sections using MAPaint software (http://www.emouseatlas.org/emap/home.html). (E) 3D expression domain of GAP43 expression in the head and part of the body built up by mapping data from sections as shown in D. Experimental and mapped data are uploaded to a spatial database (www.hudsen.org). (F) Word cloud representation of the expression data available in the HuDSeN human gene expression spatial database (www.hudsen.org). The word cloud represents the number of entries for each gene and there are currently data from 128 genes. Scale bars: 1 mm.
 

The HDBR also provides a gene expression service using RNA in situ hybridisation or protein immunohistochemistry. Sectioned embryonic or fetal tissue is used to identify the temporal and spatial expression of specific genes or proteins. Gene expression data from this service, as well as data generated by external projects, are digitally imaged and made accessible via an open access database (www.hudsen.org). Some stained sections are also available at high resolution (http://nbb-slidepath.ncl.ac.uk/dih; username and password available on request).

Material can be provided to researchers in the UK without the need for project ethics review, as well as to international groups with relevant ethical review body approvals. Over 10,000 slides and tissue samples have been distributed to registered users in the last 5 years, and ∼100 projects are registered per year. The majority of projects are based in the UK, but a growing number of users are in the USA (17%), mainland Europe (11%) and other locations worldwide. Distribution of human embryonic and fetal tissue is prioritised to projects that investigate congenital disorders. Of particular interest are studies that aim to understand the function of genes important for early development, genes linked to human-specific functions (e.g. cognitive function and language) and genes associated with significant anatomical or functional differences between mice and humans.

A wide variety of studies have been carried out using HDBR materials (Fig. 2). These range from investigation of single genes underlying genetic disorders (Tischfield et al., 2010;Thomas et al., 2014) to high-throughput studies of transcriptomes (Kang et al., 2011) and regulatory sequences (Necsulea et al., 2014). Advances in high-throughput sequencing technologies have opened the door to large-scale cross-species comparisons that are highlighting differences in transcript sequence, alternative splicing, expression level and regulation between humans and model organisms (Cotney et al., 2013; Bae et al., 2014). Some studies, such as the investigation of tail bud development in chick and human (Olivera-Martinez et al., 2012), dissect key processes of early development. Organ-specific tissues have been used for the derivation of primary cell lines and stem cells (U et al., 2014).

Fig 2. HDBR material has been used in many different types of studies.Examples are shown of the types of study carried out using HDBR material. (A,B) Examples from the gene expression service. HDBR staff perform gene expression analysis on sectioned tissue by in situ hybridisation (A) or immunohistochemistry (B) on behalf of researchers. (C-E) The types of studies that researchers carry out in their own laboratories with material provided by HDBR: to produce cell lines or perform functional analysis (C); gene expression studies in paraffin fixed sections (D); and transcriptomics studies in cells or tissues (E).

Other tissue banks

A number of other groups, in the UK and USA, have set up collections of human fetal material. These are normally organised around defined scientific projects and the samples are not usually available to the wider scientific community. However, there are exceptions where banks have been established to provide material for use in research. For example, the South Wales Initiative for Fetal Tissue (http://www.biobankswales.org.uk/swift-research-tissue-bank/) provides clinical grade fetal tissue (5 and 12 pcw) primarily for human therapeutics, and the University of Maryland Brain and Tissue Bank in the USA (http://medschool.umaryland.edu/btbank/catalog.asp) can provide access to both adult and fetal tissue.

Bioinformatics portals

A number of sites provide valuable information on human development for researchers. For example, the BrainSpan project (www.brainspan.org) has generated transcriptome data and gene expression data from multiple regions of the embryonic, fetal and adult brain. The UNSW Embryology portal is an education and research website that has links to many collections of human embryonic and fetal specimens (https://embryology.med.unsw.edu.au/embryology/index.php/).

In the UK a consortium of UKCRC funders has established The National Tissue Directory and Coordination Centre (www.biobankinguk.org). This directory will enable researchers to find human biobanks within the UK and gain access to their collections through one system. These and other bioinformatics databases are essential resources for researchers, particularly those whose access to primary tissue is limited.

Archive resources

The Carnegie collection (www.ehd.org/virtual-human-embryo/)

Seven thousand human embryos are stored in the Carnegie collection at the National Museum of Health and Medicine, Washington, D.C. This material was used to develop the comprehensive Carnegie staging system based on internal as well as external features. Carnegie staging (CS1-23) is now employed universally in human embryo research. Individual embryos throughout the embryonic period have been sectioned and, in an attempt to make the collection more accessible for research and teaching, digital images from a subset of these have been acquired. The images are labelled with standard anatomy terms to help with interpretation, or used to generate 3D models and 252 movies.

The Kyoto collection (http://bird.cac.med.kyoto-u.ac.jp/index_e.html)

This is the largest human embryo collection in the world, with over 44,000 specimens between CS7 and CS23. Maternal epidemiological data and detailed clinical information on the pregnancies were collected for each specimen. Five hundred normal and 500 abnormal embryos have been serially sectioned, and a further 1300 staged human embryos have been digitally imaged by magnetic resonance (MR) microscopy and 3D reconstructions produced.

Conclusions

The landscape for developmental biology and clinical research has changed within the last few years, with more emphasis being placed on large-scale sequencing projects such as the Genotype-Tissue Expression Project (GTEx Consortium, 2013), Geuvadis (Lappalainen et al., 2013) and the UK 100,000 Genomes Project (Siva, 2015). These projects and numerous others aim to map variations in gene expression in thousands of individual patients and correlate this with disease phenotypes and bioinformatics information on sites such as the Encyclopedia of DNA Elements (ENCODE; https://www.encodeproject.org/;Kellis et al., 2014). Other studies are using novel algorithms to interrogate the sequencing data to investigate gene networks (Liu et al., 2014). These projects are now identifying candidate genes that could play a role in a range of human diseases and syndromes.

The next step in this gene discovery pipeline will be to test candidate genes in model organisms and human tissue. This analysis needs to be performed at the cellular level to determine whether the genes are expressed in tissues and cell types relevant to the disease under study. The HDBR is ideally placed to assist researchers wishing to investigate genes thought to be responsible for congenital abnormalities. In addition, some groups are using material provided by the HDBR to study epigenetic regulation and in functional studies. Other projects include the derivation of stem cells and scaffolds for tissue engineering projects. It is likely in the coming years that the HDBR will not only support projects wishing to understand key developmental processes but will also increasingly provide resources to underpin translational research.

References

Bae, B.-I., Tietjen, I., Atabay, K. D., Evrony, G. D., Johnson, M. B., Asare, E., Wang, P. P., Murayama, A. Y., Im, K., Lisgo, S. N. et al. (2014). Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning. Science 343, 764-768. doi:10.1126/science.1244392

Bae, B.-I., Jayaraman, D. and Walsh, C. A. (2015). Genetic changes shaping the human brain. Dev. Cell 32, 423-434. doi:10.1016/j.devcel.2015.01.035

Blaschke, R. J. and Rappold, G. (2006). The pseudoautosomal regions, SHOX and disease. Curr. Opin. Genet. Dev. 16, 233-239. doi:10.1016/j.gde.2006.04.004

Cadman, S. M., Kim, S.-H., Hu, Y., González-Martínez, D. and Bouloux, P.-M. (2007). Molecular pathogenesis of Kallmann’s syndrome. Horm. Res. 67, 231-242. doi:10.1159/000098156

Cotney, J., Leng, J., Yin, J., Reilly, S. K., DeMare, L. E., Emera, D., Ayoub, A. E., Rakic, P. and Noonan, J. P. (2013). The evolution of lineage-specific regulatory activities in the human embryonic limb. Cell 154, 185-196. doi:10.1016/j.cell.2013.05.056

Dolk, H., Loane, M. and Garne, E. (2010). The prevalence of congenital anomalies in Europe. Adv. Exp. Med. Biol. 686, 349-364. doi:10.1007/978-90-481-9485-8_20

Eichholzer, M., Tönz, O. and Zimmermann, R. (2006). Folic acid: a public-health challenge. Lancet 367, 1352-1361.doi:10.1016/S0140-6736(06)68582-6

Gautam, P., Anstey, K. J., Wen, W., Sachdev, P. S. and Cherbuin, N. (2015). Cortical gyrification and its relationships with cortical volume, cortical thickness, and cognitive performance in healthy mid-life adults. Behav. Brain Res. 287, 331-339. doi:10.1016/j.bbr.2015.03.018

GTEx Consortium (2013). The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580-585. doi:10.1038/ng.2653

Kang, H. J., Kawasawa, Y. I., Cheng, F., Zhu, Y., Xu, X., Li, M., Sousa, A. M. M., Pletikos, M., Meyer, K. A., Sedmak, G. et al. (2011). Spatio-temporal transcriptome of the human brain. Nature 478, 483-489. doi:10.1038/nature10523

Kellis, M., Wold, B., Snyder, M. P., Bernstein, B. E., Kundaje, A., Marinov, G. K., Ward, L. D., Birney, E., Crawford, G. E., Dekker, J. et al. (2014). Defining functional DNA elements in the human genome. Proc. Natl. Acad. Sci. USA 111, 6131-6138. doi:10.1073/pnas.1318948111

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D. Bullara* and Y. De Decker
*domenico.bullara@mail.com

When Catarina Vicente (Community Manager of “The Node”) proposed us to write a post about our recent paper on pattern formation in zebrafish [Bullara2015] we were very glad for the opportunity she was giving us to tell the background story about our work in this blog. We are not biologists (we are two theoretical chemists working in the field of nonlinear chemistry and self-organization) and we took Dr. Vicente’s invitation as an opportunity to present our outsiders’ point of view on a quite debated question related to morphogenesis. We therefore very much hope to gain inspiring feedbacks from your comments.

Following this spirit, we initially wrote our post including a number of theoretical details and comments, in the hope to bridge the gap between the typical jargon and assumed basic knowledge of theoretical nonlinear chemistry and experimental developmental biology. We however realized that the final manuscript was too long to fit the scopes of this blog. So – following Dr. Vicente’s advice – we decided to leave the full version in a separate file (which can be downloaded here) for the interested reader, and summarize what we think may be the more interesting paragraphs in the following post.

— Alan Turing and the reaction-diffusion mechanism

Morphogenesis and nonlinear chemistry share a special bond since the British mathematician Alan Turing published his seminal paper “On the chemical basis of morphogenesis” [Turing1952], which set the basis for a theoretical development of both disciplines. The basic question that Turing wanted to answer was: How can a system with such a high degree of symmetry as an egg cell (essentially a sphere) develop organisms with a much lower degree of symmetry (i. e. living beings)?

The pivotal idea of Turing is that “a system of chemical substances, called morphogens, reacting together and diffusing through a tissue, is adequate to account for the main phenomena of morphogenesis. Such a system, although it may originally be quite homogeneous, may later develop a pattern or structure due to an instability of the homogeneous equilibrium [NOTE1], which is triggered off by random disturbances” [Turing1952]. This mechanism has since then being referred to as the “reaction-diffusion (RD) mechanism”, and the corresponding stationary patterns as “Turing patterns”.

From a molecular point of view, a chemical reaction is essentially an exchange of atoms between molecules, or between molecular segments of a single molecule. But theoretical approaches to reactive systems are often based on a much coarser level of description: one usually divides the whole space into a collection of infinitesimal volumes (or points), within which chemical reactions are considered as local processes. In this framework, diffusion is a physical mechanism which allows molecules to migrate from one point in space to another in a Brownian motion. Both concepts can straightforwardly be extended to non-chemical systems, as long as one can define local events taking place between the units composing a system whose outcome is to change the number of units (reactions) and Brownian motions of these units (diffusion). From this point of view a wolf killing a rabbit or a cell undergoing mitosis may be both considered as “reactions”, although not chemical ones.

Precise mathematical requirements involving the parameters of the system must be fulfilled in order for a RD system to undergo the kind of dynamical instability described by Turing. When this happens, one says that a “Turing instability” or “Turing bifurcation” occurs, and stationary patterns with an intrinsic wavelength can be generated. The original model proposed by Alan Turing as well as several other pattern-generating models undergo precisely this type of instability, which led in practice to an identification of the terms “Turing instability”, “Turing patterns” and “reaction-diffusion mechanism”. It is important however to understand that these terms express separate concepts, and therefore a Turing instability (as well as a Turing pattern) is not limited to reaction-diffusion mechanisms.

— Turing patterns without diffusion? The riddle of the zebrafish stripes

Our interest in zebrafish patterning began in 2012, when we discovered the experimental work of Shigeru Kondo and coworkers [Yamaguchi2007, Nakamasu2009, Inaba2012, Hamada2014]. In their experiments the zebrafish skin patterns exhibit a dynamics which closely resemble what can be observed in typical RD equations schemes forming Turing patterns. Moreover, the experiments clearly shows that the stripes of the zebrafish possess an intrinsic wavelength, which is recovered even after total ablation of the pattern. Both these results would strongly suggest that a RD mechanism could be behind the observed pattern formation. We believe however that this idea should be ruled out for several reasons, among which the following two stand as the most important.

The first reason is that the cell-to-cell interactions, which are at the core of the pattern formation mechanism, cannot be considered as local events like reactions in RD systems. They involve instead two specific distances. When two skin pigment cells of different colors (the yellow xantophore and the black melanophore) are in close contact, they mutually inhibit each other’s growth. However, xantophores can also increase the rate at which melanophores appear (and their survivability) at long distance. The nonlocal character of the cellular interactions makes it impossible to cast them into chemical-like reactive terms, which (as said before) are supposed to act locally at each point in space.

The second – and perhaps even more important – evidence is that the pigment cells do not diffuse across the skin of zebrafish. They do exhibit some degree of mobility, but their movement – which has been characterized in vitro as a “run-and-catch” motion [Yamanaka2014] – cannot be represented as a Brownian motion. Even more importantly, this motion is very limited and is not enough to induce by itself a migration of pigment cells into separate domains [Mahalwar2014] [NOTE2]. In other words, cells are in a first approximation almost immobile.

The patterns on the skin of zebrafish thus look like RD patterns, but cannot be explained by reaction and diffusion. In order to solve the riddle posed by these patterns, we took inspiration from nonlinear nanochemistry. When chemical reactions are described at the nanoscale they cannot be interpreted as local processes, but as “propagating” in space. In mathematical terms, this effect translates into virtual diffusion terms [DeDecker2004] even if the molecules are immobile, because the reaction itself can induce a redistribution of the molecular populations in space. We thus thought that a similar effect could also exist for pigment cells on the skin of zebrafish.

— A new mechanism: differential growth

The question we wanted to answer was essentially the following: Is the the nonlocal character of the short-range and long-range interactions able to create a “virtual movement” of cells across the zebrafish skin, and to generate in such a way a pattern with an intrinsic wavelength?

To test our hypothesis, we needed a simple mathematical model which is also biologically relevant. In order to test whether the observed pattern formation can be explained only in terms of non-local interactions between xantophores and melanophores, we decided to completely remove any form of cellular motion from our model. For the same reason, we did not explicitly include a third type of pigment cell (iridophores), which was shown to be of some importance in the pattern formation on the body of the fish [Singh2014], but not in the fins [Patterson2013]. We then introduced the short-range and long-range interactions as stochastic processes occurring with different probabilities, opting again for the simplest possible implementation: pairwise cell-to-cell interactions. For the sake of completeness we also included the spontaneous differentiation and death of both pigment cells on the skin of the fish [NOTE3]. Finally we further simplified our model by finding a mathematically simple yet biologically representative set of parameters which would trigger pattern formation.

Numerical simulations showed that patterns with an intrinsic wavelength could be formed with our model. We moreover observed that the morphology and the periodicity of the patterns resemble those of the experiments. An analytical study of the evolution equations also showed that the patterns emerge from a Turing bifurcation, despite the absence of cellular motion, thanks to the non-local cellular interactions. This mechanism is intrinsically different from the reaction-diffusion mechanism proposed by Turing although, in our opinion, the patterns thus generated may still be called Turing patterns, because they result from a Turing bifurcation generated by nonequilibrium processes. The key ingredient to form the patterns is that cells can “be born” and die with different rates – or in more mathematical words can have different growth rates – depending on their surrounding. In order to give a unambiguous connotation to this mechanism and distinguish it from others, we proposed to call it “differential growth”. Differential growth promotes a non-trivial redistribution of cells across space by combining short-range and long-range cellular interactions in an appropriate way. In such situations cellular migration becomes accessory to pattern formation, so one cannot rule out the possibility of having Turing patterns solely because of lack of extensive cellular movement.

As a final note, we would like to mention a related, very interesting article which has recently been published in Development [Hiscock2015]. The authors propose a way to rationalize the different patterns-generating mechanism under a common mathematical framework, and try to derive simple rules for the control parameters which can be used as a guide to design experiments. It is interesting to note that the only mechanism for which the authors could not calculate a simple parametric constraint is precisely the type of mechanism we consider here. For reaction-diffusion systems, classical toy models can be used to derive the general rule that “the inhibitor must diffuse faster than the activator”. For the class of systems which fall under the differential growth mechanism, our model suggests that “the inhibitor must grow faster than the activator”, provided that the growth of the former is controlled by a long-range positioning of the latter.

— Notes

[NOTE1] Intended as the mathematical equilibrium of the set of equations describing the dynamics of the system, or in other words any reference homogeneous steady state solution of the latter.

[NOTE2] One of our initial guesses was that the short-range movement shown by the pigment cells could have been important in shaping the fine details of the stripes, more particular the small gap observed between two adjacent stripes. Because of the nature of our model, we could not test this hypothesis ourselves, but we recently discovered a preprint paper by A. Volkening and B. Sandstede titled “Modeling stripe formation in zebrafish: an agent-based approach” which independently proves this hypothesis true with a different modelling approach.

[NOTE3] To this regard, we feel like we should somehow apologize to the biology community for the choice of jargon we made in our paper: we there call “birth” what should more correctly be called “differentiation”. The reason of this choice is that the name commonly used in the stochastic mechanics literature for the class of processes we used is “birth/death” processes, so we felt that the model could be more easily understood by a broader audience of also non-biological scientists if we stuck to these names.

— References

[Bullara2015] Bullara, D., & De Decker, Y. (2015). Pigment cell movement is not required for generation of Turing patterns in zebrafish skin Nature Communications, 6 DOI: 10.1038/ncomms7971

[DeDecker2004] De Decker Y, Tsekouras GA, Provata A, Erneux T, & Nicolis G (2004). Propagating waves in one-dimensional discrete networks of coupled units. Physical review. E, Statistical, nonlinear, and soft matter physics, 69 (3 Pt 2) PMID: 15089388

[Hamada2014] Hamada, H., Watanabe, M., Lau, H., Nishida, T., Hasegawa, T., Parichy, D., & Kondo, S. (2013). Involvement of Delta/Notch signaling in zebrafish adult pigment stripe patterning Development, 141 (2), 318-324 DOI: 10.1242/dev.099804

[Hiscock2015] Hiscock, T., & Megason, S. (2015). Mathematically guided approaches to distinguish models of periodic patterning Development, 142 (3), 409-419 DOI: 10.1242/dev.107441

[Inaba2012] Inaba M, Yamanaka H, & Kondo S (2012). Pigment pattern formation by contact-dependent depolarization. Science, 335 (6069) PMID: 22323812
[Mahalwar2014] P. Mahalwar, B. Walderich, A.P. Singh and C. Nüsslein-Volhard, Local reorganization of xantophores fine-tunes and colors the striped pattern of zebrafish, Science 345:1362-1364 (2014).

[Nakamasu2009] Nakamasu, A., Takahashi, G., Kanbe, A., & Kondo, S. (2009). Interactions between zebrafish pigment cells responsible for the generation of Turing patterns Proceedings of the National Academy of Sciences, 106 (21), 8429-8434 DOI: 10.1073/pnas.0808622106

[Patterson2013] Patterson, L., & Parichy, D. (2013). Interactions with Iridophores and the Tissue Environment Required for Patterning Melanophores and Xanthophores during Zebrafish Adult Pigment Stripe Formation PLoS Genetics, 9 (5) DOI: 10.1371/journal.pgen.1003561

[Singh2014] Singh, A., Schach, U., & Nüsslein-Volhard, C. (2014). Proliferation, dispersal and patterned aggregation of iridophores in the skin prefigure striped colouration of zebrafish Nature Cell Biology, 16 (6), 604-611 DOI: 10.1038/ncb2955

[Turing1952] Turing, A. (1952). The Chemical Basis of Morphogenesis Philosophical Transactions of the Royal Society B: Biological Sciences, 237 (641), 37-72 DOI: 10.1098/rstb.1952.0012

[Yamaguchi2007] Yamaguchi, M., Yoshimoto, E., & Kondo, S. (2007). Pattern regulation in the stripe of zebrafish suggests an underlying dynamic and autonomous mechanism Proceedings of the National Academy of Sciences, 104 (12), 4790-4793 DOI: 10.1073/pnas.0607790104

[Yamanaka2014] Yamanaka, H., & Kondo, S. (2014). In vitro analysis suggests that difference in cell movement during direct interaction can generate various pigment patterns in vivo Proceedings of the National Academy of Sciences, 111 (5), 1867-1872 DOI: 10.1073/pnas.1315416111

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A 4-year PhD position is available in the group ‘ Evolution of nutrient and growth homeostasis in animals’ at the Sars Centre in Bergen/Norway. The successful candidate will study the molecular and cellular links between feeding, nutrient availability and reproduction using the sea anemone Nematostella vectensis as a main model organism.

Further details on the position, group and application procedure are available here:
http://www.sars.no/jobs/2015-10092_phd_steinmetz.php

Contact details:

Dr Patrick Steinmetz

e-mail:patrick.steinmetz@uib.no

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