This obituary first appeared in Development.

Patrick Müller and Christiane Nüsslein-Volhard reflect on the life and career of their colleague Hans Meinhardt.

Hans Meinhardt, a pioneer in the field of theoretical biology, died on 11 February 2016 in Tübingen. He made numerous important contributions to developmental biology by spearheading the use of mathematical models to investigate the logic of patterning in complex biological systems. His work expanded our understanding of the mechanisms behind diverse biological processes, from the generation of patterns on sea shells to the evolution of the brain.

Meinhardt grew up in the German Democratic Republic. His family fled to West Germany before the Wall was built. He studied physics at the University of Cologne and received his PhD in 1966. As a postdoc at the European High Energy Laboratory (CERN) in Geneva he gained expertise in computer-based modeling, but over time became more interested in biological processes and decided to move into the emerging field of molecular biology.

In 1969, Meinhardt joined the group of Alfred Gierer at the Max Planck Institute for Virus Research in Tübingen, Germany (which has since become the Max Planck Institute for Developmental Biology). Gierer, a physicist by training, and famous for the demonstration that RNA, not only DNA, could be the genetic material (Gierer and Schramm, 1956), was looking for new challenges in developmental biology. He had started a research group to study the miraculous regenerative capabilities of Hydra, which can self-organize perfect animals even after complete dissociation. Meinhardt’s initial project in Gierer’s department was purely experimental, isolating chromosomal proteins from cow blood cells. Meinhardt was convinced that this could be accomplished without using an ice bucket, arguing as a theoretician that the proteins should be stable at room temperature because they are also stable in living warm-blooded cows. However, discouraged by many wet lab failures, he looked for theoretical rather than experimental challenges.

Stimulated after a seminar by Günter Gerisch (a group leader at the newly founded Friedrich Miescher Laboratory) on oscillations and chemotaxis in the slime mold Dictyostelium, Meinhardt considered applying his expertise in computer modeling to simulate the aggregation of Dictyostelium. Gierer was intrigued by the thought of applying computational methods to developmental biology problems, but suggested that Meinhardt instead use this approach to develop a theory explaining the surprising regenerative capabilities of Hydra. This idea was inspired by two major influences. First, Magoroh Maruyama had demonstrated the importance of positive feedback – selfenhancement – that could dramatically amplify small deviations from initial conditions in diverse processes, from morphogenesis to economy (Maruyama, 1963). Second, neurophysiological work in the neighboring Max Planck Institute for Biological Cybernetics showed that contrast enhancement in the visual system is achieved by a local activation from a stimulus together with an inhibitory effect on surrounding areas of the retina, a mechanism termed lateral inhibition (Kirschfeld and Reichardt, 1964). The synthesis of these two concepts of local self-enhancement and lateral inhibition led Meinhardt and Gierer to formulate a theory explaining the emergence of polarity and pattern from near-uniform states.

Meinhardt and Gierer hypothesized that patterning could be mediated by a short-range activator with strong self-enhancing capabilities, coupled to an inhibitor of longer range that suppressed the expansion of the activator in the surrounding areas. Meinhardt then performed computer simulations to test whether their hypothesis could explain experimental observations. In the 1970s, no biological institute had a computer, so the numerical simulations had to be done using punch cards on a Hollerith machine at the computer center in the University of Tübingen. Much of the theory was based on Meinhardt’s remarkable intuition, which made the tedious computations feasible. Their famous theory of biological pattern formation was published in Kybernetik (Gierer and Meinhardt, 1972), followed by a paper on applications in the Journal of Cell Science (Meinhardt and Gierer, 1974). Although the theory was driven by the experimental work on Hydra, it also provided an important general recipe for self-organization. Strikingly, even in the absence of specific molecular data these models correctly predicted the behavior of several biological systems (Meinhardt, 1982; Meinhardt and Gierer, 2000).

Meinhardt and Gierer’s work is often regarded as equivalent to the earlier work of Alan Turing (Turing, 1952). However, they were not aware of Turing’s paper at the time of submission (Meinhardt, 2006a, 2008; Roth, 2011), and in fact the Meinhardt–Gierer model provided three important advances that were missing in Turing’s work. First, the fundamental concept of local self-enhancement and long-range inhibition, although inherent in Turing’s equations (Gierer, 1981), was not explicitly described in Turing’s paper. Strikingly, Meinhardt and Gierer had also intuitively found the only two possible realizations of self-organizing systems with two components: the activator/inhibitor system and the substratedepletion model (Murray, 2003). Second, Meinhardt and Gierer incorporated realistic pre-patterns that are often found in developing systems – the ‘source density’ – which provides the competence for autocatalysis. Turing’s model instead focused purely on selforganizing mechanisms in a homogenous field of cells. Third, using realistic Michaelis–Menten-based kinetics combined with the source density, the Meinhardt–Gierer models achieved robust and highly reproducible patterns that also scale with tissue size. This was possible because Meinhardt and Gierer introduced saturation kinetics and non-linear terms for the autocatalysis as opposed to Turing, whose models with linear kinetics have a fixed length scale (Roth, 2011). The molecular implementation of the Meinhardt– Gierer models was not strictly specified. Diffusion and degradation of molecules was the simplest way to implement short-range activation and long-range inhibition in the models, but Gierer and Meinhardt also considered other transport and inhibition mechanisms (Gierer, 1981).

In the mid-1980s, Meinhardt proposed models for Drosophila segmentation based on the discovery of mutations affecting segmentation in very specific ways (Nüsslein-Volhard and Wieschaus, 1980). He proposed, using simple logic, that periodic structures such as segments require at least three states to form unambiguous segment borders, not two states as had been previously assumed (Meinhardt, 1984, 1985, 1986). The molecular basis of the genes involved was not yet clear at the time, but the basic idea was to make stripes by assuming cooperation between neighboring cells with mutually exclusive states. Meinhardt’s attempts at modeling embryonic axis formation in Drosophila by self-organizing gradients failed, however, because Drosophila embryogenesis is strongly influenced by pre-patterns of localized maternal determinants and a transmission of this information by complex gene cascades (Akam, 1989; St. Johnston and Nüsslein-Volhard, 1992).

In the 1980s, Meinhardt had key insights into insect and vertebrate appendage development and regeneration (Meinhardt, 1980, 1983a,b). At the time, appendage patterning was explained by the ‘polar coordinate’ model (French et al., 1976). This theory proposed abstract circumferential positional values and complicated rules to explain regeneration experiments, but it was hard to envision how this could be implemented on a molecular level. Meinhardt instead postulated a much simpler and more elegant model, in which the intersection of three compartments could serve as an organizing center for the production of new peaks and subsequent appendage patterning. The theory was initially highly controversial; indeed, three journals rejected his manuscript describing this key insight before it was published in Developmental Biology (Meinhardt, 1983b). However, strong experimental support for this model was subsequently found (Vincent and Lawrence, 1994).

Together with his student, Martin Klingler, Meinhardt developed another breakthrough theory on the patterning of sea shells (Meinhardt, 1984; Meinhardt and Klingler, 1987). The inspiration came when he ordered spaghetti frutti di mare in an Italian restaurant in 1980 and realized that the patterns on the shells on his plate could arise from a self-organizing system. One day, he came into the lab with an excerpt of Doktor Faustus by Thomas Mann. He cited one of the protagonists lamenting on how difficult, if not impossible, it was to ever understand the complicated patterns on cone snails. But Meinhardt had found a general mechanism of how it might work. He published his findings in his classic book The Algorithmic Beauty of Sea Shells, which also supplies the source code that enables readers to reproduce and extend computer simulations of these and other biological patterns (Meinhardt, 1995).

Meinhardt worked on numerous other processes, from bacterial patterning to chemo- and phyllotaxis (Meinhardt et al., 1998, 1999; Meinhardt and de Boer, 2001). He also had a keen interest in comparative aspects of patterning systems, was driven to understand how different organisms solved similar tasks differently throughout evolution, and proposed that an ancestral body pattern evolved into the brain and heart of higher organisms (Meinhardt, 2002).

After his retirement in 2003, Meinhardt continued to work enthusiastically on his projects, publishing more than 20 papers. Unusually for modern times, he published most of his papers as the sole author. His most fruitful collaboration was with Alfred Gierer, with whom he also shared a life-long friendship. Meinhardt’s last publication dealt with the Spemann organizer, developing a unified theory of bone morphogenetic protein signaling and dorsoventral patterning and its relationship with anterior-posterior patterning in different organisms (Meinhardt, 2006b, 2015), but his latest work on planarian regeneration remains unfinished.

Meinhardt was known for riding his bicycle up the large hill to the Max Planck Institute every day, even after he retired. He was an ardent traveler and loved the desert, but was similarly fascinated by the local nature around him, discovering new facets in the old and gaining inspiration for his scientific questions. Much of his work was based on intuition that he then tested with computer simulations. His goal was to find organizing principles, to understand the logic of patterning systems despite apparent complexity, and to develop minimal models with predictive power.

Hans Meinhardt was a happy and dedicated scientist. He spoke softly, and his steel-blue eyes were always full of contagious enthusiasm for his work. Once convinced of a certain strategy, he was stubborn and insisted on his theories, but he could also adjust his models based on new experimental findings. His contributions inspired new generations of biologists to find beauty in algorithms and apply them to the study of life. As Hans was fond of saying: “So wird’s gemacht” – that’s how it’s done.

References

Akam, M. (1989). Drosophila development: making stripes inelegantly. Nature 341, 282-283.

French, V., Bryant, P. J. and Bryant, S. V. (1976). Pattern regulation in epimorphic fields. Science 193, 969-981.

Gierer, A. (1981). Generation of biological patterns and form: some physical, mathematical, and logical aspects. Prog. Biophys. Mol. Biol. 37, 1-47.

Gierer, A. and Meinhardt, H. (1972). A theory of biological pattern formation. Kybernetik 12, 30-39.

Gierer, A. and Schramm, G. (1956). Infectivity of ribonucleic acid from tobacco mosaic virus. Nature 177, 702-703.

Kirschfeld, K. and Reichardt, W. (1964). Die Verarbeitung stationärer optischer Nachrichten im Komplexauge von Limulus. Kybernetik 2, 43-61.

Maruyama, M. (1963). Second cybernetics – deviation-amplifying mutual causal processes. Am. Scientist 51, 164.

Meinhardt, H. (1980). Cooperation of compartments for the generation of positional information. Z. Naturforsch. 35c, 1086-1091.

Meinhardt, H. (1982). Models of Biological Pattern Formation. London: Academic Press.

Meinhardt, H. (1983a). A boundary model for pattern formation in vertebrate limbs. J. Embryol. Exp. Morphol. 76, 115-137.

Meinhardt, H. (1983b). Cell determination boundaries as organizing regions for secondary embryonic fields. Dev. Biol. 96, 375-385.

Meinhardt, H. (1984). Models for positional signalling, the threefold subdivision of segments and the pigmentation pattern of molluscs. J. Embryol. Exp. Morphol. 83 Suppl., 289-311.

Meinhardt, H. (1985). Mechanisms of pattern formation during development of higher organisms: a hierarchical solution of a complex problem. Ber. Bunsenges. Phys. Chem. 89, 691-699.

Meinhardt, H. (1986). Hierarchical inductions of cell states: a model for segmentation in Drosophila. J. Cell Sci. 1986 Suppl. 4, 357-381.

Meinhardt, H. (1995). The Algorithmic Beauty of Sea Shells. Berlin; Heidelberg; New York: Springer-Verlag.

Meinhardt, H. (1999). Orientation of chemotactic cells and growth cones: models and mechanisms. J. Cell Sci. 112, 2867-2874.

Meinhardt, H. (2002). The radial-symmetric hydra and the evolution of the bilateral body plan: an old body became a young brain. Bioessays 24, 185-191.

Meinhardt, H. (2006a). From observations to paradigms; the importance of theories and models. An interview with Hans Meinhardt by Richard Gordon and Lev Beloussov. Int. J. Dev. Biol. 50, 103-111.

Meinhardt, H. (2006b). Primary body axes of vertebrates: generation of a nearCartesian coordinate system and the role of Spemann-type organizer. Dev. Dyn. 235, 2907-2919.

Meinhardt, H. (2008). Hans Meinhardt. Curr. Biol. 18, R401-R402.

Meinhardt, H. (2015). Dorsoventral patterning by the Chordin-BMP pathway: a unified model from a pattern-formation perspective for Drosophila, vertebrates, sea urchins and Nematostella. Dev. Biol. 405, 137-148.

Meinhardt, H. and de Boer, P. A. J. (2001). Pattern formation in Escherichia coli: a model for the pole-to-pole oscillations of Min proteins and the localization of the division site. Proc. Natl. Acad. Sci. USA 98, 14202-14207.

Meinhardt, H. and Gierer, A. (1974). Applications of a theory of biological pattern formation based on lateral inhibition. J. Cell Sci. 15, 321-346.

Meinhardt, H. and Gierer, A. (2000). Pattern formation by local self-activation and lateral inhibition. Bioessays 22, 753-760.

Meinhardt, H. and Klingler, M. (1987). A model for pattern formation on the shells of molluscs. J. Theor. Biol. 126, 63-89.

Meinhardt, H., Koch, A. J. and Bernasconi, G. (1998). Models of Pattern Formation Applied to Plant Development. Singapore: World Scientific Publishing.

Murray, J. D. (2003). Mathematical Biology. Berlin: Springer-Verlag.

Nüsslein-Volhard, C. and Wieschaus, E. (1980). Mutations affecting segment number and polarity in Drosophila. Nature 287, 795-801.

Roth, S. (2011). Mathematics and biology: a Kantian view on the history of pattern formation theory. Dev. Genes Evol. 221, 255-279.

St. Johnston, D. and Nüsslein-Volhard, C. (1992). The origin of pattern and polarity in the Drosophila embryo. Cell 68, 201-219.

Turing, A. M. (1952). The chemical basis of morphogenesis. Philos. Trans. R. Soc. B Biol. Sci. 237, 37-72.

Vincent, J. P. and Lawrence, P. A. (1994). Developmental genetics: it takes three to distalize. Nature 372, 132-133.

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Xenbase, the Xenopus model organism database (MOD), is building it’s developer team.

We a looking to hire 2 software developers and a database administrator. These positions are based at the University of Calgary, at the foot of the Rocky Mountains in Calgary, Alberta, Canada.

Ideally, we like to find people who have some biology background, or have worked in other MODs- (e.g., Zfin, Flybase, MGI) or biology databases (e.g., NCBI, UniProt, BeeGee)

Please share this job posting with anyone you think might be interested.

Two Developers: http://careers.ucalgary.ca/jobs/5247311-software-developer-biological-sciences-faculty-of-science

One DBA: http://careers.ucalgary.ca/jobs/5247363-research-associate-biological-sciences-faculty-of-science

Xenbase has received a new grant from the NICHD/NIH to fund its expansion over the next 5 years, but due to a rule about advertising jobs beyond the current grant year, the job ads say “7 months with possibility of renewal”. Don’t let this discourage anyone from applying!

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New Lectureships are available in the School of Biological Sciences, University of East Anglia, Norwich. We are looking for dynamic individuals who complement and extend the activities in BIO in both research and teaching.

BIO’s research portfolio includes: Cell and Developmental Biology, Cell signalling, Musculoskeletal Biology, Cancer, Matrix Biology, RNA Biology and more information can be found on our Research pages.

Details and links to the application forms can be found on our current vacancies page:

ATR1302 (Lecturer in Bioinformatics)
https://www.uea.ac.uk/hr/vacancies/academic/-/asset_publisher/h0n2rDvu3ug8/content/lecturer-in-bioinformatics

ATR1303 (Lecturer in Biomedicine)
https://www.uea.ac.uk/hr/vacancies/academic/-/asset_publisher/h0n2rDvu3ug8/content/lecturer-in-biomedicine

ATR1304 (Lecturer in Evolutionary Biology, Ecology, conservation)
https://www.uea.ac.uk/hr/vacancies/academic/-/asset_publisher/h0n2rDvu3ug8/content/lecturer-in-evolutionary-biology-ecology-conservation

The closing dates for all the above posts are: 12 noon on 27 April 2016.

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Developmental biologists use antibodies extensively to study the gene expression during different stages.  However, there is a lack of specific antibodies against many proteins related to development.  In addition, some antibodies yield unspecific and/or irreproducible results.   To help alleviate this antibody quality and specificity problem, Labome sought to organize antibody applications cited in formal publication since 2008 and developed Validated Antibody Database  (VAD).  The most recent version, 2.2,  contains manually curated 143357 entries from 38430 formal articles, covering 35146 antibody products from 110 suppliers.   The suppliers include both commercial entities and non-profit organizations such as Developmental Studies Hybridoma Bank (DSHB) at University of Iowa, and Neuromab from University of California at Davis.   A small number of antibodies from academic researchers are included as well, if these antibodies are validated in knockout models.

One of the side benefits of our curation effort is the identification of cross-reactive species for many antibodies.  Antibodies tend to be developed for human/mouse proteins and tend to be tested by commercial suppliers for their applicability in human or mouse system.   Development models often use more readily manipulatable models such as flies, worms, zebrafish, and frogs.  Labome is able to obtain information about many antibodies having cross-reactivities with the model organisms from the literature.

The database is freely browsable at www.labome.com.    Information about antibody validation using knockout models is also posted at Labome Facebook page www.facebook.com/LabomeNews.

Feedback and suggestions are most welcome.  We hope to work with everybody to develop a useful tool.

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Max-Planck-Institut für molekulare Biomedizin

The Max-Planck-Institute for Molecular Biomedicine in Muenster, Germany has an opening for a

Postdoctoral Scientist
(position-code 07-2016)

The position is available in the DFG Emmy Noether junior group of Dr. Ivan Bedzhov that is focused on understanding the self-organization of the pluripotent lineage in mammalian embryos at the time of implantation (I. Bedzhov and M. Zernicka-Goetz, Cell, 2014). The successful candidate will investigate the mechanisms of self-organization of the pluripotent epiblast in the context of the developing embryo and in vitro using embryonic stem cell as a model system.

We are looking for a talented and highly motivated post-doctoral scientist with strong cell and molecular biology background. Previous experience with RNA-seq analysis, genome editing and embryonic stem cells will be an advantage.

The Max Planck Institute for Molecular Biomedicine offers dynamic, multidisciplinary environment with state-of-the-art transgenic, imaging, genomics and proteomics equipment and core facilities. The working language in the institute is English. The institute is located in Muenster, a vibrant city with a highly international academic environment.

The position is initially available for two years with the possibility of extension. Starting date will be as soon as possible. All conditions for the employment will be according to the regulations of the contracts for the civil service (TVöD, Tarifvertrag für den öffentlichen Dienst) level 13 TVöD.

The Max-Planck society is committed to increasing the number of individuals with disabilities in its workforce and therefore encourages applications from such qualified individuals. Furthermore, the Max Planck Society seeks to increase the number of women in those areas where they are underrepresented and therefore explicitly encourages women to apply.

Please send your application (with the position-code 07-2016), letter of motivation, CV including a complete list of publications and the contact information of 2 referees to:
career@mpi-muenster.mpg.de
or
Max Planck Institute for Molecular Biomedicine
Roentgenstrasse 20
48149 Muenster
Germany

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Last week, Development announced a special issue on organoids. In vitro organogenesis is a burgeoning new field, with applications in the study of human development, drug testing and ultimately the possibility of producing functional organs in the dish that could be used for transplantation. Every new technological advance brings with it a new set of ethical issues, and this is particularly true with regards to brain organoids. Whilst there have been enormous advances in this area, brain organoids are still far from being functional ‘mini brains’. However, it is not impossible that in the near future we may be able to generate a brain organoid that has a sensory area that is able to functionally connect with a processing centre. At what point could we say that these organoids can ‘think’? And does it matter? This month we are asking:

What are the ethical issues surrounding the generation of brain organoids?

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!

Below is an interview with brain organoid researcher Juergen Knoblich, which may be of interest to you:

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By Liangyu Zhang and Abby F. Dernburg 

The nematode Caenorhabidis elegans is among the most widely used and powerful model organisms for studying mechanisms underlying cellular and developmental processes. Although a variety of approaches for conditional protein expression have been developed in C. elegans, available tools for conditional protein depletion are far more limited, particularly in the germ line. We were thus motivated to develop a technique to control the abundance of proteins in living animals, which we felt would be a great addition to the toolbox available in this system.

In the Dernburg lab, we are interested in studying the molecular mechanisms underlying meiosis. In many cases we can use genetic mutations to interrogate the roles of individual proteins, but this approach does not work well if the proteins perform essential functions during mitosis, which is required for proliferation of the germ line. We therefore sought to develop a method that would enable inducible, rapid, and quantitative protein depletion in the germ line. After considering a number of possible strategies, we focused on the auxin-inducible degradation (AID) system, which has been applied in cultured cells and single-celled organisms (Nishimura et al., 2009). This approach was originally adapted from the plant auxin perception system. Inducible degradation relies on a small molecule phytohormone produced by all plants, auxin (indole-3-acetic acid). In addition, it requires TIR1, an F-box protein, which forms part of an Skp1–Cullin–F-box (SCF) E3 ubiquitin ligase complex. In the presence of auxin, TIR1 recognizes peptide sequences (degrons) that are present in a large number of target proteins, mostly transcriptional regulators, expressed by plants, and targets these proteins for polyubiquitylation and proteasome-mediated degradation. We thought this system might be transplantable to nematodes, since auxin is a very small, fairly water-soluble molecule, potentially making it easy to deliver to living animals and readily diffusible through tissues.

A rotation student, Ze Cheng, first accepted the challenge of adapting the AID system to C. elegans. He generated a number of constructs to test its feasibility. Because there is no endogenous auxin receptor in C. elegans, he made a strain stably expressing a modified Arabidopsis thaliana TIR1 from a single copy transgene using MosSCI; (Frokjaer-Jensen et al., 2008). He also made a construct to express a degron- and GFP-tagged SMU-2 from extrachromosomal arrays in the germ line. After treating worms expressing both constructs with auxin for a couple of hours, he was excited to observe a disappearance of the green fluorescent SMU-2::GFP signal, indicating the AID system might indeed be useful in C. elegans.

We then systematically expanded and tested the AID system in C. elegans. To maximize the chances of success, we incorporated two amino acid changes in AtTIR1 that were found to increase its binding affinity for degron-tagged substrates and to thereby increase its sensitivity to auxin (Yu et al., 2013). We created strains expressing TIR1 under control of various promoters and 3’ UTR sequences to drive germ line-specific or temporally regulated expression. We used a 44-amino acid minimal degron sequence derived from Arabidopsis thaliana IAA17 (Morawska and Ulrich, 2013) and tagged proteins of interest with this sequence using CRISPR/Cas9-mediated editing (Dickinson et al., 2013). Gratifyingly, we detected efficient inducible-degradation in the germ line when growing the transgenic worms with auxin-containing liquid culture or plates. Excitingly, rapid degradation was consistently achieved within a reasonable range of auxin concentrations (<1 mM), which did not seem to have any effects on wild-type worms. We also found that the position of the degron was quite flexible; it could be placed at either end of a target protein, or even sandwiched between the target and another tag, such as GFP.

Considering the potential usefulness of the AID system for the research community, we further analyzed the inducible degradation of target proteins in the soma of C. elegans in detail. To do this, we made a variety of tissue-specific TIR1 strains with tissue-specific promoters and 3’ UTR sequences. We then combined these TIR1 transgenes with different types of degron-tagged transgenic targets. We found either cytoplasmic or nuclear proteins tagged with the degron can be tissue specifically degraded at various developmental stages in an auxin concentration dependent manner. After trying a wide range of auxin, we also noticed that the degradation is reversible upon auxin removal, with lower auxin doses accelerating recovery. To our surprise, we further detected efficient inducible degradation of targets in early embryos inside the mother and in laid eggs, suggesting promising usefulness of the AID system for studying mechanisms underlying embryo development. Notably, the inducible degradation is also efficient in the absence of food, making it useful for studying starvation-induced processes, such as autophagy and larvae arrest.

When we shared these findings with some colleagues, they were extremely excited about the potential of the system. One of them, Jordan Ward at UCSF, wanted to test the ability of this system to address key questions underlying nuclear hormone receptor-mediated control of developmental gene regulatory networks. He was able to tag two essential nuclear hormone receptors, NHR-23 and NHR-25, with the degron sequence and found that each could be depleted within 40 min, enabling detailed functional dissection of these proteins during development.

Another exciting finding was that the AID system can produce more penetrant phenotypes than depletion by RNAi, not only in the worm soma but also in the germ line. Given the high efficiency of CRISPR/Cas9-mediated genome editing in C. elegans, tagging proteins of interest with the 44-amino acid degron is now quite easy and fast, further augmenting the utility of the AID system for cell and developmental studies in worms.

We have made the AID-related worm strains and plasmids available through the CGC and Addgene, respectively. A large number of worm laboratories have already tried the AID system to deplete proteins of interest in C. elegans. We are getting great feedback from our colleagues, several of whom have told us that the AID system works spectacularly in their hands. In principle, this approach may be applicable to a wide range of other organisms. We thus look forward to seeing the application of this technology in not only worm labs but also other metazoan model organism labs.

Full article at: http://dev.biologists.org/content/142/24/4374.long

References:

Dickinson, D. J., Ward, J. D., Reiner, D. J. and Goldstein, B. (2013). Engineering the Caenorhabditis elegans genome using Cas9-triggered homologous recombination. Nat. Methods 10, 1028-1034.

Frokjaer-Jensen, C., Davis, M. W., Hopkins, C. E., Newman, B. J., Thummel, J. M., Olesen, S. P., Grunnet, M. and Jorgensen, E. M. (2008). Single-copy insertion of transgenes in Caenorhabditis elegans. Nat. Genet. 40, 1375-1383.

Morawska, M. and Ulrich, H. D. (2013). An expanded tool kit for the auxin-inducible degron system in budding yeast. Yeast 30, 341-351.

Nishimura, K., Fukagawa, T., Takisawa, H., Kakimoto, T. and Kanemaki, M. (2009). An auxin-based degron system for the rapid depletion of proteins in nonplant cells. Nat. Methods 6, 917-922.

Yu, H., Moss, B. L., Jang, S. S., Prigge, M., Klavins, E., Nemhauser, J. L. and Estelle, M. (2013). Mutations in the TIR1 auxin receptor that increase affinity for auxin/indole-3-acetic acid proteins result in auxin hypersensitivity. Plant Physiol. 162, 295-303.

(3 votes)

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

Drosophila as a model to study human disease

The latest issue of Disease Models & Mechanisms highlights the translational impact of Drosophila research. In this issue, Moulton and Letsou review several Drosophila models of human inborn errors of development (read here), while the poster and review by Bellen and colleagues examine some of the tools and assays available in Drosophila  to study human disease (read here).

Nanog suppresses senescence

Thummer, Edenhofer and colleagues analysed the outcomes of Nanog gain-of-function in various cell models employing a recently developed cell-permeant version of this protein. They show that  Nanog blocks cellular senescence of fibroblasts through transcriptional regulation of cell cycle inhibitor p27^KIP1. Read the paper here [OPEN ACCESS].

Skeletal development

Panx3 and Cx43 are two important gap junction proteins expressed in osteoblasts. Yamada and colleagues show that Panx3 and Cx43 regulate skeletal formation through their distinct expression patterns and functions. Read the paper here.

Asymmetric cell division in the worm

Phillips and colleagues show that two Dishevelled paralogs have both redundant and non-redundant roles in β-catenin regulation during asymmetric cell division in C. elegans. Read the paper here.

MOBP in oligodendrocyte differentiation

Myelin-associated oligodendrocytic basic protein (MOBP) resembles myelin basic protein (MBP), but the signals initiating its synthesis and function remain elusive. In this paper, White and colleagues show, by several approaches in cultured primary oligodendrocytes, that MOBP synthesis is stimulated by Fyn activity, and reveal a new function for MOBP in oligodendroglial morphological differentiation. Read the paper here.

How bacteria can affect development
Mushegian and colleagues examined the effect of temperature and presence of bacteria in diapausing eggs of the water flea Daphnia magna. They show that the presence of bacteria increases successful development of resting eggs at an elevated temperature. Read the paper here.

Water deprivation affects snake development

Dupoué and colleagues examined the effects of water availability on corticosterone secretion in breeding snakes. They show that water deprivation induces an increase in baseline corticosterone level in pregnant aspic vipers, which may subsequently influence offspring growth. Read the paper here.

Controlling tissue polarity 

Planar cell polarity sigalling directs the polarization of cells within the plane of many epithelia. Sharp and Axelrod examine the signals that Prickle and Spiny-legs respond to and the mechanisms they use to control the direction of tissue polarity in the distal wing and the posterior abdomen of Drosophila. Read the paper here [OPEN ACCESS].

From fibroblasts to neural crest 

Motohashi and colleagues identified the transcription factors specifically expressed in developing mouse neural crest cells, and showed that SOX10 and SOX9 directly converted fibroblasts into neural crest cells. Read the paper here [OPEN ACCESS].

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We have PhD position available to start in October 2016 at the University Göttingen (3 yrs, 75% E 13 TV-L).

The main aim of the project will be to study intra-specific variation in compound eye size in Drosophila melanogaster. The successful PhD candidate will address this question by analyzing the genetic basis of eye size variation in various inbred strains of the Drosophila melanogaster Genetic Reference Panel (DGRP). For all DGRP lines genome sequences are available. For representative strains, developmental transcriptome data using RNAseq will be generated so that data across several scales (genome, transcriptome, phenotype) can be integrated. Similar data will be generated for artificial selection experiments based on a subset of the DGRP fly lines. The successful candidate will work in an interdisciplinary team at the Department of Animal Sciences (Prof. Dr. Henner Simianer) and the Department of Developmental Biology (Dr. Nico Posnien) as well as during an extended research stay in the group of one of the international collaborators overseas.

Please visit the website of the Research Training Group “Scaling Problems in Statistics” (http://www.uni-goettingen.de/en/156579.html) for more details about the general setting of this position.

A detailed description of the project, information about the application procedure and further requirements are available here: http://tinyurl.com/gn3az25

Please forward this job ad to all your motivated future PhD students.

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I am Aaron Harnsberger, a second year Master’s degree student in the Department of Biological Sciences at Idaho State University in Pocatello, Idaho.  The focus of this lab is on genetic regulatory divergence that results in the diversity of mammalian morphologies.  These morphological differences can be observed at various stages of development.  In this lab we use bats as our model organism.  There are no other members working in this lab besides myself.  There are a growing number of labs throughout the world that also use bats to study evolutionary and developmental biology.  The species of bat that I use is Carollia perspicillata (C. perspicillata) or simply Carollia (Fig. 1).  On average an adult Carollia bat is about 19 grams (Fig. 2).  Although it is possible to maintain Carollia as a laboratory bat (Rasweiler et al., 2009), we do not have a bat colony in the lab so before I can conduct experiments I make trips to the field to collect animals from the wild.

At this point, you might be asking, “Why use bats?”.  Bats have some very interesting adaptations that make them a great model for studying evolutionary development.  They are the only mammal to achieve powered flight.  The development of wings where other mammals have paws, fins, hooves or hands is one adaptation that I find fascinating.  Another very interesting adaptation discovered in bats is delayed development.  This is when a pregnant female delays development of the embryo.  In other mammalian species this typically occurs at the blastocyst stage before implantation in the uterus.  However, in Carollia delayed development occurs after implantation at the gastrulation stages (Rasweiler et al., 1997).  This delay may be highly synchronous in colonies, and cues that initiate the delay and end it are still unknown.  Bats can have a long life span when compared to other mammals of similar size.  In addition, bats may respond differently to injury and the healing process may lack inflammation.  There are more features, but as you can see bats are unique models for many biological questions.

Back to the field, which in this case, is the country of Trinidad and Tobago (Fig. 3).  These field collection trips to the island of Trinidad require careful planning and weeks of time to catch bats and collect embryos.  I do not catch the bats on these trips by myself.  The ‘Bat Team’ this year consisted of John Rasweiler, Richard Behringer, Simeon (Patsy) Williams, Joseph Truechen and myself.  Patsy and Joseph are local field assistants who help us find and collect the bats.  The ‘Bat Team’ has consisted of many other biologists that have made this collection trip throughout the years, starting with the initial trip in 2000.

First and foremost, a collection permit through the Wildlife Section of the Division of Forestry of Trinidad and Tobago is required.  We give them a specific number of bats we would like to collect and plan our trip according to this number.  Next we need a place to process our samples.  This is the Department of Life Sciences at the University of West Indies (UWI) in St. Augustine that has lab space, microscopes and other facilities.  We also need lodging since the trips take several days.  This is arranged through University Housing.  Finally, we rent a car to take us into the deep forest that has enough room for several passengers and our gear.  Once all of this is in order we can begin catching bats.

To catch bats, we have to travel into the northern or central areas of the island.  We look for certain habitats that can lead us to specific roosting sites.  To achieve this, we conduct scouting trips and spend many hours driving, parking, looking around, taking notes, and if all goes well catching bats.

We use lots of different gear to catch bats.  We occasionally need ladders to get into some of the places that bats roost, for example abandoned concrete water tanks (Fig. 6).  On the occasions that we do need a ladder we have to carry it in, sometimes through thick forest (Fig. 4).  We use nets similar to butterfly nets to catch the bats, but much longer to reach high places where they roost (Fig. 6).  After catching the bats, we sort through them, releasing males and checking females for age and stage of pregnancy using external visual appearances.  We keep these female bats in a field box which allows for safe transport of the bats (Fig. 5).  After a morning of collecting, we return to the lab at UWI with the bats to isolate the embryos.  Once embryos are dissected we process them for various types of analyses, including morphological, histological and molecular studies.  To bring the bat embryos back to the lab in Idaho, we obtain an exportation permit, also from the Wildlife Section of the Division of Forestry of Trinidad and Tobago.

Now that I have the bat embryos to work with I can spend time in the lab back in Idaho conducting experiments.  I use whole-mount in situ hybridization (WISH) to examine the spatial distribution of transcripts for specific genes at different stages of development.  Using the Carollia embryo staging techniques (Cretekos, et al. 2005), I can identify embryos at specific stages of development.  This gives me specific time points to look for gene expression at critical developmental stages (Fig. 7).  Many times these expression patterns are similar yet different from those in the mouse.

I have also used micro computed tomography (uCT) to visualize the tissue anatomy of bat embryos (Fig. 8).  A uCT scan is a high resolution x-ray that is used to make a three-dimensional image.  The differences in contrast allow me to identify different tissue types in the bat embryos.  Again, taking advantage of the Carollia staging system, I have uCT scanned stages of development in C. perspicillata to examine particular tissues of interest for my project.  The data collection was completed in a few weeks’ time.  The image processing and analysis of this data has been an ongoing project in the lab.

As you can see a day in the life of a bat lab is not usually just a day, and some of the work may not be typical in other developmental biology labs (Fig 9).

References

Cretekos, C. J., Weatherbee, S. D., Chen, C., Badwaik, N. K., Niswander, L., Behringer, R. R. & Rasweiler, J. J. IV. (2005). Embryonic staging system for the short-tailed fruit bat, Carollia perspicillata, a model organism for the mammalian order Chiroptera, based upon timed pregnancies in captive-bred animals. Developmental Dynamics, 233: 721-738.

Rasweiler, J. J. IV & Badwaik, N. K. (1997). Delayed development in the short-tailed fruit bat, Carollia perspicillata.  Journal of Reproductive Fertility, 109(1): 7-20.

Rasweiler, J. J. IV, Cretekos, C. J. & Behringer R. R. (2009). The short-tailed fruit bat Carollia perspicillata: a model for studies in reproduction and development. Cold Spring Harbor Protocols, 2009(3): pdb.emo118.

Tags: Bat, Carollia, WISH, in situ, uCT, microCT, development, ISU, Idaho State University

This post is part of a series on a day in the life of developmental biology labs working on different model organisms. You can read the introduction to the series here and read other posts in this series here.

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