Tenure track positions as Assistant Professor within the Wallenberg Centre for Molecular Medicine at Umeå University, Sweden.
Deadline 1st of December 2015
The Wallenberg Centre for Molecular Medicine (WCMM) at Umeå University, Sweden, has been established as part of a national agenda with the goal of regaining a leading position for Sweden within medical research. The Centre is a collaboration between Knut and Alice Wallenberg’s Foundation, Umeå University, Västerbotten County Council, the Kempe Foundations and the Cancer Foundation for Northern Sweden. In this call, the Centre is looking for up to four outstanding researchers, to be positioned within one or more of the following areas of molecular medicine: cancer, infection biology, metabolism/diabetes or neuroscience. The positions are provided with a generous support package including funding for Postdoctoral Associates and PhD Student recruitments. The successful candidates will be working in strong internationally recognized research environments and have access to excellent local and national research infrastructures including unique collections of longitudinal samples in existing biobanks.
Work description The successful candidates will be working in close in close proximity to established research groups within one or more of the focus areas of cancer, infection biology, metabolic disorders including diabetes or neuroscience. The candidates are expected to initiate and maintain a strong research program complementing on-going research within molecular medicine at Umeå University, Sweden, and to take active part in collaborative research opportunities and exchange programs within the new network of WCMM centres at other universities in Sweden.
The successful candidates will primarily be conducting research. Up to 20% of the employment can be devoted to teaching so that the criteria for promotion to a tenure position as Senior Lecturer/Associate Professor (Universitetslektor) can be fulfilled within four years.
Qualifications To be eligible for the positions, candidates must have a PhD degree, completed no more than seven years prior to the deadline for application. A candidate who has completed their degree prior to this time could be given equal priority if special circumstances exist. Special circumstances include absence due to illness, parental leave or clinical employment, appointment of trust in trade union organizations or similar circumstances. We are seeking outstanding candidates with documented excellent research in fields relevant to molecular medicine. The candidate must have appropriate postdoctoral training outside the university at which the PhD was defended.
More about the position The position will be provided with a generous support package including funding for Postdoctoral Associates and PhD Students as well as substantial support for running costs. To qualify for promotion, the candidates are expected to complement the funding with their own national and/or international grants. The researcher will work within one or more of the 13 departments of the Faculty of Medicine. The Department in which the candidate formally will be employed will be decided in consultation between the applicant and the faculty. An individual scientific and educational development plan will be formulated upon agreement between the applicant and the Head of Department at which the applicant will be employed. One pedagogical and two scientific mentors will be appointed to support the career of the candidate.
YOU FIND MORE INFORMATION ABOUT THE POSITIONS AND HOW TO APPLY:
Originally posted to the blog Genes to Genomes, reposed with permission.
Don Gibson (University of California, Davis) describes how he decided to start the Barbara on the Bill Campaign
When I heard that the U.S. Department of the Treasury announced that a woman will be on the $10 bill, I started reading several articles about which woman it should be. I was shocked that so few women of science were being mentioned. I thought we, as scientists, should fix this. One woman kept coming to mind. This woman revolutionized genetics & biology, suffered harsh discrimination during her career, and remains the only woman to single-handedly win a Nobel Prize in life science: Barbara McClintock.
This idea started back in February when I saw Neil deGrasse Tyson give a public talk. He showed currency from nations around world. Many countries had their great scientists and discoveries on their coins and paper bills. While America’s money had only one theme: old, white, male politicians. He inspired me to think about national values, and there is no place more prominent for a national value then a nation’s currency.
America may be the leader in science today, but if it does not value science, other nations may surpass this country in the future. Having a woman of science on our currency could be a turning point in the way Americans view science. It could also highlight the success of real scientists who face injustice. McClintock was held back from permanent positions multiple times in her career because of her gender. She was able to succeed despite these set-backs through hard work, eventually designing ground-breaking genetics experiments in a lab of her own. Even today, challenges as a result of gender discrimination still exist; only one in four jobs in STEM is held by a woman.
Surprisingly, when I asked fellow graduate students in science fields to name a historical American woman scientist, they were often at a loss.
“I was shocked when I realized I couldn’t name any other female American scientists from history, ” said fellow geneticist Anastasia Bodnar, Policy Director at Biology Fortified, a science education and advocacy non-profit organization.
Several of my mentors are amazing women scientists. I am a firm believer that they need to be more recognized for their contributions to science. McClintock’s contributions were prolific and I see advocating for her to be on the $10 bill as a great way to give back to the female mentors I have had.
I know that a number of scientists, including McClintock, do not seek fame. Many other great women are also being advocated for the $10 bill, but as scientists we need to advocate for ourselves in public spaces for our contributions to be widely recognized. Whether or not Barbara McClintock is selected, I consider this effort a success, if this project increases the dialogue surrounding women in science.
The campaign is seeking public support though barbaraonthebill.com, and the Department of the Treasure is taking public feedback. You can also comment via Facebook and Twitter using the hashtag #TheNew10.
Zebrafish is a common model organism in many fields of science. The study by Sundvik et al. 2015 in Scientific Reports tests the safety of acoustic levitation of an intact organism using zebrafish embryos (Figure 1). Acoustic levitation has over the last few decades been developed to provide a wall- and contactless environment to transfer and manipulate small objects, more recently cells and even entire organisms. This method has great potential that could be useful also outside physics labs. A zebrafish in a levitator encounters sound levels comparable to those next to a screaming jet engine, but the sound is still inaudible to humans. From a developmental point of view it is interesting to note that the developing zebrafish are insensitive to the harsh conditions in the levitator. The fish develops normally in the apparently gravitation-free space, in the node of the sound waves, when sonified for a short time between one and 12 hours after fertilization. It is unknown whether levitation at even later time points after fertilization affects the fish development. We found that fish do die if the water surrounding the embryo evaporates. A controllable microclimate around the levitator could permit investigating whether longer levitation periods affect the development and patterning of tissues and organs in the levitated fish. Such a setup would permit levitating the zebrafish for days, potentially without liquid immersion for some developmental stages. This study is a beginning and only imagination restricts the possibilities of this approach.
Figure 1. A levitating zebrafish embryo inside an ellipsoidal water droplet. Photography: Mr Eetu Lampsijärvi
Dimitri Perrin3, Shimpei I. Kubota1,2, Kazuki Tainaka1,2 & Hiroki R. Ueda1,2,4*
1Department of Systems Pharmacology, The University of Tokyo, Tokyo, Japan.
2CREST, Japan Science and Technology Agency, Saitama, Japan.
3School of Electrical Engineering and Computer Science, Science and Engineering Faculty, Queensland University of Technology, Brisbane, Australia.
4Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, Osaka, Japan.
Correspondence should be addressed to H.R.U. (uedah-tky@umin.ac.jp, Tel: +81-3-5841-3415, Fax: +81-3-5841-3418)
Fig.1: Thy1-YFP-H Tg brain, cleared with CUBIC reagents and imaged using Macrozoom Light-sheet Fluorescence Microscopy
The brain is an organ like no other, in part because of its function. It has been recognised as the location of imagination, memory, thought and sensation since Claudius Galenus, but details about its structure only start to emerge in the late 17th century. Thomas Willis proposes the concept of a regionalisation of brain activities and Antonie van Leeuwenhoek’s work on microscopy reveals that nerves are not hollow conduits for ‘animal spirits’.
While further advances (such as Luigi Galvani on the role of electricity in the nervous system) move 18th century scientists closer to understanding the brain, the mystic surrounding the organ remains after Matthias Jakob Schleiden and Theodor Schwann propose their cell theory. All organs follow the three tenets that all living organisms are composed of one or more cells, the cell is the most basic unit of life, and all cells arise from pre-existing, living cells. All organs, except the brain. Dyes used to reveal the cellular structures of tissues only show a dense and entangled network of fibres. No cells are visible in the brain.
Fifty years later, Santiago Ramón y Cajal starts using Camillo Golgi’s reazione nera, which has the distinct advantage of staining a limited number of cells at random and in their entirety. Fine details can, finally, be observed. Ramón y Cajal pushes forward the idea of a modular brain and cells as emitter/receptor. By viewing less, the method allows to see more.
While EEG, implants and fMRI now allow measurements of group cells or indirect observation of overall activity patterns, light diffraction due to lipids means that brains cannot be directly imaged. Slicing is still used, and requires time-consuming and error-prone computational reconstruction of the whole organ.
Tissue clearing, by contrast, removes these lipids and finally allows high-resolution whole-brain imaging, therefore preserving important structures. It is a crucial step, and it is fitting that Karl Deisseroth and his team show a transparent brain sitting over a Ramón y Cajal quote in their 2013 article on CLARITY. By viewing less, we can see more, but seeing is only the beginning.
Learning, memory, behaviour and all other cognitive functions emerge from structure and cell-to-cell interactions, making understanding cellular circuits in the brain essential to advances in Neuroscience. Coupled with key technologies such CRISPR/Cas-mediated genetic engineering, tissue clearing has the potential to have for this field the impact that microarrays had on Genetics.
This requires two properties: (i) tissue clearing must be safe, rapid, efficient and easily reproducible, (ii) computational tools must be developed to analyse these new high-resolution 3D images. Our method, CUBIC, has been developed to address these needs.
Fig.2: Overview of the CUBIC protocol, reproduced from our recent Nature Protocols article [4]
Our new aminoalcohol-based clearing cocktails have no safety concerns and preserve signals from fluorescence proteins. Whole-brain clearing can be achieved by immersing a whole brain in CUBIC reagents for two weeks. In our 2014 Cell article, we showed this protocol is also applicable to a marmoset brain, which is a model animal closer to the human.
For the biologist end-user, imaging the cleared sample is a largely automated process. Our vision is to make the analysis as straightforward, with information about the experimental setup enough to identify the anatomical brain regions where changes in expression occur (and estimate the statistical significance of these changes). We have already developed tools for these analysis steps, with an initial pipeline described in our recent Nature Protocols article and available for download, and we are now working on improving the registration steps and the detection of active cells.
We have also shown that tissue clearing is useful not only for the brain but also for other organs and for whole-body imaging. Because we noticed aminoalcohols in the CUBIC reagent could decolourise the endogenous pigments such as heme, we developed a direct transcardial perfusion of the CUBIC reagent for further transparency. This perfusion protocol enables whole-body or whole-organ clearing within 10 days to 2 weeks.
Our new protocol provides access to a new world. CUBIC makes it possible to visualise and quantify a targeted small minority cells in the 30 billion cells of a mouse body. This is helpful to understand cellular mechanisms of autoimmune disease and cancer micrometastasis. Of course, our new protocol is not limited to model organisms expressing fluorescent proteins. CUBIC is compatible with immunohistochemistry so we can apply our method to human pathology, for which fluorescence imaging is not possible.
Further reading:
K. Chung, J. Wallace, S.-Y. Kim, S. Kalyanasundaram, A. S. Andalman, T. J. Davidson, J. J. Mirzabekov, K. A. Zalocusky, J. Mattis, A. K. Denisin, S. Pak, H. Bernstein, C. Ramakrishnan, L. Grosenick, V. Gradinaru and K. Deisseroth (2013). Structural and molecular interrogation of intact biological systems. Nature 497, 332–337. DOI: http://dx.doi.org/10.1038/nature12107
E. A. Susaki, K. Tainaka, D. Perrin, F. Kishino, T. Tawara, T. M. Watanabe, C. Yokoyama, H. Onoe, M. Eguchi, S. Yamaguchi, T. Abe, H. Kiyonari, Y. Shimizu, A. Miyawaki, H. Yokota and H. R. Ueda (2014). Whole-brain imaging with single-cell resolution using chemical cocktails and computational analysis. Cell 157, 726–739. DOI: http://dx.doi.org/10.1016/j.cell.2014.03.042
K. Tainaka, S. I. Kubota, T. Q. Suyama, E. A. Susaki, D. Perrin, M. Ukai-Tadenuma, H. Ukai and H. R. Ueda (2014). Whole-body imaging with single-cell resolution by tissue decolorization. Cell 159, 911–924. DOI: http://dx.doi.org/10.1016/j.cell.2014.10.034
E. A. Susaki, K. Tainaka, D. Perrin, H. Yukinaga, A. Kuno and H. R. Ueda (2015). Advanced CUBIC protocols for whole-brain and whole-body clearing and imaging with single-cell resolution. Nature Protocols 10, 1709–1727. DOI: http://dx.doi.org/10.1038/nprot.2015.085
In autumn, crickets generally exhibit chirping songs in the temperate East Asian country of Japan. While the African field cricket Gryllus bimaculatus originates from tropical countries, it is an emerging model animal globally because of its ability to regenerate amputated legs during nymph and its developmental mode (short germ band) (Mito and Noji, 2008).
Many living organisms in the animal kingdom are able to regrow their body parts following injury. Examples of body parts that may be regrown include the lens and tail of amphibians, the head of planarians, and the heart of fish. In contrast, it has long been assumed that humans cannot restore lost body parts, except for particular tissues, including the epidermis, the liver, and the ovarian surface after ovulation. Therefore, it is important to elucidate the molecular mechanisms involved in regeneration processes using animal models that are able to regenerate body parts for subsequent application in non-regenerative human organs and tissues.
Within the last 2 years, comparative genomic studies of two planarian species with different regenerative abilities led to the successful regeneration of heads by reducing beta-catenin activity from otherwise non-regenerative tail fragments (Umesono et al., 2013). Studies of vertebrates with the ability to restore limbs, including newts, frogs, and salamanders, have demonstrated that limb regeneration occurs in a stepwise manner. The limb regeneration process is divided into at least three phases: wound healing, dedifferentiation, and redevelopment, with the redevelopment phase mimicking embryonic development (Endo et al., 2004).
The cricket leg is composed of six segments that are arranged along the proximo-distal (PD) axis: coxa, trochanter, femur, tibia, tarsus, and claw (Figure 1). The tarsus is further subdivided into three tarsomeres. When the tibia of the third-instar nymph is amputated, the leg regenerates and recovers its allometric size and proper shape by the sixth instar (i.e., within 20 days of amputation), being restored to almost normal adult size and shape. Soon after healing, the blastema (a pool of cells that proliferate) develops in the distal region of the amputated leg. Blastema cells proliferate and form the missing structures by intercalary processes between the most distal region and the remaining part of the leg (French et al., 1976).
Previously, we performed comparative transcriptome analysis of regenerating and normal amputated legs of crickets to profile mRNA expression associated with leg regeneration (Bando et al., 2013). We first focused on the upregulation of Jak/Stat pathway genes, which are linked to the immune system. RNA interference (RNAi) of genes in this pathway thoroughly disturbed leg regeneration. In contrast, RNAi against Socs, a suppressor of cytokine signaling, caused leg elongation. Additional experiments showed that the Jak/Stat pathway promotes cell proliferation downstream of the Ds/Fat pathway.
Subsequently, we investigated epigenetic regulation during cricket leg regeneration. Tetsuya Bando, a senior investigator in our group, identified one gene for histone H3 lysine 27 (H3K27) methyltransferase, E(z), and one gene for histone H3K27 demethylase, Utx, in G. bimaculatus. Cloning Gryllus genes is now a straightforward process due to information being available about the cricket genome (Mito and Noji, personal communication). Methylation of histone H3K27 by E(z) represses the expression of target genes by recruiting Polycomb group proteins. Conversely, demethylation of the trimethylated histone H3K27 by Utx promotes gene expression. Tetsuya found that the transcription of both E(z) and Utx genes is upregulated in the blastema cells of amputated legs (Bando et al., 2013). In situ hybridization verified that both genes are ubiquitously transcribed in the regenerating legs of crickets, and that both genes are expressed in developing embryos (Hamada et al., 2015). Immunostaining on the amputated tiny legs after RNAi by Yoshimasa Hamada (a PhD student) confirmed that E(z) and Utx contribute to the methylation and demethylation at histone H3K27me3, respectively, during leg regeneration.
However, Yoshimasa unexpectedly found that the extra leg segment is formed after RNAi against E(z) (Figure 1). Initially, we were not able to determine the identity of the leg segment. Morphologically, the leg segment appeared to be a tibia, because it had spines and spurs that were characteristic to an authentic tibia. Our opening hypothesis was that the phenotypes after RNAi might depend on the amputation site in the tibia. However, even when a leg is amputated in the distal part of the femur, the extra tibia-like segment emerges. Pattern formation along the antero-posterior and dorso-ventral axes remained unchanged, except along the PD axis. We then examined whether the amputation site along the PD axis in the tibia influenced phenotypic severity. The extra-tibia that formed became longer the more proximal the amputation sites on the tibia (Figure 1). Conversely, RNAi against Utx resulted in the loss of joint formation between tarsomere 1 (Ta1) and Ta2 (Figure 2). In situ hybridization showed that the expression of leg patterning genes altered along the PD axis. Specifically, the domain of dachshund (dac) expression expanded in E(z)RNAi regenerating legs, whereas Egfr expression diminished in UtxRNAi legs. Therefore, E(z) may repress dac expression during normal leg regeneration, whereas Utx induces Egfr expression.
dac encodes a transcriptional co-repressor that is categorized in leg gap genes. dac produces crude positional values along the PD axis of the leg and mediates the formation of the distal tibia and Ta1 (the proximal tarsomere) during cricket leg regeneration (dac expression domain is shown in green in Figure 2) (Ishimaru et al., 2015). Specifically, dac promotes tibial cell proliferation. Therefore, because RNAi against E(z) upregulates dac, E(z) expression in the blastema cells may suppress the blastemal overproliferation by repressing extra dac expression.
This information raises the question of how E(z) specifically regulates dac expression. Furthermore, what is the mechanism that determines the target genes of E(z)? E(z) belongs to the Polycomb repressive complex 2 (PRC2), which is one of three Polycomb group (PcG) complexes (Schuettengruber et al., 2007). During cricket embryogenesis, E(z) represses the anterior expansion of Hox gene expression and provides proper identity in embryos (Matsuoka et al., 2015). This information indicates that the target genes of E(z) differ depending on the cellular context. A DNA binding protein, Pleiohomeotic (Pho), along with other factors, binds to the Polycomb response elements (PRE) of target genes, after which E(z) trimethylates histone H3K27. Although PREs have only been identified in Drosophila, the meta-analysis of putative target genes for PcG proteins has shown that many of the target genes are common to the fly, mouse, and humans. dac and Egfr are included among these genes (Schuettengruber et al., 2007). Thus, the regulatory region of the cricket dac gene probably contains PREs, through which E(z) epigenetically regulates the expression of dac during cricket leg regeneration (Figure 2). Ongoing research is focused on characterizing the functions of the Pho gene and other PcG complex genes and epigenetic modifiers during Gryllus leg regeneration.
Finally, why does E(z) RNAi cause extra-tibia formation? One hypothetical scenario is that when the tibia is amputated at the proximal position where dac expression is low, Utx expression (which dominates E(z) expression) permits dac expression (Figure 3a) to restore the tibia. Thus, these histone modifiers sense the positional values along the PD axis of the amputation site, and fine-tune the expression level of leg patterning genes, like dac. In the case of E(z) RNAi just before proximal amputation, intense dac expression is induced and expands in the regenerating leg (Figure 3b). Distal-less (Dll) expression, which is another leg gap gene that specifies the distal domain of the leg (Angelini and Kaufman, 2005), may shift more distally depending on expanded dac expression (Figure 3b). Thus, the Egfr-expressing domain may be separated into two parts where (1) Dll expression is low and (2) Dll is high. The extra-tibia probably forms between the two different Egfr-expressing domains by intercalating cell proliferation and patterning (Figure 3c).
Our goal is to elucidate blueprints for “making a regenerated leg” by using this attractive hemimetabolous insect model. The blueprints are expected to clarify how the number of leg segments is determined. Our striking observations on RNAi against E(z) leading to “extra tibia formation” represent an important step towards elucidating this process.
Journal of Cell Science is pleased to welcome submissions for consideration for an upcoming Special Issue on 3D Cell Biology. We have a limited understanding of cells within their natural context of tissues and organs, but recent advances in imaging techniques, organoids and other more complex systems are making it easier for cell biology research to be conducted in more complex and physiologically relevant settings. Ultimately, we hope to achieve a sophisticated molecular understanding of how cells build organs during development and corrupt their structure and function during disease processes. Journal of Cell Science is a natural home for the research that will help to address these fundamental biological questions.
We invite you to showcase your breakthrough research on all aspects of 3D Cell Biology in this Special Issue, which is scheduled for publication in mid 2016 and will be widely marketed and distributed at relevant conferences worldwide. The articles within this issue will receive extensive exposure to a broad audience of cell biologists.
The issue will be guest edited by Andrew Ewald (Johns Hopkins School of Medicine, USA), who is also the Journal of Cell Science Guest Editor and will handle all 3D cell biology papers submitted to the journal for one year, from August 2015.
We encourage submissions of Research Articles and Short Reports, and Tools & Techniques papers. Articles must be received by January 16th, 2016 for consideration for the Special Issue. Please refer to our author guidelines for information on preparing your manuscript for Journal of Cell Science, and submit your manuscript via our online submission system. Please highlight that your submission is to be considered for the Special Issue in your cover letter. For rapid feedback on the potential suitability of an article for this Special Issue, please submit a presubmission enquiry.
Here is some developmental biology related content from other journals published by The Company of Biologists.
Modelling Alzheimer’s Disease in vitro
Hall and colleagues established an in vitro model of Alzheimer’s Disease by culturing and differentiating embryonic stem cells isolated from the APPsw transgenic minipig. They use this system to provide insights into astrocyte and radial glia pathology in this disease. Read the paper here [OPEN ACCESS].
RhoC regulates VEGF signalling
The small GTPases RhoA and RhoB are involved in vasculogenesis and angiogenesis; however, the role of another Rho family member, RhoC, in these processes is less understood. Now, Mukhopadhyay and colleagues show that RhoC maintains vascular homeostasis in endothelial cells yet is dispensable for vascular development. Read the paper here.
MyoD gets rid of Twist-1 with miR-206
MyoD and Twist-1 are transcription factors known to promote and inhibit muscle cell differentiation respectively. Phylactou and co-workers identify a mechanism of myogenesis in which MyoD and miR-206 downregulate the expression of Twist-1. This pathway might also play an important role in muscle disease. Read the paper here.
PP6 gets oocytes out of meiosis
PP6 is known to modulate Aurora A activity in mitosis, but what is its role in meiosis? Xu, Yang, Su and colleagues present in vivo evidence showing that PP6 suppresses Aurora A activity in oocytes in meiosis II, and is crucial for meiosis II exit, euploid egg production and female fertility. Read the paper here.
The relationship between bone adaptation and mesenchymal stem cells
Wallace and colleagues expose growing mice to exercise, showing that the ability of the progenitor population to differentiate toward bone-forming cells may be a better correlate to bone structural adaptation than external forces generated by exercise. Read the paper here.
A portuguese person, a spanish person and an english person meet in a bar…
… and start discussing developmental biology. This may sound like the beginning of a joke, but in fact happened during the Joint Meeting of the Portuguese, Spanish and British Societies for Developmental Biology, which took place in Algarve, Portugal, in early October. The meeting venue, besides having the aforementioned bar, was also closely located to the beach, which we were able to enjoy thanks to a pleasant weather. Some of the participants also took advantage of the beautiful and family-friendly location to bring their own families. Nevertheless, the scientific talks and poster sessions still managed to draw the participants away from the seaside.
A meeting by the sea. Photo by Catarina Vicente @the_node.
The meeting started with early development, with a plenary lecture on the principles of pluripotency presented by Austin Smith. The lecture focused on the ongoing quest to establish human naïve embryonic stem cells in vitro independently of pluripotency transgenes, showing the progresses achieved so far and presenting the challenges that still need to be overcome.
The transition from pluripotency to lineage commitment was explored by Sally Lowell, whose work identified some of the factors that prime cells for differentiation and revealed a role for adhesion molecules in the decision to differentiate. Berenika Plusa presented the advantages of using rabbit as an alternative model to study early mammalian development. Andrew Johnson showed that axolotl, an organism without extraembryonic tissues, can be used to study later roles of the pluripotency factor Nanog.
The regulation of neuronal differentiation was also the focus of several talks. Kate Storey showed how differentiating neurons in the chick neural tube undergo apical abscission and revealed new evidence for the involvement of microtubule dynamics and adhesion molecules in this process. Also in the chick neural tube, Elisa Marti presented work on the role of Shh signalling in the decision to proliferate or differentiate and showed that the subcellular localisation of several Shh pathway components contributes for this decision. Anna Philpott also talked about division/differentiation in the nervous system and the regulation of proneural factor activity by phosphorylation in Xenopus. François Guillemot highlighted the role of the proneural factor Ascl1 in adult brain neurogenesis and how modulation of Ascl1 stability affects the balance between quiescence and differentiation. The talk by Alexandre Raposo was also on Ascl1 and its function promoting chromatin accessibility during neurogenesis.
The link between adult neural stem cells and cancer was discussed by two drosophilists. Cláudia Barros is using a fly brain tumour model to identify new factors involved in tumour initiation, while Rita Sousa-Nunes is using this model to study the interaction between tumour cells and the microenvironment.
Moving away from neural lineages, we also heard about regulation of proliferation, differentiation and cell movement of presomitic mesoderm progenitors from Leonor Saúde and single cell oscillators as components of the segmentation clock during somitogenesis from Andrew Oates.
Later in development, the formation of the inner ear lumen in zebrafish was introduced by Berta Alsina, revealing that mitotic cell rounding and epithelial thinning regulate lumen expansion. Juan R. Martinez-Morales talked about optic cup morphogenesis in zebrafish, showing that both rim involution and basal constriction contribute to cup folding. Zebrafish embryos were also the stars in the beautiful movies shown by Claudia Linker, whose work combined live imaging with cell ablation to test the role of leader, follower and pre-migratory cells in the collective migration of neural crest cells.
At the chromatin level, Ana Pombo proposed that the priming of developmental genes for future expression in embryonic stem cells involves the Polycomb complex, a specific modification of the RNA polymerase II and local transcript degradation. Rui Martinho showed how chromatin remodelling is involved in the transcriptional reactivation of the Drosophila oocyte during meiosis. Javier Lopez-Rios presented his work on a limb-specific enhancer responsible for the spatial differences in Ptch1 expression between mice and bovine, which underlies their distinct limb anatomy.
The meeting ended with a plenary talk by Moisés Mallo, who presented his work on Gdf11 as the coordinator of the trunk to tail decision during vertebrate embryogenesis and revealed an unexpected role for a pluripotency gene in trunk specification.
The meeting included many other exciting talks that have not been reported here. Overall, the meeting programme showcased the diversity of the developmental biology field in terms of subjects and model systems. The meeting also achieved a perfect gender balance among speakers – 17 female and 17 male speakers. Outside the lecture hall, scientific discussions continued throughout the free afternoons and outdoor poster sessions while enjoying the warm weather. And, of course, in the bar.
As the meeting came to an end, the sunny weather turned into a rainy storm, which made the departure a little less sorrowful.
Mike Levine, director of the Lewis-Sigler Institute for Integrative Genomics at Princeton University, is a developmental biologist who has dedicated his career to understanding how gene expression is regulated during development. Some of his most significant research, such as the co-discovery of the homeobox genes and his work on even skipped stripe 2, was performed in Drosophila, but he has since branched out to Ciona intestinalis, which he is using as a model to understand how vertebrate features have evolved. We had a lively chat with Mike at this year’s Society for Developmental Biology (SDB) meeting, where he was awarded the Edwin Grant Conklin Medal.
Here at the SDB meeting you will be awarded the Conklin Medal by the society. What does it mean to you to receive this prize?
It is a really special honour for me, for a number of reasons. First, the list of people who got it before me is pretty awesome, so I am very proud to be among them. People like John Gurdon, Nicole LeDouarin, and some of my friends and peers like Richard Harland, Cliff Tabin, Marianne Bronner… The other reason why this award is special for me is because Conklin did his lineage-tracing studies in sea squirts, and half my lab has worked on this model system for 20 years. To my knowledge, I am only the second sea squirt guy to get the Conklin Medal, after my good friend Nori(yuki) Satoh. For those of us who work on the same material that Conklin himself studied, this is a very special honour. He was always one of my scientific heroes.
You were SDB president a few years ago. What do you think is the role of the society?
A field of study is only as good as its smartest young people. I think it is important for the society to reach out to the young, talented stem cell, computational and genomics researchers and say: ‘Hey, this is a really cool field of study’. We have one advantage over most other fields: we work on intrinsically beautiful material. What is more beautiful than a developing embryo? I remember when I was an undergraduate seeing for the first time movies of developing chick and frog embryos and I was just mesmerised. I just thought: ‘Oh man, that is what I want to study’. And it is not only visual, it is a highly integrated science. It really pulls together so many different disciplines. We have a lot to offer to the next generations of discoverers, and the SDB needs to reel these young men and women in.
How did you first become interested in biology? I understand that you considered becoming a medical doctor…
I always had an interest in the life sciences, and enjoyed going to my backyard to dissect bugs with my little microscope. I came from a blue-collar family, so if you were good at biology, which I was, it was only logical that you should become a doctor and make some money. For a modest Jewish family, being a doctor is a big escalation in status. I tried to be a good boy and even took the medical school admissions test and went to a couple of interviews, but it really was not for me. I have always been a hypochondriac, so I can’t even imagine how many times I would have tested my own urine and blood for whatever disease I was learning about! So I had this ‘going to medical school’ thing hanging over me during my undergraduate studies, but I was lucky to discover the wonderful world of biological research.
It was really hard in Berkeley to find a lab where you can do research as an undergraduate. Fortunately, I had an amazing stroke of luck to get to work in Allan Wilson’s lab. He and Mary-Claire King had proposed that regulatory DNAs were really important in evolution and in distinguishing chimps and humans, and this definitely infiltrated my thinking.
During your scientific career you have examined how gene regulation is controlled. What excites you about this topic and why did you choose Drosophila as a model?
I love gene regulation. I love the process of transcription so much that I regard RNA as an unfortunate by-product of an otherwise elegant process! I think part of it is that when I was an undergraduate I must have learned about the lac operon in three different classes: genetics, molecular biology and protein biochemistry. It is an inherently beautiful mechanism. Who would have thought that a bacterium exposed to sugar would deploy this elaborate and elegant transcriptional response? The developmental biology classes by Fred Wilt also really stayed with me. So I had a strong sense that gene regulation was a cool process from my undergraduate studies. This was reinforced by my undergraduate research in Allan Wilson’s lab. There they were talking about regulatory DNA, but instead of bacteria they were looking at animal cells.
I first became interested in flies because of a Scientific American article written in 1975 by the Swiss molecular geneticist Ernst Hadorn on transdetermination. He took wing imaginal discs out of larvae and cultured them in the stomachs of recipient flies, so they proliferated for longer than they normally would. He then grafted these discs back into a recipient larva that underwent metamorphosis, and found that sometimes the grafted tissue didn’t become the original structure that it was slated for, but the whole thing transformed into a leg. I thought that was a really exciting discovery. Later on, I read about the homeotic mutants that Tom Kaufman and Ed Lewis were working on and figured: ‘It has got to be gene regulation, and it has got to be in flies’.
As you mentioned earlier, part of your lab now works on Ciona. Why this organism?
I was co-director of the embryology course at Woods Hole for a few years, and this gave me the chance to get exposed to a lot of different systems in developmental biology. When I heard Richard Whittaker and Nori Satoh talk about Ciona, I immediately loved the system. I don’t know if it triggered recollections about Conklin’s work, which I had been taught about as an undergraduate, but I just liked the simplicity. Embryogenesis is amazingly complex, and I really don’t think in 3D so well. But when I heard Whittaker and Satoh discuss Ciona, where the movements are not that complex, I thought: ‘This is a system I can understand’.
Our fly studies have always been pretty abstract, studying gene regulation but never connecting it to morphogenesis. I always thought we should be able to link the two, but at least for me it seemed hopeless to try it in flies. There are so many cells, the processes are complex and occur very late in development. But I thought Ciona might be a good place to attempt this and complement our fly studies. The thinking was: ‘Let us extend our studies from gene regulation in Drosophila to a model organism in which we can study gene regulation and the connection to cellular morphogenesis in development’.
Bob Zeller, who trained with Eric Davidson studying sea urchins but had done undergraduate work in sea squirts, came to my lab as a postdoc to set up this system. I thought we were nearing the end of the line with the flies, so the plan was to wind down and eventually just convert completely to sea squirts. But every time I think I am going to drop the flies, I just can’t. I like sea squirts, don’t get me wrong, but I am really a fly guy. I feel like Michael Corleone in The Godfather III: “Every time I try to get out, they keep pulling me back”. The early fly embryo is the sweetest system in the world for looking at gene activity in development. The last 10 years have been dominated by fantastic new technologies, such as single-molecule live imaging, and these just work like a charm in the early fly embryo. So I can’t leave it!
You did your postdoc with Walter Gehring at the University of Basel. How did your time there influence your career?
Where do I begin in describing my 15 months in Basel? Culturally, it was a defining experience for me. I had never been a political person. But in Basel people would stay up drinking and discussing politics, and I learned that not everyone agreed with American policy. I had never realised how parochial my experience was until I went there, so it was really eye opening and gave me a broader perspective. There was also a special camaraderie that I had never experienced before. Ah, and Europe! I had never been to Europe before, and it is like a giant museum, with its cathedrals and art… It was truly a mind-blowing, defining experience.
As for the lab, it was a hot and cold experience. The hot part was that I met some of my best friends and collaborators, like Markus Noll, Erich Frei, Bill McGinnis and Ernst Hafen. Also on the good side, everything I have done with Drosophila for the ensuing 30 years was a direct consequence of my time in Basel working on gene expression in the fly embryo. Unfortunately, Walter and I just didn’t get along, so I eventually had to leave. But as difficult as my personal relationship was with Walter, I would probably do it again, because I got an enormous amount from the experience, both culturally and scientifically.
What would you consider to be your most important discovery?
The work I did with McGinnis and Hafen on homeobox genes was pretty good, but I don’t like to think I did my best stuff in those 15 months as a postdoc. I think that I am proudest of my work on eve stripe 2. The project was launched by a student named Dusan Stanojevic who was very mercurial, very high maintenance, but absolutely brilliant. When he started the project he said: “This is going to be the lacoperon and the lambda switch of developmental biology!”. At the time I thought he was cracked, but 25 years or so later I would say that there is something to it! Our work on eve stripe 2 was less a single discovery than a war of attrition. It took 3 to 4 years of really hard work, doing DNA binding assays, targeted mutagenesis and transgenesis, which were harder methods then than they are now. Some amazingly talented scientists, including Tim Hoey and Steve Small, worked through that problem.
Which scientific questions would you like to tackle in the future?
TA few years ago Delsuc et al. (2006) showed that the urochordates (which include sea squirts) and not the cephalochordates, as most text books still say, are the closest living sister group to the vertebrates. This paper has been extremely influential in our thinking because it means that if you are interested in understanding the evolutionary origin of some of the major vertebrate innovations, such as the neural crest, neurogenic placodes and second heart field, Ciona tadpoles are a good place to look. Of course Ciona doesn’t have a neural crest, but it does have a cell type with some of the properties of neural crest. We also found that Ciona tadpoles have neurogenic proto-placodes, another feature of the vertebrate head.
On the fly side I am very excited about the use of single-molecule live imaging. One of the big benefits of my recent move to Princeton is the close proximity to two of my favourite young Drosophilacollaborators: Thomas Gregor, a physicist who does live imaging in the fly embryo, and Stanislav Shvartsman, a chemical engineer studying signalling in fly eggs and embryos. Collaborating with these two labs is going to invigorate our studies. One line of research that I am most excited about is visualising enhancer-promoter communication directly. The human genome is just riddled with hundreds of thousands of enhancers. In other words, a typical gene in the human genome is regulated by up to 50 different enhancers. So all of a sudden you have to worry about trafficking: how do the right enhancers get to the right promoters at the right time? For all we know, this could be the rate-limiting determinant in the patterning of the Drosophila embryo. Thomas is devising strategies for directly visualising the interaction of remote enhancers with promoters in living embryos during key patterning events. That is very exciting.
You mentioned that you have moved to Princeton, where you are now the director of the Lewis-Sigler Institute for Integrative Genomics. What are you hoping to achieve in this new position?
The Lewis-Sigler is called a genomics institute but it really started as a systems biology institute, initially led by Shirley Tilghman and then David Botstein. Botstein was the first person I heard explain properly what systems biology is and the concept really turned me on. Systems biology is the systematic identification of every component of a complex process. You need the experimentalists to generate the big data, the computer scientists to handle the big datasets, and then quantitative biologists to model these datasets so that you can understand emerging properties of the process. I can know everything about a neuron in the neocortex but if I multiply that by a million I am not going to learn how consciousness works. You have to do something different. This is the philosophy of systems biology and I still believe in it. The Lewis-Sigler institute is like a scientific Noah’s Ark: it has a couple of computer scientists, a couple of high-throughput biologists, a couple of physicists, a couple of engineers. It is just the right mix of talents for systems biology, so I see no need to deviate from Botstein and Tilghman’s original vision. I just want to have some fun, and bring people together towards this enterprise of trying to learn the emerging properties of really complex processes, like the patterning of the fly embryo. I think there are wonderful challenges and opportunities, and with these new technologies we can take systems biology into the new millennium.
What is your approach to running a successful lab?
The alumni of my lab are an amazing group of people, and so many of them run their own labs now. I would love to take credit for it but, believe me, they came in pretty good! I have a reputation of being pretty demanding, a pretty tough boss. I have in me a bit of my Jewish uncle, who fought in World War II and had this warmth on the one hand and this tough ‘you are not quite good enough’ on the other hand. And I think I do a little bit of that in the lab.
I aim to keep my lab members excited about their project. I try to constantly look at the big picture and, if I have an idea, I try to give it to them when I am at my most enthusiastic. They might tell you that I am tough, but I hope they’ll also tell you that I do love science. It’s like with sports people getting towards the end of their careers: when you ask them what keeps them going they all say the same thing – they love the process. They like getting up in the morning, working out, training, they like the banter in the locker room. I really enjoy the process too. I like going in to the lab. I think whatever influence I have had in helping my lab members has been my enthusiasm for the process.
What is your advice for young scientists?
It is much harder now to find an identity for yourself in science. I was in the right place at the right time, I admit it. I got a great job when I was young and the field was wide open. It is much more crowded now. The whole ‘follow your passion and everything will work out’ may have been true 20-30 years ago, but it is not as true now. My hard-nosed advice to young scientists who want to continue being scientists (and you can do this in many capacities, it doesn’t have to be as the PI of a lab) is to learn technology. Go to a graduate programme or do a postdoc where you have access to the cutting-edge technologies. When I was a postdoc in the Gehring lab, Ernst Hafen and I helped develop the first in situ hybridisation methods with fixed tissues and I think it was that method that really got me a job. When you know a good technology, people are interested in it, even if they are not interested in the specific process you are working on. You increase your value. Discovery depends on technology now more than it ever did. The old guys did the easy stuff: we pillaged the low-hanging fruit a long time ago. I do believe the best is yet to come, but it requires technology. I would advocate imaging or genomics, or, best of all, somewhere in between! I also relate what I heard from many people over the years, including James Watson: “Don’t go straight up the middle in an established discipline. The action is at the cusps”. I think that is also very good advice.
What would people be surprised to find out about you?
There is the perception that I am a bit of an eccentric, and I think that even the people in my lab would be surprised to see how ordinary my private life really is. I am a family man, and I enjoy a tightknit relationship with my wife and two sons. We enjoy conventional suburban pleasures, such as going to the movies.
BONUS!: Hear Mike give his account of when he almost set one of his postdocs on fire!
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MyoD and Twist-1 are transcription factors known to promote and inhibit muscle cell differentiation respectively. Phylactou and co-workers identify a mechanism of myogenesis in which MyoD and miR-206 downregulate the expression of Twist-1. This pathway might also play an important role in muscle disease. Read the paper 
