Illustrator Natalya Zahn on the role of observation and visual interpretation in her work creating an addendum to Nieuwkoop and Faber’s classic Normal Table of Xenopus laevis
As an artist of science and nature subjects, I’m often asked what makes the work I do better than a photograph. It makes perfect sense to imagine that a direct photographic capture of an object would offer the very most accurate description of that object – and photography certainly is a brilliant format for capturing detail. What that imagination fails to take into account is that a camera must capture everything that it sees in any given shot. Depending on the complexity or ambiguity of the subject, a highly detailed photograph may just as easily overwhelm or confuse a viewer, rather than offer clarification. The beauty of illustration is that it can precisely isolate specific forms or features of a subject, omitting irrelevant details and making clear essential attributes. It is this quality of simplified clarification, produced through execution and interpretation, that can, under the right circumstances, make scientific illustration a more successful form of visual communication than photography.
In early 2016 I was commissioned by Dr. Michael Levin and Dr. Dany Adams, at the Tufts Center for Regenerative and Developmental Biology, to create a new series of embryo development illustrations for Xenopus laevis, in the style of Nieuwkoop and Faber’s classic Normal Table, originally illustrated by J. J. Prijs in 1956. The new illustrations would be similar enough in drawing quality so as to seamlessly fit into the existing atlas, but they would feature views of embryos and tadpoles that had not previously been generated (including anterior and ventral views that highlight craniofacial changes).
My work began with many hours observing and sketching live specimens under a Nikon SMZ1500 stereomicroscope; multiple individuals from each stage were used as models. Photographic captures were made using digital micrograph, for later reference, but even high-quality photos can include areas of vague detail. The subtle surface contours in early stage embryos, and the intricacy of numerous visible layers of translucent anatomy in later tadpole stages, made the value of snapshots in time a distant second to my live study. By personally observing numerous embryos of the same stage (taking variation and anomaly into account), and periodically adjusting the angle of my view (to illuminate areas of ambiguity), I was able to completely understand each developmental stage in three dimensions, which brought significantly higher accuracy to my interpretation and rendering of each two-dimensional illustration.
Preliminary Xenopus sketches, drawn in colored pencil from live embryo specimens under a microscope (artist’s notations visible).
Once I was satisfied with the form and detail of my sketches, I imported each drawing into Adobe Illustrator. Drawing in a vector-based application allowed me to generate the final illustration outlines in extremely clean and consistent line weights. Minimal shading was added in Photoshop, though many of the illustrations are available for use in both shaded and outline-only versions (the later potentially being useful to those interested in adding their own visual notation to an illustration).
My hope for this body of work is that it becomes an invaluable standardized reference for the scientific community, just as Mr. Prijs’ beloved Xenopus illustrations have been for the last half century. Micrographs have only improved since the 1950s but the enduring nature of the drawings within the Nieuwkoop and Faber classic Normal Table is a testament to the enormous teaching power and utility of well executed illustration.
Illustration process for the “The Zahn Drawings”; A: live embryo reference (observed and photographed), B: pencil sketch, C & D: vector line drawing in Adobe Illustrator, E: shading in Photoshop, F: merging of line and shading layers to create finished illustration.
Illustration process for the “The Zahn Drawings”; A: live embryo reference (observed and photographed), B: pencil sketch, C: vector line drawing in Adobe Illustrator, D: shading and merging of layers to create finished illustration.
Natalya Zahn is a Boston-based illustrator, designer and visual story-teller. Deeply inspired by animals and nature, her award-winning work explores the intersection of art, design and science and has been featured by National Geographic, Longwood Botanical Gardens, the San Diego Zoo, and MIT Media Lab, among many others. She is skilled in both traditional media and digital techniques, and works fluently across commercial, educational, editorial, and corporate industries.
Here are the highlights from the current issue of Development:
AdamTS-A keeps the CNS in shape
The Drosophila central nervous system (CNS) is covered by a thick basement membrane that mediates interactions with glial cells and governs the shape of the tissue. Basement membranes are formed from a meshwork of secreted extracellular matrix (ECM) proteins and must be continually remodelled to accommodate growth during development. Metalloproteinases, such as those in the AdamTS family, can break down ECM proteins in the basement membrane and thus allow for tissue expansion. On p. 3102, James Skeath and colleagues identify one protein in the family, AdamTS-A, that is critical for both maintaining the structural integrity of the Drosophila CNS and keeping cell lineages anchored in the tissue. When the function of this protein is reduced, neurons escape the CNS and invade the peripheral tissues of the developing larva. AdamTS-A acts through protease-dependent and possibly protease-independent mechanisms to retain neurons within the developing CNS, and regulates tissue stiffness by restricting Collagen IV/Viking accumulation in the basement membrane. These findings demonstrate the crucial role for extracellular proteases in tissue development and highlight the importance of the basement membrane in shaping the nervous system.
Morphogens and microcolonies: directing stem cell fate
Morphogens are long-range signals that provide cells in the embryo with positional information, helping to ensure cells differentiate appropriately for their position along the body axes. In vivo, and in vitro when cell colonies are large, the function of a single morphogen is difficult to study in isolation. This is because interaction between cells and crosstalk from other signalling factors can confound results. On p. 3042, Aryeh Warmflash and colleagues show that upon stimulation with BMP4, which induces a mixture of fates in large colonies of human embryonic stem cells (hESCs), colonies of just one to eight cells instead acquire trophectoderm-like fate uniformly. They show that above a threshold concentration, BMP4 acts as an ‘on-off’ switch to specify trophectoderm-like cells in these microcolonies, and that a community effect ensures all cells acquire the same fate. In contrast, the mixed cell fates in larger colonies result from the activity of a secondary signal, Nodal, which is produced endogenously by the cells. These findings provide insight into how cells in culture might be directed to specify a single lineage more reproducibly, and demonstrate how the same morphogen signals can be used repeatedly in development to achieve different outcomes, depending on their context.
Pax8+ secretory cells: progenitors of the oviductal epithelium
The mammalian oviduct is lined by a pseudostratified epithelium comprising two main cell types: secretory cells and ciliated cells. Like many other epithelia, it is thought to also contain a population of stem cell-like progenitors, which are important to maintain tissue homeostasis. Such progenitors are hypothesised to actively divide, to facilitate epithelial regeneration upon wounding and to ensure the tissue remains healthy. However, these cells have remained unidentified. On p. 3031, Pradeep Tanwar and colleagues use lineage tracing in mice to identify the oviductal progenitors as secretory cells expressing the Pax8 marker gene. They show that these cells actively divide in the oviductal epithelium, and that this cell population is expanded in humans who are predisposed to ovarian cancer. Like progenitor populations in other tissues, the Pax8+ cells respond to canonical Wnt signalling, which governs their differentiation into ciliated cells and simultaneously maintains the stem cell-like population. These results are a step forward in understanding tissue homeostasis in the oviduct, and may provide insight into how cell proliferation is regulated and subsequently becomes dysregulated in ovarian cancer.
PLUS…
Meeting Review
Alecia-Jane Twigger andChristina H. Scheel report from an EMBO meeting on advances in stem cells and regenerative medicine
Reviews
Andrew Muroyama andTerry Lechler summarize current knowledge of how microtubule organization and dynamics change upon cellular differentiation, and Dirk G. de Rooij provides an overview of the organization and timing of spermatogenesis.
Laboratory of Protein Metabolism in Development and Aging
International Institute of Molecular and Cell Biology in Warsaw
is seeking a talented Postdoctoral fellow
Location: Warsaw, a vibrant city with an international academic research environment. International Institute of Molecular and Cell Biology (www.iimcb.gov.pl) – one of the most dynamic and top ranked Polish research institutes.
Job description: Laboratory of Protein Metabolism in Development and Aging, which will be opening on August 2017, is seeking highly motivated and talented Postdoc to join young team investigating the protein homeostasis in development and aging. We use both genetic, molecular and biochemical approaches, primarily in the C. elegans, to study proteolytic networks. Postdoc fellowship is funded in frame of National Science Centre OPUS grant.
Summary: Organismal development or environmental stimuli challenge the homeostatic protein balance (proteostasis) of individual cells, tissues or the entire organism. The ubiquitin proteasome system (UPS) is a key determinant of proteostasis as it regulates the turnover of damaged proteins supporting cellular protein homeostasis and thereby maintains the proteome during stress and aging. Our long-term objective is to understand the mechanistic and developmental aspects of protein degradation pathways defined by combinations of particular ubiquitin ligases (E3). The identification of stress and aging-induced signals that coordinate the interplay between specific E3s will offer intriguingly new mechanistic insights how proteolytic networks are fine-tuned to maintain the cellular proteome and support development and longevity.
Qualifications:
• PhD (or be close to completion) in Molecular Biology, Cell Biology, Protein Chemistry, Genetics or a related discipline;
• experience in C. elegans or cell culture is an advantage;
• experience in Next Generation Sequencing techniques (RNA-Seq, ChIP-Seq) and genomic engineering is an advantage;
• good writing and oral communication skills in English, and competence in scientific writing.
How to apply:
Please send your application including CV, motivation letter and the list of publications to the e-mail address: wpokrzywa@iimcb.gov.pl, until 20th September 2017. Thanking all applicants for their interest, we will contact only selected candidates for an interview.
Please include in your application the following statement: “In accordance with the personal data protection act from the 29th of August 1997, I hereby agree to process and to store my personal data by the Institution for recruitment purposes”.
The recruitment procedure fulfills the National Science Centre’s regulations on granting the scholarships to young scientists.
Selected publications:
Riga T*, Pokrzywa W*, Kevei E, Akyuz M, Vishnu Balaji, Svenja Adrian, Hoehfeld J, Hoppe T. (2017). The ubiquitin ligase CHIP integrates proteostasis and aging by regulation of insulin receptor turnover. Cell. 169: 470-482.
Ackermann L., Schell M., Pokrzywa W., Gartner A., Schumacher B., Hoppe T. (2016). E4 ubiquitin ligase specific degradation hubs coordinate DNA double strand break repair and apoptosis. Nat Struct Mol Biol. 23: 995-1002
Kaushik S, and Cuervo AM (2015). Proteostasis and aging. Nat Med. 21, 1406-15
Frumkin A, Dror S, Pokrzywa W, Bar-Lavan Y, Karady I, Hoppe T, Ben-Zvi A. (2014). Challenging muscle homeostasis uncovers novel chaperone interactions in Caenorhabditis elegans. Front Mol Biosci., doi: 10.3389
van Oosten-Hawle P, and Morimoto RI (2014). Organismal proteostasis: role of cell-nonautonomous regulation and transcellular chaperone signaling. Genes & Dev. 28: 1533-43
Segref A, Kevei E, Pokrzywa W, Mansfeld J, Schmeisser K, Livnat-Levanon N, Ensenauer R, Glickman M.H, Ristow M, Hoppe T. (2014). Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome-system. Cell Metab. 4:642-652
Pokrzywa W. and Hoppe T. (2013). Chaperoning myosin assembly in muscle formation and aging. Worm. 2:e25644
Gazda L*, Pokrzywa W*, Hellerschmied D, Loewe T, Forné I, Mueller-Planitz F, Hoppe T, Clausen T. (2013). The myosin chaperone UNC-45 is organized in tandem modules to support myofilaments formation in C. elegans. Cell. 1, 183-195.
Kuhlbrodt K, Janiesch PC, Kevei E, Segref A, Barikbin R, and Hoppe T (2011). The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis. Nat Cell Biol. 13, 273-81
Laboratory of Protein Metabolism in Development and Aging
International Institute of Molecular and Cell Biology in Warsaw
is seeking PhD student
Location: Warsaw, a vibrant city with an international academic research environment. International Institute of Molecular and Cell Biology (www.iimcb.gov.pl) – one of the most dynamic and top ranked Polish research institutes.
Job description: Laboratory of Protein Metabolism in Development and Aging, which will be opening on August 2017, is seeking highly motivated PhD candidates to join our young team investigating the protein homeostasis in development and aging. We use both genetic, molecular and biochemical approaches, primarily in the C. elegans, to study proteolytic networks. PhD fellowship is funded in frame of National Science Centre OPUS grant.
Summary: Organismal development or environmental stimuli challenge the homeostatic protein balance (proteostasis) of individual cells, tissues or the entire organism. The ubiquitin proteasome system (UPS) is a key determinant of proteostasis as it regulates the turnover of damaged proteins supporting cellular protein homeostasis and thereby maintains the proteome during stress and aging. Our long-term objective is to understand the mechanistic and developmental aspects of protein degradation pathways defined by combinations of particular ubiquitin ligases (E3). The identification of stress and aging-induced signals that coordinate the interplay between specific E3s will offer intriguingly new mechanistic insights how proteolytic networks are fine-tuned to maintain the cellular proteome and support development and longevity.
Qualifications:
• master degree in any field related to biological sciences obtained within the last two years;
• general laboratory experience;
• expertise in either of the following areas will be preferred: cell biology, molecular biology, genetics, biochemistry, fluorescence microscopy
• analytical and creative thinking;
• ability to communicate knowledge in English (written and spoken);
• motivation and passion for experimental work;
• excellent interpersonal skills.
How to apply:
Please send your application to the e-mail address: wpokrzywa@iimcb.gov.pl, until 20th September 2017. The application should include cover letter, CV including candidate’s research achievements, university scores, and marks for candidate’s master degree. Thanking all applicants for their interest, we will contact only selected candidates for an interview.
Please include in your application the following statement: “In accordance with the personal data protection act from the 29th of August 1997, I hereby agree to process and to store my personal data by the Institution for recruitment purposes”.
The recruitment procedure fulfills the National Science Centre’s regulations on granting the scholarships to young scientists.
Selected publications:
Riga T*, Pokrzywa W*, Kevei E, Akyuz M, Vishnu Balaji, Svenja Adrian, Hoehfeld J, Hoppe T. (2017). The ubiquitin ligase CHIP integrates proteostasis and aging by regulation of insulin receptor turnover. Cell. 169: 470-482.
Ackermann L, Schell M, Pokrzywa W, Gartner A, Schumacher B, Hoppe T. (2016). E4 ubiquitin ligase specific degradation hubs coordinate DNA double strand break repair and apoptosis. Nat Struct Mol Biol. 23: 995-1002
Kaushik S, and Cuervo AM (2015). Proteostasis and aging. Nat Med. 21, 1406-15
Frumkin A, Dror S, Pokrzywa W, Bar-Lavan Y, Karady I, Hoppe T, Ben-Zvi A. (2014). Challenging muscle homeostasis uncovers novel chaperone interactions in Caenorhabditis elegans. Front Mol Biosci., doi: 10.3389
van Oosten-Hawle P, and Morimoto RI (2014). Organismal proteostasis: role of cell-nonautonomous regulation and transcellular chaperone signaling. Genes & Dev. 28: 1533-43
Segref A, Kevei E, Pokrzywa W, Mansfeld J, Schmeisser K, Livnat-Levanon N, Ensenauer R, Glickman M.H, Ristow M, Hoppe T. (2014). Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome-system. Cell Metab. 4:642-652
Pokrzywa W. and Hoppe T. (2013). Chaperoning myosin assembly in muscle formation and aging. Worm. 2:e25644
Gazda L*, Pokrzywa W*, Hellerschmied D, Loewe T, Forné I, Mueller-Planitz F, Hoppe T, Clausen T. (2013). The myosin chaperone UNC-45 is organized in tandem modules to support myofilaments formation in C. elegans. Cell. 1, 183-195.
Kuhlbrodt K, Janiesch PC, Kevei E, Segref A, Barikbin R, and Hoppe T (2011). The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis. Nat Cell Biol. 13, 273-81
With a new grant of almost 15 million EUR from the Novo Nordisk Foundation, DanStem scientists will be focused on a new programme for translational hematology.
The Programme could have a major impact on treatment of haematological malignancies. The primary aim is to identify novel treatments for patients with blood cancers AML (Acute Myeloid Leukaemia) and MDS (Myelodysplastic Syndrome) for which treatments and success rates have changed little in the last decades.
Professor Kristian Helin will head the Programme, which will include collaboration with researchers from Rigshospitalet, Denmark’s largest hospital. Major activities include:
Identifying and characterizing cancer stem cells from patients with blood cancer;
Identifying the best available treatment for individual patients by screening patient-derived cancer stem cells for sensitivity toward a panel of approved drugs (personalized medicine); and
Collaborating with companies to develop new drugs for treating blood cancer.
The Division of Developmental Biology at the FAU Erlangen-Nürnberg, invites applications for a
PhD student position (Salary Scale E13 TV-L/65%) on
Molecular mechanisms of muscle lineage reprogramming
in the group of Dr. Christoph Schaub. The position will start at the earliest possible date and will be limited to three years with a possible extension.
The Schaub group is interested in the molecular mechanisms that regulate syncytial muscle cell lineage commitment, maintenance and plasticity using the Drosophila embryonic and adult musculature as a model. The PhD project will focus on the molecular mechanisms that guide a naturally occurring direct lineage reprogramming process during the metamorphosis of the Drosophila musculature. In particular, the project will define the molecular processes that initiate and execute the dedifferentiation of syncytial embryonic muscles into mononucleate myoblasts which in turn are reprogrammed into the progenitors of adult heart associated muscles (Schaub et al. 2015, Curr Biol (25), 488-494). The PhD student will use a broad spectrum of state of the art techniques ranging from genome editing to modern live imaging approaches to analyse these questions.
We are looking for a highly motivated candidate with experience in Drosophila genetics and/or cell and molecular biology. Experience in microscopic tissue dissections is an advantage but not a requirement. We offer an exciting project utilizing our combined expertise in muscle cell biology and Drosophila genetics in a well-equipped lab. The project is embedded in an interdisciplinary scientific landscape in association with the Muscle Research Center Erlangen (MURCE, http://www.murce.fau.de/) and the Optical Imaging Center Erlangen (OICE, http://www.oice.uni-erlangen.de/) and will have access to high end imaging microscopes (Confocal, Spinning disk and Light-sheet microscopy).
If you are interested in the position please send a cover letter stating your motivation, your curriculum vitae, copies of Bachelor/Masters certificate (or equivalent) and two letters of recommendation or contact information for two scientific references in a single PDF to christoph.schaub@fau.de.
The Marsden Lab in the Department of Biological Sciences at North Carolina State University is seeking a full-time Research Assistant/Lab Manager. The successful applicant will facilitate the lab’s day-to-day operations, participate in training undergraduate and graduate students, and engage in research projects focused on understanding the genetic and neural circuit basis of behavior.
This is a 12-month, full-time, exempt position with a comprehensive benefits package. The position will present opportunities for co-authorship of publications, and training in essential techniques will be provided.
Who you are:
You are a biologist, preferably a neuroscientist, with previous experience working with zebrafish.
You have excellent organizational skills and pay keen attention to detail.
You think strategically and communicate clearly.
You enjoy working in a team, teaching, and mentoring others.
You are curious and love to learn.
Your essential duties:
Care for and maintain a zebrafish colony, including daily feeding and water quality monitoring
Perform routine zebrafish husbandry to generate larvae for experiments
Order and manage inventory of laboratory supplies
Conduct research, working with the principal investigator to plan, design, and perform experiments in 3 areas:
Analyze the behavior of zebrafish in response to visual, auditory and olfactory stimuli using high-speed imaging and automated tracking software; develop new behavioral assays to measure learning, anxiety, and social behavior
Use molecular biology techniques to assay gene expression, design and create transgenic constructs, and microinjections to establish transgenic zebrafish lines for visualization of neural circuit connectivity and activity
Use confocal microscopy to image neural development, connectivity and activity, as well as gene expression patterns using in situ hybridization and immunohistochemistry
Interact with and participate in training students in the laboratory
Qualifications:
Master’s degree or Bachelor’s degree plus 3 or more years of relevant experience in a research laboratory
Experience feeding and maintaining zebrafish
Basic laboratory skills as well as familiarity with genetics, molecular biology techniques including basic cloning and PCR, and microscopy
Application instructions:
Go to https://jobs.ncsu.edu/postings/86205 and follow the instructions. You will need to submit a Cover Letter, CV, and list of References. For further questions, contact the principal investigator at kcmarsde@ncsu.edu.
“Forget the textbook picture” is what I proclaim when I teach master students in a course on Cell biology and Advanced Microscopy. Although the textbook is a fantastic resource for teaching, it largely fails to convey the complexity of cells, including their size, dynamics and structure. To fully appreciate the intricacies of cells, one needs to get in touch with the material. This involves going to the lab, prepare samples, observe the cells through a microscope and acquire images.
One of the most fun experiments that I supervise during a cell biology course deals with the size and shape of organelles. In this experiment, the organelles of cells are labeled with fluorescent markers that are genetically encoded on a plasmid. The students have to examine five different samples and infer which organelles are highlighted in each of those samples. The eagerness of getting it right motivates the students to carefully observe the cells and compare between different patterns of localization. Once every group of students has reported their findings on a white board, the results are discussed. The public reporting and discussion brings an element of competition to this experiment and it adds to the motivation to correctly identify the organelles.
Two examples of markers that highlight organelles in a human cell. Samples and images made by students
To perform this experiment, we use plasmids that encode different ‘cellular markers’, each capable of highlighting an organelle in a mammalian cell*. The plasmids are isolated from bacteria by the students in a blind fashion, i.e. the students do not know what organelle is labeled by the markers they isolate. The students transfect the cells with the unknown markers (we use HeLa cells for ease of culture and robust transfections). The next day, the students are given the task to prepare samples, observe cells with the different markers and identify them**. Many iterations of this experiment are imaginable, depending on the time and equipment*** that is available. For instance, endogenously tagged human stem cells (e.g. from the Allen cell collection) can be used to make the assignment more relevant from a biomedical perspective.
Two examples of cartoons of cells that display the distribution of organelles in cells. These drawings are made by students based on their observations of five fluorescent markers (the explanation of the colors is hidden on purpose).
In addition to identifying the organelles that are labeled, I ask the students to compare their results to a textbook image and generate an improved picture based on their observations. Altogether, this assignment is fun and I’m convinced that observing fluorescently labeled organelles (or other structures) in cells results in a better understanding of cellular function. I’d love to hear about your experiences in teaching cell biology and the experiments that students perform to learn about the intricacies of cells.
**I decided not to disclose which markers we use for obvious reasons. If you would like to know which markers we use, or if you would like more background on the experiment feel free to contact me by email or a tweet.
***The possibilities to implement a practical course in cell biology will depend primarily on the equipment that is available. At our university, we are lucky enough to have 14 basic fluorescence microscopes available for teaching 40 students at a time (160 in total). These microscopes are equipped with basic fluorescence filter sets (DAPI/FITC/TRITC) and simple CCD cameras.
it is our great pleasure to announce the 2nd International FishMed Conference on Zebrafish Research(FishMed2018), which will be held on March 25-27, 2018 at the International Institute of Molecular and Cell Biology in Warsaw (IIMCB), Poland. We organize this event to share with you the most recent knowledge and developments in zebrafish research and give you the opportunity to meet and discuss your work. The program will include keynote lectures, plenary talks, short oral presentations, poster sessions, and extensive time for discussions.
The special focus of the conference are early stage researchers, for whom dedicated competitive sessions called Young FishMed have been designed. Thus, fourteen early stage researchers who submit the best abstracts will be invited to give short presentations: Young FishMed lectures. Moreover, three best posters will be awarded. Registration starts on October 1, 2017, so please mark your calendars.
For more information including preliminary program, please visit the conference website: http://fishmed2018.pl/.
Confirmed Speakers
Keynote Speaker
Randall Peterson, University of Utah, USA
Young FishMed Keynote Speaker
Benoit Vanhollebeke, Université libre de Bruxelles, Belgium
Speakers
Catherina G. Becker, University of Edinburgh, UK
Filippo del Bene, Institut Curie – Centre de Recherche, France
Peter Currie, Monash University, Australia
Carl-Philipp Heisenberg, Institute of Science and Technology, Austria
Corinne Houart, Kings College London, UK
Adam Hurlstone, University of Manchester, UK
Anna Huttenlocher, University of Madison, USA
Hernan Lopez-Schier, Helmholtz Zentrum München, Germany
Ferdinand le Noble, Max Delbrück Center for Molecular Medicine, Germany
Paul Martin, University of Bristol, UK
Annemarie Meijer, Leiden University, The Netherlands
Marina Mione, University of Trento, Italy
Claire Russell, University of London, UK
Karuna Sampath, University of Warwick, UK
Stefan Schulte-Merker, University of Münster, Germany
Kristin Tessmar-Raible, University of Vienna, Austria
Tanya Whitfield, University of Sheffield, UK
Cecilia L. Winata, International Institute of Molecular and Cell Biology in Warsaw, Poland
Mehmet Fatih Yanik, ETH Zurich, Switzerland
Scientific Committee
Lilianna Solnica-Krezel, Washington University School of Medicine, USA
Steve Wilson, University College London, UK
Ewa Snaar-Jagalska, Leiden University, The Netherlands
Uwe Strähle, Karlsruhe Institute of Technology, Germany
Vladimir Korzh, International Institute of Molecular and Cell Biology in Warsaw, Poland
Jacek Kuźnicki, International Institute of Molecular and Cell Biology in Warsaw, Poland
Jennifer Nichols is a Principal Investigator at the Cambridge Stem Cell Institute and Department of Physiology, Development and Neuroscience at the University of Cambridge, UK. Her lab works on lineage segregation and the establishment of pluripotency in the mammalian embryo. In 2017 she was awarded the British Society for Developmental Biology’s Cheryll Tickle Medal, given to mid-career female scientists with outstanding achievements in developmental biology. We met Jenny in her Cambridge office to talk about pluripotency in vitroand in vivo, the importance of collaboration in her career path, and what playing a musical instrument has in common with research.
Jenny Nichols
This year you were awarded the Cheryll Tickle Medal. What does the award mean to you?
Well it really meant a huge amount to me – the nominations come voluntarily from our peers, and then it’s voted on by people on the committee, so I was just really touched by that. And I hadn’t really thought of myself at all as someone who would receive medals.
Let’s start at the beginning: what got you into science in the first place?
My father was a naturalist interested in marine biology, and so when we went to the beach he’d be fishing around in rock pools and I’d tag along with him. So I was kind of brought up with biology that way – I always loved animals and finding things under rocks. I then went through education knowing that I wanted to do some kind of research: I quite liked physics and maths in the early days, but I could just see myself doing biology because I’d have the chance to work with animals.
In the final year of my degree, I knew I wanted to do developmental biology, and I wrote to various developmental biologists, one of whom was Richard Gardner. He wrote back to say that although he didn’t have anything open at the moment, he was always glad to meet people who were interested in developmental biology. So I hitchhiked up to visit him, and talked to him about the kind of work I was doing at the time, and it was great – I really liked him and liked Oxford. And then a couple of months later he wrote to tell me that his postdoc, Ginny Papaioannou, was going to be leaving. This was in the good old days when there were positions and resources available in universities and one didn’t have to depend on grants, so when Ginny left there was space in the lab. Richard asked whether I was interested in becoming his research assistant, and I arrived in his lab in 1981.
Figure 1 from Jenny’s first paper
In terms of how the paper came about, in the 1950s and 1960s the work of Tarkowski and colleagues had suggested that the development of the trophectoderm was very much dependent upon position within the early embryo. By the time I joined Richard’s lab things had moved on a little bit – for instance, it became possible to isolate the ICM and culture it, and that’s what Richard and other people such as Alan Handyside had been doing. This work led to the notion that, in addition to position, timing was crucial too: isolated ICMs from very early blastocysts could regenerate the trophectoderm, whereas those from later embryos gave rise only to epiblast and primitive endoderm. When you cultured ICMs from an intermediate stage, you could get both trophectoderm and primitive endoderm, at least by morphology, and that first paper focussed on the question of whether the outer layer of the ICM was a mosaic of the two cell types. We never really got to the bottom of what it all meant at the time, but the most important aspect of that work for my career was that I became an expert in dissecting embryos and culturing ICMs. And because I’d inherited the lab space from Ginny, there was a micromanipulation rig and a dissecting microscope for me: I had all this kit, and the mice were provided by the institution, so I had the opportunity while I was there to develop hand skills.
In Gardner’s lab you worked alongside Rosa Beddington: I understand she was a great influence on you?
Rosa was just finishing her PhD as I joined. She was incredibly clever and very good at manipulating embryos, and wouldn’t take no for an answer – if she wanted to do something, she’d find a way, and that made you think that if Rosa could do it, perhaps you could do it too.
For me, I think the most important thing she did was to invite me to help on the Cold Spring Harbor course ‘Molecular Embryology of the Mouse’. I started there as a teaching assistant just before I left Oxford in 1990. At the time I didn’t really have a great deal of confidence, being overshadowed by all the brilliant people in Oxford, and being a teaching assistant gave me something that I could do usefully. I also got to meet all of these amazing embryologists, and of course to mix with the participants. That gave me a big confidence boost and got me in contact with people in the field.
You moved from Oxford to Edinburgh with Austin Smith, getting your PhD in 1995 and then working as a postdoc. How did you come to meet Austin and, in the early days of his lab, what were the key questions you were aiming to answer?
When I was with Richard, Austin had come to work with John Heath across the road – he’d been interested in embryonic stem cells (ESCs), and his PhD had been devoted to finding what it was in the feeder layer on which mouse ESCs were grown that allowed them to self-renew and propagate. Being a biochemist, Austin wanted to understand what signalling pathways were involved, and then figure out how to make the process more efficient and relate it better to the embryo. John Heath introduced me to Austin and suggested that we might want to work together, and it took off from there. Being in Richard’s lab, everyone was a brilliant embryologist, but working with Austin – who was a biochemist and didn’t do embryo work – provided me with a niche. Then, when Austin got the job in the Centre for Genome Research in Edinburgh – another core-funded venture – he asked if I would go with him.
During his postdoc Austin had done HPLC to analyse what components in the medium secreted from the feeder layer promoted ESC renewal and found the active agent, which he called differentiation inhibitory activity (DIA) and turned out to be leukaemia inhibitory factor (LIF). So then the question was: if LIF is able to maintain ESCs in a self-renewing state in vitro, does it have any relevance in the embryo? When I started working with him, we wanted to look at the cells in culture, but also to understand how precursor ESCs in mouse embryos can self-renew. During my PhD I did in situ hybridisation on components of the LIF pathway in the embryo. In situ hybridisations had been going for a few years but were radioactive and quite laborious, and I spent a lot of time cutting sections of embryos from wax in preparation.
After many years in Austin’s lab you became an independent Principal Investigator (PI) in 2006 at the Cambridge Stem Cell Institute. How did you find the transition?
When Austin was planning to move down to Cambridge, I had a bit of uncertainty over whether to go with him, but decided in the end that it was the right move – we got on very well and made a very good partnership, and of course we still had so much left to discover about the system. It was an unusual transition to being a PI – all of a sudden, I was! But I hadn’t really thought about it; as far as I was concerned I worked with Austin. We did, by then, have joint grants, but my purpose at that time was to set up the transgenics facility. I didn’t have a fellowship but I did have a permanent job, and independence was a gradual transition from then, so I didn’t really notice any difference.
It seems that your research has been collaborative from the start. Does this reflect how you see science?
It’s how I see science going. In the old days people could get single-author papers, but I never really felt up to that, and so was always glad to collaborate. And I think that now it’s good advice that you collaborate – you need to have so many aspects to what you are doing and you can’t possibly be an expert in every one. The expectations for what is supposed to go into a paper are also very different from when I started. Plus, I enjoy collaborating and working with other people.
It’s good advice that you collaborate – you need to have so many aspects to what you are doing and you can’t possibly be an expert in every one
Since 2006 you have continued to work on lineage decisions and pluripotency in the early mouse embryo. What is your current understanding of how pluripotency arises, and the key open questions in the field?
The question of how the epiblast becomes pluripotent is of course fascinating in itself, but it’s also something you can get funding for. If I’d taken the other approach and focussed on primitive endoderm specification, even though it’s basically the same question, it’s much less easy to justify.
From research performed with a brilliant postdoc, Thorsten Boroviak, we’re pretty clear that the state of pluripotency in mice is acquired in the epiblast cells as a result of contact with the extracellular matrix that comes from the primitive endoderm cells as they are becoming specified. Thorsten found that the primitive endoderm cells are producing laminin and fibronectin at this stage, and that single cells from the ICM of earlier embryos would now make ESC colonies simply by the addition of the right matrix components. So it seems that interaction with factors secreted by neighbouring primitive endoderm cells is how pluripotency is established.
One of the key questions in the field is how cells start deciding which lineage to go down. Back when I started in Richard’s lab, the trophectoderm was known to form from the outside cells, and as the embryo was about to implant one could see the epiblast and the primitive endoderm, with the latter on the outside of the ICM. We assumed in those days that the cells that were exposed to the cavity would be the ones that would make the primitive endoderm – that it was solely a positional thing. So it was quite a breakthrough when Clare Chazaud and Janet Rossant, and then Berenika Plusa and Kat Hadjantonakis, showed that the primitive endoderm fate is specified in a salt-and-pepper distribution in the ICM. We still don’t really know how they start deciding which one to become, and the basis of this decision making is, I think, one of the key open questions.
How did working with human ESCs change the way that you thought about pluripotency?
Once we could derive human ESC lines – and it took quite a long time – it became clear that they are different from mouse ESCs. They make two-dimensional rather than small and dome-shaped colonies, and couldn’t be derived from single cells, suggesting that the population has to grow intact before passaging. They look different, express different molecular markers, require different factors in the culture and different ways of passaging. So the big question was what is the difference between the mouse and human ESC states? Then two groups, one headed by Roger Pedersen and the other by Ron McKay, derived what they called epi-stem cells (epiSCs) from the epiblast of later stage mouse embryos, using the culture conditions that had been successfully employed to make human ESCs. The logical explanation for the difference between mouse and human ESCs is, therefore, that during human ESC derivation the cells advance to the equivalent of a post-implantation state during culturing, and you recover cells in what we subsequently called the ‘primed’ pluripotent state.
So then the question was whether a condition exists in the human embryo or in other mammals similar to the mouse ESC state? EpiSCs can make pretty much every tissue you need, so would the embryo require a more naïve state? From my point of view, I was interested in the developmental biology. Others were also interested from a practical perspective, as mouse ESCs are so much easier to culture and you can do gene targeting more readily. When Takahashi and Yamanaka showed that one could reprogram differentiated cells to pluripotency – generating induced pluripotent stem cells (iPSCs) – this raised the possibility of reprogramming primed human lines to the naïve state. Many papers came out, incrementally addressing this question. Within the last few years two postdocs in Austin’s lab, Yasu Takashima and Ge Guo, found conditions in which many of the pluripotency markers in the mouse embryo were expressed differentially from the primed human cells, and crucially these were expressed in the human embryo.
There do seem to be quite a few paths to pluripotency across mammals. As far as I know, all mammals make a structure that looks like a blastocyst, but then what differs is what happens after that, how quickly it happens, and the pathways that are involved. For example, in the mouse primitive endoderm specification is entirely dependent on FGF signalling, but this is not the case in other species such as cattle or humans. Rodent embryos have quite a special way of developing that involves the formation of ‘egg cylinders’, unlike other mammalian species, and this structural difference might be key. Non-rodent embryos form a flat, polarised epithelium of the epiblast quite quickly, which might be significant in terms of the endurance of the naïve pluripotent state in the embryo.
In a time when iPSCs are being increasingly employed by developmental and stem cell biologists, what do mouse or human ESCs still have to offer us?
iPSCs have obvious uses and benefits, although of course it’s a given that if we hadn’t had ESCs then iPSCs wouldn’t have come about. But deriving iPSCs can be inefficient and take time, whereas if you want to derive an ESC line from a transgenic mouse line it is very easy from embryos, and the cells are pristine. For all these derivations, the acid test is whether they can make a chimera when put into an embryo, and whereas ESCs generally make good chimeras, iPSCs can be a bit fussier.
That is from the mouse perspective; from the human point of view, I have just established a collaboration with Wolf Reik where we are trying to derive human ESC lines clonally from embryos donated from IVF programmes. About 60% of these embryos are thought to be mosaic for aneuploidies, and a lot of those aneuploidies are likely to be chromosomal defects like trisomies. So they are actually potentially useful models for in vitro modelling of disease, and by being able to derive multiple clonal lines from an individual human embryo, one can powerfully compare a normal line with an abnormal line. This has the potential to be very useful and isn’t something we can do with iPSCs.
Don’t just follow fashions – you need a deep-rooted question that you wake up thinking about
Do you have any advice for young scientists?
Well, I said earlier that collaboration is important. In addition I think that, especially these days, you should find something that you are really interested in. You should be obsessed with your work. Don’t just follow fashions – you need a deep-rooted question that you wake up thinking about.
Finally, is there anything Development readers would be surprised to find out about you?
Several people probably know this but I am a keen oboe player and play in local orchestras. I think this is definitely connected to being a preimplantation mammalian developmental biologist – when we’re moving our embryos around, we use a pulled-out Pasteur pipette that we control with a mouth tube. And if you play a wind instrument, you don’t dribble! In playing musical instruments, you know you have to practise, and you know you’re not going to be brilliant straight away; learning how to dissect mouse embryos is similar – you can’t just follow a protocol and expect data immediately.
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