This interview by Aidan Maartens originally appeared in Development, Volume 143, Issue 13.
William ‘Bill’ Harris is Head of the Department of Physiology, Development and Neuroscience at the University of Cambridge, UK, and a Fellow of both the Royal Society and Academy of Medical Sciences. His lab works on the development of the vertebrate nervous system, with a particular focus on cell lineage in the retina. In 2017 he was awarded the British Society for Developmental Biology’s Waddington Medal for outstanding research performance and services to the community. We met Bill in his Cambridge lab to talk science, art and ice hockey.
This year you were awarded the Waddington Medal: what does the award mean to you?
Well, it was a signal that developmental biologists appreciated what I’ve done over my career. I’ve always considered myself first as a neuroscientist, but a developmental neuroscientist, and as I’ve progressed in my career I’ve come to appreciate that the problems I’ve been working on in neuroscience are problems that are common to lots of developmental systems. So to get the appreciation of the field as a whole is very gratifying. It’s the same kind of feeling you get whenever something you’ve done gets accepted, whether a paper or a grant or whatever, that what you’ve done has got through certain hurdles and been deemed OK. Also, as it was near the end of my career and was basically a lifetime achievement award, I was particularly pleased about that.
Let’s go back to the beginning: what got you interested in science, and neuroscience in particular, in the first place?
I got interested in science when I was an undergraduate at the University of California Berkeley, though I guess you could say that before that I was as interested in science as any other kid might be. I did a senior project using one of the early scanning electron microscopes, and decided to look at Drosophila, knowing that no one had ever seen fruit flies blown up to this magnification before. All of a sudden I could see these hidden things, and I knew that geneticists would be interested in them – it was a bit of real, useful science, but was also just amazing to see that level of detail in such a small organism. I keep an image of a Drosophila head from that project up on my office wall to this day.
So that project got me interested in science, but getting interested in the development of the nervous system was a completely different ball game – I got there by a more osmotic, slow process. As a PhD student with Seymour Benzer at CalTech, I was interested in behaviour and genes, in the function of the nervous system. I worked on learning mechanisms in flies, and spent a lot of time in a little dark room getting flies to run to different coloured lights and punishing them if they went to some lights and not others. Then I got some advice that I would spend my whole graduate career just learning about the psychology of flies and not learning any biology if I kept on with that project, so I switched to looking at the fly visual system, and found some mutants that didn’t see certain colours. That got me into the cells, the molecules, the photochemistry and physiology – it was a door into ‘wet’ biology and into the anatomy of the nervous system. That was a better fit for me – I felt I was really learning something.
Seymour Benzer (source), and David Hubel (l) and Torsten Weisel (r) (source)
How did you come to work on the vertebrate nervous system?
As a postdoc I went to Harvard Medical School to work in the labs of David Hubel and Torsten Weisel, who were doing beautiful work on the way the visual cortex operates and the relationship between the physiology of the cortex and its cytoarchitecture. I got interested in the developmental problem of how the early function of the nervous system shapes the way it continues to develop. It was a very exciting time, and the postgrads and postdocs were doing all kinds of interesting, fun experiments. But then one day we were called into the tea room and got a lecture from Hubel and Weisel, who said we shouldn’t just do all these different projects – some of which we had started without even consulting them – and that we were just using their labs as a launching point for our things, whereas they had their own vision for where they wanted the lab to go. They said ‘We’ve planted this plum tree, and now all the plums are very ripe and you guys are just picking them off without even asking!’. Although some of the people were absolutely committed to the visual cortex and didn’t know why they were being told off for doing interesting experiments, it changed my approach to my work – I understood somehow that I should be more independent and that I should try to find my own niche.
So that’s when I switched to a more developmental programme of interests. I moved to axolotls first, largely due to Of Scientists and Salamanders, a book by Victor Twitty, which showed me the wonders of salamander developmental biology. Twitty had found a species of Californian newt that was full of tetrodotoxin, and if you parabiotically joined an embryo of that species to the embryo of an axolotl, the toxin would percolate from the newt embryo (which was insensitive to the toxin) to the axolotl embryo, blocking all of the neural activity in the latter. That allowed me to get back to the earlier question of the role of neural activity in development, which led me to do an experiment revealing that a lot of neural development, including accurate wiring up of the nervous system, did not require any electrical activity. This was an important step forward for the field, which previously thought that neural activity was key to making appropriate connections in the brain. I then started to work on axon guidance – since axons can get to their targets in the absence of neural activity, how exactly do they get there?
So I started with behaviour and have kept going backwards in time until where I am now, which is to ask how different cells in the nervous system get born. That’s probably as far back as I’m going to go or else I’ll move out of the nervous system altogether!
I started with behaviour and have kept going backwards in time until where I am now, which is to ask how different cells in the nervous system get born
Since the early eighties, your lab has mainly focussed on the development of the vertebrate retina. With your wife Christine Holt, you described techniques for labelling neurons to determine lineage and fate – what were the main lessons this early labelling taught you?
In 1980 I started as an Assistant Professor at the University of California San Diego, and a bit later on Christine came to the lab as a postdoc, bringing Xenopuswith her. I used to have a nice life before Christine, in that for the axolotl work you’d get the embryos in the autumn, do your embryonic manipulations, wait for them to grow until you could see what had happened later in the year, then work on writing up these results until the next autumn when the cycle started again. With Xenopus, Christine found a way that you could label specific populations of axons even when they were growing, and not only that, but you could get embryos all year round in the lab – now you could do experiments any day you wanted to and get the results as early as the next day! It was a much more powerful system and allowed the work to go at a faster pace, making the work more exciting and more demanding.
We were interested in the very earliest decisions that retinal ganglion cells made as they were navigating the pathway into the brain. We thought about injecting the cells to label them at earlier and earlier stages, just after they were born, so you could see the first thing the cell did after it was born and knew it was going to be a retinal ganglion cell, to ask how its axon started the journey. We then realised we could inject the cell even before it was born, to look at the mother cell. At the same time, Connie Cepko’s lab had started to use replication-incompetent retroviruses to look at similar problems, and Scott Fraser’s lab had similar ideas, also in Xenopus. We all ended up publishing at around the same time, and had more or less the same results.
The main lesson this labelling taught us was that progenitors in the retina and in the brain were multipotent – they would give rise to many different cell types, ruling out the possibility that there were committed progenitors for each cell type. One thing that puzzled all of us, and led us in the wrong direction for quite a while, was the variability of the lineages – you’d never get the same lineage twice. We all reported this, but didn’t understand it – it might have had to do with different cells experiencing different microenvironments, but it turns out it is a much more intrinsic thing.
In recent years you have had a productive collaboration with Benjamin Simons from the Cavendish Laboratory – how important has mathematical modelling been to your understanding of cell fate in the retina?
It’s shaped the way I think about the variable nature of cell lineages in the retina. Ben came to me after working with Phil Jones on the epidermis of the mouse tail: he was looking at tissues that are homeostatic, where you are losing cells and replacing them at the same rate. Being a physicist he could look at the cell fate data and somehow see in these patterns the underlying model. So he came to me and said that the retina could be a great model to understand how lineages evolve, but I thought that this would probably be too difficult because, during development, things are moving and the rules are going to be changing all the way through. Jie Hie (a postdoc in the lab) and I listened very carefully to the kind of data that he would need, which he could analyse powerfully, and figured out how we might be able to provide it. The analysis revealed that there is very likely a stochastic phase in the development of clones of retinal cells which produces the variability – now we have a model whereby a period of stochasticity means that genes may or may not get expressed, and that this then affects fate in a probabilistic way.
The underlying mathematics isn’t really that hard, but to actually run the simulations and statistically compare the results against the real data is something that Ben is more of an expert at than I. Back when we first published our early clonal data and saw this variability, all I was really able to say was that you can’t discriminate our data from just randomising the numbers of cells that went into the different layers; Ben’s analysis gave us a model that suggests something about the biology. So it really helped to understand those things, and is still helping to motivate work that we’re doing.
In your acceptance speech for the Waddington Medal, you compared the models for cell fate that came out of your work with Waddington’s famous epigenetic landscape. How do Waddington’s ideas relate to your current understanding of stochasticity and determinism in retinal development?
Every developmental biology student has seen Waddington’s epigenetic landscape drawing – it’s a wonderful way to think about development in a diagrammatic way.
Waddington’s landscape fused with a Galton board, courtesy of Bill Harris
As I was preparing the lecture I wondered what Waddington thought about how cells made decisions to go down one valley or another, but I could not really find much – he described the geography of cell fate decisions, but not how cells made the decisions. His one vague suggestion was that something might be pushing the marbles toward one valley or another. But I was thinking about these probabilities that we’ve been working on, and asked myself if there was a way to join his landscape with probability distributions. As I was thinking about this, my mind went to these Galton boards – you drop a marble, it hits a pin and goes to the right or the left, and then hits another pin and does the same thing, and at the end of that, if you put enough marbles in, you get a beautiful normal distribution in the wells at the bottom. It’s a great way of creating a distribution that is always the same shape even though any particular marble could end up in any of the wells – and if you want to make an organism that’s the same, you want to make a distribution of cell types that’s the same. So let’s run these marbles down through the Waddington landscape, which is really a kind of a Galton board – at each junction it has two choices – but the probabilities are set because of the deepness of the valley and how the ball was rolling. The important thing is that you won’t get the same balls in the same valleys in every organism, but you’ll get the same distribution. So in the talk I just took Waddington’s epigenetic landscape and turned it into a Galton board.
The Waddington Medal lecture can be viewed here
You have been Head of the Department of Physiology, Development and Neuroscience in Cambridge since its inception in 2006. What has it been like steering such a diverse department of researchers?
I came to Cambridge in 1997 as Professor of Anatomy, and the next year I started to take over the reins as Head of Department. In 2006, Anatomy merged with Physiology; there were a lot of similarities in terms of the students we taught and the kinds of research that went on in both departments, so it was a natural union. I think the merger gave a new lease of life to the two departments, and it also helped us with scales of efficiency as we were both running in the red at the time. I don’t consider it a particular challenge to be Head of Department – it’s quite easy if people are motivated to help make the department better. It’s important that everyone has a say in how the place is run – so in meetings I prefer to present ideas and see what everyone thinks, and then together we’ll agree on a way forward democratically.
How did the Cambridge Advanced Imaging Centre (CAIC) come about?
When I came here there was already an installation downstairs that had two electron microscopes, and at the time I was becoming increasingly interested in issues of lineage and taken with making movies of development. We initially applied for a two-photon microscope as a tool to visualise these things. There were clearly advances in light microscopy that were going on and it was important to me that there was a facility in Cambridge that offered top-end microscopy for biologists. I also knew that there were people in the physical sciences at Cambridge that were really interested in advancing microscopy, without necessarily being interested in biological questions. CAIC was an idea that came out of these interactions – we wanted to build a new generation of advanced light microscope instruments specifically for biologists, and quickly tuneable to their specific needs. So in CAIC we build microscopes not just to see how far microscopy can go, but to tackle crucial issues in biology. It has become an amazing facility that a lot of people are using, and is a hub of a wider set of microscopy centres around the university.
You enjoy painting, and in studying the visual system your lab generates beautiful images of retinal organisation. Have you always been a visually oriented person, and has this directed your research?
Since I was a kid I’ve always liked to draw, though I wouldn’t consider myself a particularly talented artist. The science that I’ve done has always depended on imaging – from that very first time when I looked through the scanning electron microscope as an undergraduate, I was hooked on seeing the microscopic world. I can appreciate bands on gels and things like that, but I like to see the cells, and the questions that I’ve ended up asking over the years – like how do axons get from A to B, or how lineages arise – mean that I want to see the processes occurring. I like to see things in three or four dimensions, and the prettier they are the better it is somehow. I particularly love it when a student or postdoc runs into the office saying ‘Bill, you’ve gotta see this!’, and takes me over to the microscope to show me what’s going on.
In my painting – which I turned to again about ten years ago as a serious hobby, in preparation for my retirement – I took some of my doodles, bits of retina and things like that, and started to colour them in with paints. I think I will continue to do biology-themed paintings for a while now.
From that very first time when I looked through the scanning electron microscope as an undergraduate, I was hooked on seeing the microscopic world
I hear you’re into ice hockey? It must be quite a niche pursuit in Cambridge?
In fact, there are quite a few people playing ice hockey in the UK: it’s a niche sport but it’s growing. I grew up as a Canadian, and was on skates when I was four or five – we used to flood our back yard to make an ice rink, and I would play ice hockey with my brothers. I was never a great player, like I’m not a great painter, but I liked it enough that I kept doing it. When I came here to Cambridge, I discovered there was a team – in fact, the oldest ice hockey rivalry in the world is between Oxford and Cambridge. So I quickly got involved, became the coach of the team, and also play in the recreational team, though there I’m more of a hazard than a help.
Is there anything that Development readers would be surprised to find out about you?
I am the youngest of four children – an older sister and two older brothers. So I was the baby of the family and have always been treated that way. I keep thinking that after all my years of experience as Head of Department, and in life more generally, I’m going to meet them one day and be able to hold my own. But no, they still treat me as a useless baby brother who doesn’t know anything and is not worth listening to. After all these years, it hasn’t changed!
Our latest monthly trawl for developmental biology (and other cool) preprints. See last year’s introductory post for background, and let us know if we missed anything
We started this feature a year ago, and each month it’s taken a little longer to curate as more labs decide to deposit preprints alongside conventional channels of publication, and as this practise is encouraged by an increasing number of journals, funding bodies and academic organisations.
Highlights this anniversary month include a lot of neural development, analyses of a controversial CRISPR off target paper (and a word from the authors of the original paper), an analysis of stem cells and mutation in long lived trees, a slew of new genomes (gar, greyling, reindeer, zucchini and colonial tunicate!), and the routine acronym-fest of new data analysis tools (incorporating mimosas and pineapples this time). The preprints were hosted on bioRxiv, PeerJ and arXiv.
Genome Architecture Leads a Bifurcation in Cell Identity. Sijia Liu, Haiming Chen, Scott Ronquist, Laura Seaman, Nicholas Ceglia, Walter Meixner, Lindsey A. Muir, Pin-Yu Chen, Gerald Higgins, Pierre Baldi, Steve Smale, Alfred Hero, Indika Rajapakse
Epigenetic resetting of human pluripotency. Ge Guo, Ferdinand von Meyenn, Maria Rostovskaya, James Clarke, Sabine Dietmann, Duncan Baker, Anna Sahakyan, Samuel Myers, Paul Bertone, Wolf Reik, Kathrin Plath, Austin Smith
Low Rate of Somatic Mutations in a Long-Lived Oak Tree. Namrata Sarkar, Emanuel Schmid-Siegert, Christian Iseli, Sandra Calderon, Caroline Gouhier-Darimont, Jacqueline Chrast, Pietro Cattaneo, Frederic Schutz, Laurent Farinelli, Marco Pagni, Michel Schneider, Jeremie Voumard, Michel Jaboyedoff, Christian Fankhauser, Christian S. Hardtke, Laurent Keller, John R. Pannell, Alexandre Reymond, Marc Robinson-Rechavi, Ioannis Xenarios, Philippe Reymond
Transgenic flatworms from Wudarksi, et al.’s preprint
A platform for efficient transgenesis in Macrostomum lignano, a flatworm model organism for stem cell research. Jakub Wudarski, Daniil Simanov, Kirill Ustyantsev, Katrien de Mulder, Margriet Grelling, Magda Grudniewska, Frank Beltman, Lisa Glazenburg, Turan Demircan, Julia Wunderer, Weihong Qi, Dita B. Vizoso, Philipp M. Weissert, Daniel Olivieri, Stijn Mouton, Victor Guryev, Aziz Aboobaker, Lukas Scharer, Peter Ladurner, Eugene Berezikov
Chd8 haploinsufficient mice display anomalous behaviours, increased brain size and cortical hyper-connectivity. Philipp Suetterlin, Shaun Hurley, Conor Mohan, Kimberley L. H. Riegman, Marco Pagani, Angela Caruso, Jacob Ellegood, Alberto Galbusera, Ivan Crespo-Enriquez, Caterina Michetti, Robert Ellingford, Olivier Brock, Alessio Delogu, Philippa Francis-West, Jason P. Lerch, Maria Luisa Scattoni, Alessandro Gozzi, Cathy Fernandes, Albert Basson
Evolutionary proteomics uncovers ciliary signaling components. Monika Abedin Sigg, Tabea Menchen, Jeffery Johnson, Chanjae Lee, Semil P. Choksi, Galo Garcia III, Henriette Busengdal, Gerard Dougherty, Petra Pennekamp, Claudius Werner, Fabian Rentzsch, Nevan Krogan, John B. Wallingford, Heymut Omran, Jeremy F. Reiter
Cell biology
The β3-integrin endothelial adhesome regulates microtubule dependent cell migration. Samuel J. Atkinson, Aleksander M. Gontarczyk, Tim S. Ellison, Robert T. Johnson, Benjamin M. Kirkup, Abdullah Alghamdi, Wesley J. Fowler, Bernardo C. Silva, Jochen J. Schneider, Katherine N. Weilbaecher, Mette M. Mogensen, Mark D. Bass, Dylan R. Edwards, Stephen D. Robinson
BPG: Seamless, Automated and Interactive Visualization of Scientific Data. Christine P’ng, Jeffrey Green, Lauren C. Chong, Daryl Waggott, Stephenie D. Prokopec, Mehrdad Shamsi, Francis Nguyen, Denise Y. F. Mak, Felix Lam, Marco A. Albuquerque, Ying Wu, Esther H. Jung, Maud H. W. Starmans, Michelle A. Chan-Seng-Yue, Cindy Q. Yao, Bianca Liang, Emilie Lalonde, Syed Haider, Nicole A. Simone, Dorota Sendorek, Kenneth C. Chu, Nathalie C. Moon, Natalie S. Fox, Michal R. Grzadkowski, Nicholas J. Harding, Clement Fung, Amanda R. Murdoch, Kathleen E. Houlahan, Jianxin Wang, David R. Garcia, Richard de Borja, Ren X. Sun, Xihui Lin, Gregory M. Chen, Aileen Lu, Yu-Jia Shiah, Amin Zia, Ryan Kearns, Paul Boutros
Persistent homology demarcates a leaf morphospace. Mao Li, Hong An, Ruthie Angelovici, Clement Bagaza, Albert Batushansky, Lynn Clark, Viktoriya Coneva, Michael Donoghue, Erika Edwards, Diego Fajardo, Hui Fang, Margaret Frank, Timothy Gallaher, Sarah Gebken, Theresa Hill, Shelley Jansky, Baljinder Kaur, Philip Klahs, Laura Klein, Vasu Kuraparthy, Jason Londo, Zoe Migicovsky, Allison Miller, Rebekah Mohn, Sean Myles, Wagner Otoni, J. Chris Pires, Edmond Riffer, Sam Schmerler, Elizabeth Spriggs, Christopher Topp, Allen Van Deynze, Kuang Zhang, Linglong Zhu, Braden M. Zink, Daniel H. Chitwood
Critical Assessment of Metagenome Interpretation − a benchmark of computational metagenomics software. Alexander Sczyrba, Peter Hofmann, Peter Belmann, David Koslicki, Stefan Janssen, Johannes Droege, Ivan Gregor, Stephan Majda, Jessika Fiedler, Eik Dahms, Andreas Bremges, Adrian Fritz, Ruben Garrido-Oter, Tue Sparholt Jorgensen, Nicole Shapiro, Philip D Blood, Alexey Gurevich, Yang Bai, Dmitrij Turaev, Matthew Z DeMaere, Rayan Chikhi, Niranjan Nagarajan, Christopher Quince, Fernando Meyer, Monika Balvociute, Lars Hestbjerg Hansen, Soren J Sorensen, Burton K H Chia, Bertrand Denis, Jeff L Froula, Zhong Wang, Robert Egan, Dongwan Don Kang, Jeffrey J Cook, Charles Deltel, Michael Beckstette, Claire Lemaitre, Pierre Peterlongo, Guillaume Rizk, Dominique Lavenier, Yu-Wei Wu, Steven W Singer, Chirag Jain, Marc Strous, Heiner Klingenberg, Peter Meinicke, Michael Barton, Thomas Lingner, Hsin-Hung Lin, Yu-Chieh Liao, Genivaldo Gueiros Z Silva, Daniel A Cuevas, Robert A Edwards, Surya Saha, Vitor C Piro, Bernhard Y Renard, Mihai Pop, Hans-Peter Klenk, Markus Goeker, Nikos C Kyrpides, Tanja Woyke, Julia A Vorholt, Paul Schulze-Lefert, Edward M Rubin, Aaron E Darling, Thomas Rattei, Alice C McHardy
Accessible, curated metagenomic data through ExperimentHub. Edoardo Pasolli, Lucas Schiffer, Paolo Manghi, Audrey Renson, Valerie Obenchain, Duy Tin Truong, Francesco Beghini, Faizan Malik, Marcel Ramos, Jennifer B Dowd, Curtis Huttenhower, Martin Morgan, Nicola Segata, Levi Waldron
The top and bottom of the image show how the Dpp concentration gradient affects the organisation of the wing structure of Drosophila melanogaster. In the centre, in the absence of Dpp, the wing does not grow. Image: Lara Barrio.
• Scientists at IRB Barcelona clarify the function of the genes that drive wing development in the fruit fly Drosophila melanogaster.
• Published in the journal eLife, this study unveils that the Dpp morphogen is necessary for wing growth but that its gradient does not govern this process.
• Understanding the development of limbs in Drosophila paves the way to research into congenital defects in vertebrates.
Barcelona, 5th July 2017.- Researchers working in the Development and Growth Control Lab at IRB Barcelona reveal that the Dpp gene (BMP in humans) plays a double role in the structural organisation and growth of the wings of the fruit fly Drosophila melanogaster.
This study, which has been published in the journal eLife, demonstrates that Dpp is necessary for tissue growth but that “its gradient does not direct wing growth,” explains Marco Milán, ICREA research professor and head of the study. This and two other studies published simultaneously in the journal eLife settle the intense scientific debate regarding the function of Dpp and other morphogens involved in development.
Morphogens are molecules found in concentration gradients throughout tissues and they send signals from one cell to another. “The wing of Drosophila melanogaster has several morphogens, such as Dpp (BMP in humans) and Wingless (Wnt in humans), which are necessary for growth,” explains Lara Barrio, the first author of the study and postdoctoral fellow in the Development and Growth Control Lab at IRB Barcelona. In this study, the scientists have examined how Dpp regulates growth and analysed how cells behave when Dpp levels are manipulated.
The role of the Dpp concentration gradient in the regulation of tissue is the subject of intense debate among scientists. Morphogens have been considered to be responsible for this process; however, using distinct techniques, these three studies now conclude that morphogens are necessary for growth but that their concentration gradients do not directly govern this process.
“We know that the gradient of this morphogen in particular affects the structural organisation or the identity of the tissue, but the different levels of Dpp across the tissue have no effect on growth. That is to say, whether a tissue grows or not depends on whether Dpp is present or absent. Its gradient has no influence”, explains Marco Milán.
So what regulates the size of the final structural of the Drosophila wing? “Morphogen gradients don’t. There must be another alternative and as yet unknown mechanism, and the fly wing is an ideal model to answer this question,” says Marco Milán.
This research is consistent with knowledge about the morphogen Sonic hedgehog in vertebrate limbs. The gradients of this molecule affect tissue identity (for example, for the fingers of a hand to differ from each other) but do not regulate growth. Therefore understanding how the structures of Drosophila form and develop paves the way to studying vertebrate development and congenital defects in humans.
This study has been supported by the Ministry of Economy, Industry and Competitiveness (MINECO), ERDF “Una manera de hacer Europa”, and the CERCA Programme of the Government of Catalonia.
Reference article:
Lara Barrio and Marco Milán
Boundary Dpp promotes growth of medial and lateral regions of the Drosophila wing
eLife (2017). DOI: 10.7554/eLife.22013
Post-doc in mathematical modeling on phenotypic evolution and embryonic development:
1.Job/ project description:
The postdoc could choose between three main research projects:
a. Mathematical modeling of phenotypic evolution in populations with embryonic development.
b. Mathematical modeling of gene network and embryonic development evolution.
c. Mathematical modeling of organ development and their evolution in mammalian teeth or Drosophila wing.
The actual project will be chosen together with the candidate depending on his/her interests and skills.
The research will take place in the Isaac Salazar-Ciudad’s group in the Center of Excellence in Experimental and computational developmental biology of the Biotechnology Institute of the University of Helsinki, Finland.
The job is for 1 year and renewable for 1 extra year.
2. Background:
Why organisms are the way they are?
Can we understand the processes by which complex organisms are build in each generation and how these evolved?
We are trying…
The process of embryonic development is now widely acknowledged to be crucial to understand evolution since any change in the phenotype in evolution (e.g. morphology) is first a change in the developmental process by which this phenotype is produced. Over the years we have come to learn that there is a set of developmental rules that determine which phenotypic variation can possibly arise in populations due to genetic mutation (the so called genotype-phenotype map). Since natural selection can act only on existing phenotypic variation, these rules of development have an effect on the direction of evolutionary change.
Salazar-Ciudad’s group is devoted to understand these developmental rules and how these can help to better understand the direction of evolutionary change. The ultimate goal is to modify evolutionary theory by considering not only natural selection in populations but also developmental biology in populations. For that aim we combine mathematical models of embryonic development that relate genetic variation to morphological variation with population models. The former models are based on what is currently known in developmental biology.
Salazar-Ciudad’s group is in close collaboration with Jukka Jernvall’s group and other groups within the center of excellence in experimental and computational developmental biology. The center includes groups working in tooth, wing, hair and mammary glands development. In addition to evolutionary and developmental biologists the center of excellence includes bioinformaticians, populational and quantitative geneticists, systems biologists and paleontologists.
“The Academy of Finland’s Centres of Excellence are the flagships of Finnish research. They are close to or at the very cutting edge of science in their fields, carving out new avenues for research, developing creative research environments and training new talented researchers for the Finnish research system.”
3. Requirements:
The applicant must hold a PhD in either evolutionary biology, developmental biology or, preferably, in evolutionary developmental biology (evo-devo). Applicants with a PhD in theoretical or mathematical biology are also welcome.
Programming skills or a willingness to acquire them is required.
The most important requirement is a strong interest and motivation on science and evolution. A capacity for creative and critical thinking is also required.
4. Description of the position:
The fellowship will be for a period of up to 1+1 years (100% research work: no teaching involved).
Salary according to Finnish postdoc salaries.
5. The application must include:
-Motivation letter including a statement of interests
-CV (summarizing degrees obtained, subjects included in degree and grades, average grade).
-Summary of PhD project, its main conclusions and its underlying motivation.
-Application should be sent to Isaac Salazar-Ciudad by email:
isaac.salazar@helsinki.fi
No official documents are required for the application first stage but these may be required latter on.
6. Deadline:
There is no specific deadline, the position will be filled as soon as a suitable candidate is found.
7. Examples of recent publications by Isaac Salazar-Ciudad group.
Brun-Usan M, Marín-Riera M, Grande C, Truchado-Garcia M, Salazar-Ciudad I. A set of simple cell processes is sufficient to model spiral cleavage. Development. 2017 Jan 1;144(1):54-62.
-Salazar-Ciudad I, Marín-Riera M. Adaptive dynamics under development-based genotype-phenotype maps. Nature. 2013 May 16;497(7449):361-4.
-Salazar-Ciudad I, Jernvall J. A computational model of teeth and the developmental origins of morphological variation. Nature. 2010 Mar 25;464(7288):583-6.
8. Interested candidates should check our group webpage:
Here are the highlights from the current issue of Development:
Heart tube formation: a gut reaction
Morphogenesis of the endoderm-derived foregut (FG) is tightly linked to that of the mesoderm-derived heart tube (HT), with both structures arising at approximately the same time and place in the developing embryo. However, the physical forces that create the FG and HT are unclear. Here, Larry Taber and colleagues combine experimental approaches in chick embryos with computational modelling to explore this issue (p. 2381). They propose that differential anisotropic growth between the mesoderm and endoderm drives tissue folding and formation of the FG while also bringing the bilateral heart fields (HFs) into close proximity. Indeed, inhibition of cell proliferation (using the mitotic inhibitor Aphidicolin) together with computational simulations confirm that proliferation is required for this initial step. They further propose that actomyosin contraction in the anterior intestinal portal (AIP; the caudal opening of the FG) then generates tension that elongates the FG and the fused HFs. In line with this, inhibition of contraction (using the myosin inhibitor blebbistatin) and modelling analyses reveal that contraction is required for FG and HF elongation. Finally, the authors reveal that the fused HFs thicken and expand – driven by an accumulation of cardiac jelly – to eventually create the HT. Together, these findings highlight a new model that integrates HT and FG morphogenesis.
mTORC-ing some sense into pancreas development
In recent years, much progress has been made in uncovering the signalling pathways and transcriptional networks that can influence pancreas development during embryogenesis. However, comparatively little is known about postnatal development of the pancreas, and whether nutrients can impact pancreas development and function after birth. Now, James Wells, Katie Sinagoga and colleagues demonstrate that the nutrient-sensing mTOR pathway regulates the maturation and function of mouse pancreatic islets postnatally (p. 2402). They first reveal that mTOR is dispensable for embryonic development but is required for normal postnatal islet development, with levels of mTOR signalling being highest in the first few weeks after birth. The researchers further report that deletion of mTOR in the endocrine pancreas causes a decrease in islet mass and compromised islet maturation and morphogenesis; this is accompanied by a decrease in islet function. Finally, the authors show that the two known mTOR-containing complexes – mTORC1 and mTORC2 – mediate distinct functions of mTOR: while mTORC1 predominantly regulates islet maturation and function, mTORC2 influences islet mass and morphogenesis. Overall, these findings highlight a potential role for nutrient-sensing mechanisms during postnatal islet development and maturation, a finding that has important implications for deriving functional β-cells in vitro.
A role for cell repulsion during placental labyrinth formation
The placental labyrinth – a complex structure made up of trophoblasts and endothelial cells – provides the interface for gas and nutrient exchange between the embryo and the mother and hence is essential for embryogenesis. However, the molecular mechanisms that underlie the development of this vital labyrinth, particularly those that influence its vascularization, are poorly understood. Here, on p. 2392, Yoshiaki Kubota, Satoru Yamagishi and co-workers report the unexpected finding that fibronectin leucine-rich transmembrane protein 2 (FLRT2), which is a protein that acts as a chemorepellent in neurons, regulates placental labyrinth development in mice. They report that FLRT2 is expressed in endothelial cells specifically in the placental labyrinth. The researchers further demonstrate that the vasculature is poorly formed and aberrantly organized in FLRT2-deficient placentas, with FLRT2-deficient embryos exhibiting high levels of hypoxia. In vitro assays reveal that, as occurs in neurons, FLRT2 signals through UNC5B and can mediate cell repulsion. Following on from this, the authors show that Unc5b deletion recapitulates the vascular defects observed in Flrt2-deficient placentas. Together these exciting results point towards a role for inter-endothelial repulsion, mediated by FLRT2, during placental morphogenesis.
PLUS…
An interview with Bill Harris
William ‘Bill’ Harris is Head of the Department of Physiology, Development and Neuroscience at the University of Cambridge, UK, and a Fellow of both the Royal Society and Academy of Medical Sciences. His lab works on the development of the vertebrate nervous system, with a particular focus on cell lineage in the retina. In 2017 he was awarded the British Society for Developmental Biology’s Waddington Medal for outstanding research performance and services to the community. We met Bill in his Cambridge lab to talk science, art and ice hockey. Read the Spotlight on p. 2307
MicroRNAs in neural development: from master regulators to fine-tuners
The proper formation and function of neuronal networks is required for cognition and behavior. Indeed, pathophysiological states that disrupt neuronal networks can lead to neurodevelopmental disorders such as autism, schizophrenia or intellectual disability. In recent years, it has been shown that microRNAs (miRNAs), an abundant class of small regulatory RNAs, can regulate neuronal circuit development, maturation and function by controlling, for example, local mRNA translation. Here, Marek Rajman andGerhard Schratt provide an overview of the most prominent regulatory miRNAs that control neural development, highlighting how they act as ‘master regulators’ or ‘fine-tuners’ of gene expression, depending on context. See the Review on p. 2310
Human haematopoietic stem cell development: from the embryo to the dish
Haematopoietic stem cells (HSCs) emerge during embryogenesis and give rise to the adult haematopoietic system. Understanding how early haematopoietic development occurs is of fundamental importance for basic biology and also for recapitulating the development of HSCs from pluripotent stem cells in vitro. Here, Alexander Medvinsky and colleagues discuss what is known of human haematopoietic development: the anatomical sites at which it occurs, the different temporal waves of haematopoiesis, the emergence of the first HSCs and the signalling landscape of the haematopoietic niche. They also discuss the extent to which in vitro differentiation of human pluripotent stem cells recapitulates bona fide human developmental haematopoiesis, and outline some future directions in the field. See the Review on p. 2323
I am Eleni Chrysostomou, a PhD student in Uri Frank‘s lab at the National University of Ireland, Galway. The Frank lab’s general interest is development and regeneration, stem and germ cell biology, neural fate commitment, and the chromatin biology underlying these processes. The focus of my project is the roles of SoxB transcription factors (TFs) during nervous system development and regeneration. More specifically, my hypothesis is that SoxB TFs are expressed sequentially in the neural lineage and play a role in neural progenitor cells (NPCs) migration from the body column to the site of injury to re-establish and regenerate the missing head region. The work is mostly done in an in vivo context utilizing transgenic animals, as well as various molecular techniques.
According to the Greek mythology, one of Hercules’ labours was to kill the sea monster Lernaean hydra. What he didn’t know was that every time he decapitated one of the monster’s heads, it would grow back in triplicate! But how is that even remotely related to stem cell biology…
With that said, meet our animal model Hydractinia. Hydractinia, a marine colonial hydrozoan can be described as a great representative of the Cnidaria phylum and an excellent animal model to study cell and developmental biology, as its utility let to the assembly of the very first concepts and terms in biology, including the characterization of stem cells (Weismann, 1883).
The stem cells founded in Hydractinia (aka interstitial cells: i-cells) remain collectively pluripotent throughout the organism’s life and they express germ line markers such as Nanos, Vasa and Piwi (Bradshaw et al., 2015; Plickert et al., 2012). Hydractinia can be easily cultured and genetically manipulated in the laboratory without any ethical restrictions, and its application is suitable in various disciplines.
Hydractinia has a relatively simple life cycle. Following fertilization, the embryonic development lasts 36-48 hours and upon induced metamorphosis the primary polyp is asexually reproduced to give rise to the new colony (Figure 1). The resulting members of an individual colony share a gastrovascular space, nervous system and migratory stem cells by maintaining tissue continuity (Gahan et al., 2016)
Figure 1: The life cycle of Hydractinia (Image obtained from Flici et al., 2017, Cell Reports).
What really makes this animal so intriguing is its regenerative abilities. Like the mythical creature Lernaea, upon decapitation the animal is able to regenerate a fully functional and complete head just within three days (Figure 2).
Figure 2: Live imaging of head regeneration in Hydractinia (Image obtained from Bradshaw et al., 2015, eLife).
What do we do with our “non-mainstream” animal model…
The Frank Lab is based in the National University of Ireland Galway and it is composed of post-graduate students and Post-docs with each of us exploring a different aspect of the biology of these animals in order to answer fundamental questions spanning from developmental biology to epigenetics.
Some of the projects that are currently running in our lab are: whole body regeneration from small tissue fragments (Hakima Flici – Post-Doc), the role of Piwi genes in development and regeneration (Emma McMahon – PhD student), histone variants in Hydractinia (Anna Torok – PhD student), sexual commitment (Timothy Dubuc – Post-Doc).
A typical day in our lab is anything but ordinary. We start the day by spawning the animals and collect the embryos for injection. As the time window for injection is quite narrow – only half an hour before they start dividing – you don’t have much of a choice but to wake up and run downstairs to the manipulation room. After the running and once injection is done, you can breathe for a bit but not for long. The animals need to be fed after all that effort given to the spawning. Generally, there is not much time to lay back and enjoy a nice cup of coffee – not a tea person – but we still love it (that’s why we are in research I guess). Once the feeding is done, you can go back to the lab and see what’s the plan for the day and continue with the experiments that you left from last night – most of the protocols have overnight incubations or you were just too tired and hungry to keep working, lets be honest. And before you realize it it’s already late in the afternoon! The working hours in Ireland can be a bit tricky during the summer time (not really summer, but oh well) as the day light can last until 10-11 o’clock in the night and you have no sense of the actual time! The supervisors are happy during that period…
Even though working with a not so popular animal model can be a bit demanding, it gives us the opportunity to study developmental aspects not feasible in other animal models. Although structurally simple, Hydractinia encompasses a complex gene repertoire that is highly conserved to their sister branch bilaterians. Not many organisms are able to regenerate body parts and especially their heads. This pioneering model for stem cell biology gives as a highly valuable advantage to gain insights on why other animals including humans have limited or zero abilities to regenerate missing parts of their bodies.
The Frank Lab. Some people missing as we never manage to get a picture with all of us.
A fully funded PhD position is available in the Laboratory of Regulatory Evolution (Tschopp group) at the Zoological Institute, University of Basel, Switzerland.
Our research interests focus on two main questions: How is phenotypic diversity generated during vertebrate embryogenesis? And how can developmental processes be modified to drive morphological evolution?
The present project will investigate the potential for developmental plasticity in the limb neuromuscular system in response to changes in dactyly, i.e. altering digit numbers. Specific questions we will address include: How are muscle patterning and motorneuron axonal pathfinding coping with changes in digit numbers in vertebrate hands and feet? How is motorneuron pool complexity in the spinal cord affected by additional digit targets in the periphery? We will use a range of methods, including experimental embryology in chicken, genetic mouse models, axonal backfilling, NextGeneration-Sequencing and functional experiments using gene knock-down and overexpression.
The project builds on solid foundations of confirmed preliminary data. For more information please visit http://evolution.unibas.ch/tschopp/research/index.htm
The successful candidate will have a Master (or equivalent) in developmental biology and/or molecular biology, and ideally will have skills in experimental embryology, neurobiology and NextGeneration-Sequencing. A basic understanding of Unix and the R language for statistical computing would be beneficial.
Please send your application with a brief statement of motivation, CV and contact(s) for references (where applicable) to patrick.tschopp@unibas.ch
Evaluation will begin mid-August 2017 and suitable candidates will be contacted shortly after – earliest starting date is Sept. 1st 2017.
Multiple PhD opportunities in EcoEvoDevo of sponges and corals are available at the Research School of Biology, Australian National University. The projects are related to regeneration, biomineralization, evolution of developmental gene regulatory networks and microbiomes, see http://biology.anu.edu.au/research/labs/adamska-lab-genomic-and-evolutionary-basis-animal-development for details. All projects provide exciting and varied research experience by combining cell and molecular biology approaches with bioinformatics and field work in temperate and tropical marine environments. The students will be based in the Adamska lab at the ANU, and will be involved in local, national and international collaborations. The successful candidates will commence the doctoral program in late 2017 or early 2018.
The positions come with substantial research and travel budgets, and the candidates are encouraged to apply for scholarships to fund personal living expenses. The ANU is administering domestic and international PhD scholarships ($26,682 per annum for a period of 3 years with a possibility of a 6-month extension). Scholarship application deadlines are 31st of August (international applicants) and 31st of October (domestic applicants). Queries regarding scholarship matters can be directed to rsb.studentadmin@anu.edu.au. Shortlisted candidates will receive support in preparing the scholarship applications, with a possibility of internal funding for “near miss” applicants.
Interested candidates should contact Maja Adamska maja.adamska@anu.edu.au by July 31st 2017, providing current CV, 500-1000 words description of research interest including preference for one or more of the listed projects, and contact details for two academic references.
A 3-year postdoc position is available in the group of Dr. Patrick Steinmetz at the Sars Centre in Bergen (Norway) to study the evolution of animal nutrient and growth homeostasis .
The project is based on a tissue-specific transcriptome analysis comparing fed and fasting animals in the sea anemone Nematostella vectensis. The successful applicant will be involved in further validating some of the resulting signalling, neuronal or growth control genes and studying their functional role in nutrient and growth homeostasis. With that aim, the applicant will use and further develop state-of-the-art functional techniques (CRISPR, transgenesis) and combine those with a diverse range of physiological, imaging and molecular biology techniques available.
Further details on the application, position and contact details can be found here: https://t.co/RFzeVLAG9J
A postdoctoral position is available in the laboratory of Dr. Sophie Astrof at Thomas Jefferson University to study roles of cell-extracellular matrix interactions during cardiovascular development and disease. My laboratory utilizes genetics, cell biology and confocal imaging to elucidate developmental and molecular mechanisms of aortic arch artery patterning and the formation of the cardiac outflow tract. These processes are essential for neonatal viability, and defects in the formation and remodeling of the outflow tract vasculature underlie common and severe forms of human congenital defects. Experience with genetic manipulation, embryology and cell biology is desirable. My laboratory is a part of a modern and well-equipped Center for Translational Medicine at Jefferson Medical College (http://www.jefferson.edu/university/research/researcher/researcher-faculty/astrof-laboratory.html) located in the heart of Philadelphia. To apply, send a letter of interest, CV and names and contact information of three references to sophie.astrof@gmail.com
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William ‘Bill’ Harris is Head of the Department of Physiology, Development and Neuroscience at the University of Cambridge, UK, and a Fellow of both the Royal Society and Academy of Medical Sciences. His lab works on the development of the vertebrate nervous system, with a particular focus on cell lineage in the retina. In 2017 he was awarded the British Society for Developmental Biology’s Waddington Medal for outstanding research performance and services to the community. We met Bill in his Cambridge lab to talk science, art and ice hockey. Read the Spotlight on p. 
The proper formation and function of neuronal networks is required for cognition and behavior. Indeed, pathophysiological states that disrupt neuronal networks can lead to neurodevelopmental disorders such as autism, schizophrenia or intellectual disability. In recent years, it has been shown that microRNAs (miRNAs), an abundant class of small regulatory RNAs, can regulate neuronal circuit development, maturation and function by controlling, for example, local mRNA translation. Here, 
Haematopoietic stem cells (HSCs) emerge during embryogenesis and give rise to the adult haematopoietic system. Understanding how early haematopoietic development occurs is of fundamental importance for basic biology and also for recapitulating the development of HSCs from pluripotent stem cells in vitro. Here, Alexander Medvinsky and colleagues discuss what is known of human haematopoietic development: the anatomical sites at which it occurs, the different temporal waves of haematopoiesis, the emergence of the first HSCs and the signalling landscape of the haematopoietic niche. They also discuss the extent to which in vitro differentiation of human pluripotent stem cells recapitulates bona fide human developmental haematopoiesis, and outline some future directions in the field. See the Review on p. 
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