The Novo Nordisk Foundation Section for Basic Stem Cell Biology, Danish Stem Cell Center, Faculty of Health and Medical Sciences University of Copenhagen

The University seeks to appoint three Group Leaders in Pancreatic Cancer, Stem Cell Biology and Bioengineering to The Novo Nordisk Foundation Section for Basic Stem Cell Biology (BasicStem) at the Danish Stem Cell Center (DanStem) to commence as soon as possible. The positions are for six years with possible extensions depending on the outcome of a peer reviews.

Background

The Danish Stem Cell Center (DanStem) is an international research center at the University of Copenhagen. The overall scientific goal is to develop new stem cell-based therapeutic approaches, currently in the area of diabetes and cancer addressing basic questions in stem cell and developmental biology and seeking to identify the factors that govern the development of different cell types in the body. Read about DanStem at www.danstem.ku.dk/.

Group Leader in Pancreatic Cancer

Particular interest in basic and disease-oriented pancreatic cancer biology

Group Leader in Stem Cell Biology

Particular interest in addressing fundamental questions in stem cell biology by using single cell behaviour analysis

Group Leader in Bioengineering

Particular interest in addressing fundamental questions in stem cell biology using bioengineering approaches. Experience with materials science and/or devices (e.g. microfluids) would be an advantage.

The Group Leaders duties will primarily consist of:

• Developing a strong research program.
• The Group Leaders must be willing to synergize with other DanStem scientists and contribute to common activities at DanStem such as seminars and PhD courses.
• The Group Leaders are expected to take full responsibility for training and supervision of young researchers, for management of each of their own group, and for publication/dissemination of research results.
• The Group Leaders are expected to actively contribute to teaching activities and education activities
• Academic assessments

The closing date for applications is 23.59 pm, May 1st, 2016

Apply online: http://employment.ku.dk/all-vacancies/?show=795295

Only online applications will be accepted.

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‘Rising Star’ fellowships will be very prestigious and highly competitive positions, designed to attract the very best ‘rising stars’ of academic research. ‘Rising star’ packages will be funded at approximately £0.2m per annum and can involve collaboration with relevant commercial or third sector organisations

‘Rising Star’ applications can be submitted at any time.

Eligibility Criteria

Rising Star Fellowships applicants should meet the eligibility criteria set out below:

Applicants should have over 7 years of experience since completion of PhD (or equivalent degree) and scientific track record showing great promise
Applicants should have an excellent research proposal
Applicants can be of any nationality
Applicants must submit a completed application form and associated documents (supervisor form, ethics form, and CV)
Applications must comply with the fundamental ethic principles as detailed in the ethics section
Applicants must have the support of their chosen host institution

Link

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Post doctoral position available to study the genetic and epigenetic control of stem cell attributes and pluripotency, focusing on the neural crest gene regulatory network (NC-GRN). Neural crest cells are stem cell-like progenitors that migrate extensively and whose genesis was central to the evolution of vertebrates. Misregulation of components of the NC-GRN underlies numerous human diseases and congenital disorders. Studies involve post-translational regulation of known network components, and use of proteomics and next generation sequencing to identify novel components. 

Highly motivated applicants with a PhD and strong background in cell and molecular biology and/or developmental biology are encourage to apply. Please send a CV, brief description of research interests, and the names of three references to:

Carole LaBonne, PhD (clabonne@northwestern.edu)
Department of Molecular Biosciences
Northwestern University, Evanston, IL 602028

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The 2016 Spring meeting of the British Society for Development Biology (held jointly with the British Society for Cell Biology) will start this Sunday at the University of Warwick and the Node will be there!

Pop by The Company of Biologists’ stand to chat with Cat, our community manager, and collect our new freebies! If you are a fan of our ongoing series on model organisms in developmental biology you may like to take a copy of our brand new booklet, which includes a selection of some of the earlier posts in the series. Thank you to all the authors of the posts who gave us permission to use their text and images and helped us put this booklet together!

We also have a new set of postcards featuring beautiful images from the Woods Hole Embryology course. Make sure to come to the stand to collect yours!

This meeting is also a great opportunity to chat with other people at The Company of Biologists. Development’s executive editor Katherine Brown, and reviews editor Seema Grewal will also be at the meeting, and Nicky Le Blond, who runs our travelling fellowships and grant program and organises our fabulous workshops, will be at the stand on Tuesday. Cat and Katherine will also be leading discussion tables on social media and publishing respectively at the Careers Workshop on Sunday afternoon, so plenty of chances to say hello. We look forward to meeting you then! If you can’t make it to the meeting you can always follow us on Twitter. The Node will be tweeting using the hashtag #cbdb16

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Thanks to the Cell Science Travel Fellowship of the Company of Biologists, I was able to work for 2 months at the Institut National de la Recherché Agronomique (INRA) in Jouy-en-Josas, a small town close to Paris, in France.

I just started the second year of my PhD in the group of Dr. Mostowy at Imperial College London. The Mostowy group is well known to study host cell biology, focusing on the eukaryotic cytoskeleton (actin, microtubules, intermediate filaments and septins). The discovery that prokaryotes exhibit counterparts of the major cytoskeletal components (e.g. MreB, FtsZ, CreS) radically changed the context how bacteria are studied and helped to inspire the field of bacterial cell biology. To travel from eukaryotic to prokaryotic cell biology, I went to the lab of Dr. Rut Carballido-López, who is well recognised for her pioneering work on the actin-like MreB cytoskeleton in Bacillus subtilis.

New techniques to study the cytoskeleton include genetic modifications to follow the spatiotemporal location of cytoskeletal proteins (e.g. fluorescently tagging) and to analyse their function (e.g. gene inactivation). Both approaches are applied in eukaryotes and prokaryotes, however the precise methods are completely different between these kingdoms (e.g. siRNA versus knockouts). In eukaryotes as well as in prokaryotes, cytoskeletal proteins are key structural determinants that assemble into filaments and their genes are essential for viability, which makes their genetic manipulation even more challenging. Luckily, I was working with Arnaud Chastanet, a highly experienced Research Scientist (CR1) with great visualisation and explanation skills, and Charlène Cornilleau, an Ingénieur d’Etudes with ‘magic cloning hands’, who supported me greatly with my clonings.

Picture: The actin-like MreB cytoskeleton (green) in Bacillus subtilis (red).

It was a great experience to work in the lab of Dr. Rut Carballido-López. Everyone in the working group was really friendly and helpful and I had many interesting discussions – science-related and beyond. My visit allowed me to expand my knowledge in microbial genetics. Now back in London, I can share my knowledge and tools, and allow other scientists to benefit from my stay at INRA. Working in France provided me with the unique opportunity to experience science internationally, and to network with people for my future career in science. I am deeply grateful to Dr Rut Carballido-López for enabling my collaborative visit and to The Company of Biologists for awarding me with a Cell Science Travel Fellowship.

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Notes on “Intracellular lumen formation in Drosophila proceeds via a novel subcellular compartment” by Linda S. Nikolova and Mark M. Metzstein. Development 2015 142: 3964-3973; doi: 10.1242/dev.127902

In this post, I provide additional details to a paper which we published last year in Development. In particular, I expand on our description on the method of high pressure freezing/freeze substitution, as well as why we developed this technique to examine Drosophila tracheal terminal cells, a part of the insect breathing system.

Like all terrestrial animals, insects require the ability to take oxygen from the atmosphere and deliver it to internal tissues. In vertebrates, this function is carried out by two independent systems: the lungs, used to take air into the body, and the vasculature, used to distribute oxygen throughout the body. Insects and other invertebrates use a different strategy, in which gas intake is directly coupled to the distribution system. This organization is accomplished by a single network of epithelial tubes, called trachea by analogy with vertebrate breathing systems. Openings on the surface of the insect, called spiracles, connect to large, multicellular tracheal tubes. In turn, smaller, unicellular tubes branch off the multicellular tubes and extend toward different regions of the animal. Finally, located at the ends of unicellular tubes, a number of specialized cells, known as terminal cells, are responsible for distribution of gas to all individual cells and tissues. Insect respiration is thought to be driven entirely by passive diffusion of air through the tracheal network, a method of respiration that obviously works well for this class of animals given their huge numbers and species diversity. However, it is also likely this passive diffusion of air sets the limits to organismal size, thus explaining why giant ants do not regularly rampage over the countryside.

We are particularly interested in the cell biological mechanisms of terminal cell morphogenesis. To perform their function, terminal cells undergo fascinating cell shape changes, with each individual cell undergoing an iterative process of plasma membrane outgrowth and bifurcation during larval stages. Eventually, each cell produces 20-100 thin (typically less than 1µm in diameter) subcellular branches (labeled with a cytoplasmic GFP in Fig. 1A). In terms of complexity, terminal cells rival the elaborate axonal and dendritic arbors found in neurons. However, unlike neurons, terminal cells have to undergo an additional form of morphogenesis: tubulogenesis.  For gas to flow efficiently, each of the thin branches terminal cell branches develops into a tube, with a membrane-bound, gas-filled open space, called a lumen, running through it.

In our recent paper, we focus on the cellular and molecular mechanisms by which the subcellular lumen forms in terminal branches. The lumen of terminal cell branches is extremely thin, smaller in diameter than the width of a bacteria such as E. coli. At this scale, the formation of the lumen is akin to the mechanisms required to form subcellular organelles, such as mitochondria or lysosomes, albeit the lumen is different as it is a continuous structure extending through all the branches of the terminal cell. Despite recent amazing advances in light microscopy, the only high resolution technique available to examine the membranes that form the lumen is transmission electron microscopy (TEM; EM on left; schematized on right in Fig. 1B).

One important consideration in using EM is that the technique does not visualize biological structures directly, as the electron beam immediately vaporizes essentially all biological material. Instead, tissues must be immobilized (“fixed”) and treated with stains, typically heavy metals, that can be visualized directly in the EM. By far the most common method of fixation has been the use of chemical cross-linkers, usually aldehydes. This approach has been successfully applied to numerous samples and has produced many high quality studies. However, chemical cross-linking has some significant disadvantages. First, different biological polymers, such as membranes, proteins, or nucleic acids, differ significantly in how well they are preserved by any particular cross-linking reagent, and it is hard to find conditions in which all are simultaneously well preserved. Second, chemical cross-linking takes time, during which tissues can undergo deformation. Third, it is necessary to get the fixatives rapidly into the cells. While this is relatively easy for cells in culture and for dissected tissues, it is a significant problem for an intact organism, such as a Drosophila larvae.

To avoid the problems of chemical fixation, we turned to an alternative, very different method of fixation: high pressure freezing/freeze substitution (HPF/FS). The basic principle of HPF fixation is straightforward: cells are preserved by rapid freezing. However, as is well known, water has the unusual property of expanding upon freezing. Since most tissues are composed mainly of water, expansion from water ice crystals then causes disruption of cellular structures. However, as was proposed some 40 years ago, a procedure to avoid ice crystal damage is to rapidly freeze samples while subjecting them to high pressure. Under this regime, ice crystals cannot form. Instead the water forms an amorphic arrangement, similar to a glass. Amorphic ice has essentially the same density as liquid water, thus occupies the same volume, so damage from ice crystal expansion or tissue shrinkage does not occur. Importantly, amorphic ice maintains its structure when pressure is released, as long as the sample is kept cold. This allows the second step of the HPF/FS –freeze substitution– to proceed. During this step, water ice in the sample is replaced (substituted) with solvents that do not expand upon freezing, such as ethanol or acetone. Metal stains can be included in this substitution “cocktail” to label internal cell components. After the substitution step is completed, the samples can be returned to ambient temperature. This is followed by standard procedures of embedding in a plastic resin, sectioning, and observation by an electron microscope. Fortunately, many of the steps of HPF/FS are automated with commercial instruments available to carry out freezing and substitution (Fig. 2). Samples are frozen within a high pressure freezer, which injects liquid nitrogen at ~2500 atmospheres, both compressing and cooling the samples. Freeze substitution, which takes a number of days, takes place in a special liquid nitrogen filled chamber in which substitution cocktails are automatically exchanged, and the temperature regulated to complete the solvent exchange and the return to ambient temperatures.

Much of the work leading to our paper involved testing different cocktails, and different incubation times and temperature change regimes during the substitution, in order to optimize both tissue preservation and structure visualization. One particularly important refinement we made during the course of our studies was the use of Durcupan instead of more commonly used epoxy resins, as it produced samples with better tissue preservation and membrane contrast. Overall, our results produced excellent preservation of internal tissues of intact Drosophila larvae. Different macromolecular structures, including proteins, nucleic acids, and the chitinous cuticle were very well preserved. Membranes in particular were particularly well preserved and had a smooth, curved appearance, indicative of very little tissue deformation.

As described in the paper, our new fixation techniques revealed previously unrecognized details of the terminal branch lumen formation. In particular, we found evidence of a hitherto undescribed intermediate of tube formation: a novel, multimembrane subcellular compartment that may contain the precursors of the cuticle lining the lumen. We also characterized the ultrastructural phenotypes of new genes required for lumen formation, providing further evidence for the multimembrane intermediate in the lumen formation process. Our future research will involve using our new fixation techniques to characterize other genes required for lumen formation and an analysis of the subcellular localization of proteins required for this process. In general, our fixation techniques should allow for analysis of many of the developmental and physiological processes that occur during Drosophila larval development.

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Applications are open for 3-year PhD fellowships in the Montpellier Health Science doctoral program (To apply visit http://www.adum.fr/as/ed/cbs2/page.pl?page=concoursed-gb before May 3rd 2016).

Our group is proposing three possible independent PhD projects on the embryonic development of marine invertebrates closely related to vertebrates, the ascidians (Lemaire, 2011, Development 138, 2143–2152). Most ascidian species develop with almost identical embryonic morphologies in spite of very different genomes, a paradox we are trying to understand. The projects will contribute to a better understanding of the genetic program underlying ascidian development and of its robustness to genetic changes.

The first project aims at the reconstruction and analysis of the early ascidian endodermal Gene Regulatory Network, which is currently only very partially known. We will combine the knowledge of open chromatin regions flanked with specific histone marks, transcription factor (TF) DNA-binding specificity and TF expression to predict the location of cis-regulatory sequences for endodermal regulatory genes, which will be tested and dissected by electroporation into live embryos. This network will then be used to model the flow of genetic information across time, and its robustness to genetic variations.

The second project will test the hypothesis that ascidians can buffer divergent genome information because the architecture of their Gene Regulatory Networks (GRNs) makes them quite insensitive to variations in the level of regulatory gene expression. This hypothesis will first be tested by comparing  the level of inter-individual variability in regulatory gene expression in ascidian embryos (slow morphological evolution, fast molecular evolution) and vertebrate embryos (faster morphological evolution, but slower molecular evolution). We will then monitor the phenotypic response to progressive interference with gene function in both taxa.

Finally, the third project will focus on inter-cellular communication (inductions) in ascidian embryos, and their sensitivity to changes in embryonic geometry and gene expression. We will first quantify the main biochemical parameters of an embryonic induction (concentrations of ligands and receptors, rates of diffusion, rate constants,…) and their variability across individuals. These data will then be used to construct and constrain a quantitative model of an embryonic induction.

Our group is small and interdisciplinary. Its working language is English.

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Snow, M. H. L., Tam, P. P. L. (1979) Is compensatory growth a complicating factor in mouse teratology? Nature 279, 555-557

Lewis, N. E., Rossant, J. (1982) Mechanism of size regulation in mouse embryo aggregates J. Embryol. exp. Morph 72, 169-181

Recommended by James Briscoe (Francis Crick Institute)

As our previous forgotten classic demonstrated, much can be learnt from careful observation of embryonic development. Once there is a good basis of what ‘normal’ is though, the next step is to perturb the system. These days we are used to precise genetic manipulations: removing a single gene (or even a single protein domain), affecting only a specific cell type or at a specific stage in development. However, there are certain questions that benefit from more global alterations, such as making the embryo very small or very big. The two papers recommended by James Briscoe use such approaches to address the important question of how the mouse embryo regulates its size.

The first study, published in Nature in 1979 by Snow and Tam, did not set out to examine size regulation. Mitomycin C was a known teratogen, i.e. a chemical known to cause embryonic malformations, but its effects on early mouse development were unknown. The authors found that the effects of this compound were indeed very quick: by E7 the compound had caused extensive cell death and the embryos were very small. Yet, while this treatment reduced embryonic viability and the resulting pups showed various defects, they were not noticeably smaller. As the authors stated ‘the mouse embryo can withstand a major disturbance in its early development and recover to such an extent that structural abnormalities rarely emerge’. In short, ‘the mouse embryo can be reduced to around 10% of its normal size at a time when it is about to begin organogenesis, but is nearly normal again before that phase of development is complete.’ What an extraordinary ability to regulate size, and a good example that in science you may find an interesting answer for a question that you weren’t even asking!

Reprinted by permission from Macmillan Publishers Ltd: Nature (279, 555-557), copyright (1979)

While Snow and Tam inadvertently discovered what happens when a mouse embryo becomes too small, Lewis and Rossant very purposefully tried the opposite in their paper in JEEM (now Development). By 1982, several groups had already shown that if you increase the size of a mouse embryo, e.g. by aggregating several embryos together, the end product is still a viable offspring of normal size. But at which stage of development does this regulation occur, and by what mechanism? To answer this question, the authors compared normal- and double-sized mouse embryos. They showed that while the embryos start off with different sizes, by E6.5-E7 (around the same time as observed by Snow and Tam) they have the same dimensions. They also suggested a mechanism by which this regulation of size may be happening. At E5, normal embryos undergo a period of high mitotic activity while double-sized embryos slow down their cell cycles, giving the normal embryos a chance to ‘catch up’.

As James Briscoe tells us ‘both papers demonstrate the surprising ability of early mouse embryo to regulate its size. Tam and Snow show that ~80% of the cells in an E7 embryo can be killed yet the embryo still recovers (albeit with reduced viability). Conversely Lewis and Rossant show that double sized embryos are twice the size up until ~E6 when they regulate their size back towards normal. Both papers suggest that size regulation happens at around the time of gastrulation, indeed they hint that gastrulation might depend on passing a size checkpoint.’ Despite their important findings, these papers have been cited relatively little, maybe because, as James says ‘the mechanism of size regulation continues to be a mystery today, although it is receiving increasing attention. It is a fascinating example of the self-organising ability of embryogenesis.’

From the authors:

The Lewis and Rossant paper is one of my personal favourites and I still quote it, even if it is often ignored by the field! In fact it is a still unsolved question of how the embryo manages to size regulate so well in such a relatively short period of time. I have been trying to interest new post-docs in the lab with returning to the problem and investigating whether Hippo or other growth control pathways might be involved and/or whether there is a metabolic link to mTor pathways. But so far noone has taken up the challenge!

Janet Rossant, The Hospital for Sick Children (Canada)

The study on the effect of inhibition of DNA synthesis by mitomycin C on embryogenesis was founded on an observation made by Michael Snow: that to account for the increase in cell number during mouse gastrulation, the whole epiblast cell population has to undergo a doubling in about every 6-7 hours and, in particular, a small sub-population of cells would have to proliferate at a much faster rate with a cell cycle time of about 3 hours.  It was not known previously that cell cycling could be that fast in mouse embryos. We hypothesized that this highly proliferative population may be hit more severely by blocking DNA synthesis, and the subsequent deficiency of any cell types in the embryo might reveal the developmental fate of the descendants of this population. As it turned out, the unexpected outcome of the experiment pointed instead to a mechanism for size regulation by compensatory growth. We followed up this study years later where under-sized mouse gastrula were created, not by cell killing, but by removing one to two blastomeres from the 4-cell stage pre-implantation embryo (Power and Tam, 1993). Results of this study further highlighted the attribute of size (or cell number) up-regulation in the control of post-implantation development. The under-sized embryo does not initiate gastrulation until it has attained a threshold cell number and this is accomplished by extending the phase of rapid cell proliferation beyond the normal duration of 24 hours into gastrulation. Recently, there has been heightened interest in the mechanism of size regulation and the control of the timing of morphogenetic events during development and the connection of this process to the mechanosensory activity and the intercellular communication among cells in a community.

Reference: Power, M. A., Tam P. P. L. (1993) Onset of gastrulation, morphogenesis and somitogenesis in mouse embryos displaying compensatory growth. Anatomy and Embryology 187,493-504

Patrick Tam, University of Sydney (Australia)

Further thoughts from the field

These are two really fantastic papers that are indeed often overlooked, and well worth revisiting. Both studies use classic mouse embryology (and teratology – now that’s a word we don’t see too often these days) methods to describe the remarkable regulative capacity of the mammalian embryo. In the intervening (almost 4!?) decades, we’ve come full circle. Armed with sophisticated genetics tools, an increasing ability to accurately measure (and perturb) the behavior of individual cells within a population, and spurned by studies yielding information on (possibly conserved) mechanisms regulating tissue size and scaling in other systems, for example Drosophila, there’s been an upsurge of interest in this phenomenon in the mouse. Interestingly, two recent studies from Miguel Torres’ lab at the CNIC Institute in Madrid, and Tristan Rodriguez’s lab at Imperial College in London, revisited the question in a contemporary setting and pin-pointed the same window of time (approximating to the onset of gastrulation) as noted in the earlier Tam and Rossant studies, when everything seems to have happened, and any outlier embryos have either managed to catch-up or slow-down (Claveria et al., Nature 2013; Sancho et al., Dev Cell 2013). Moving forward, it’ll be interesting to see how our understanding of this phenomenon deepens, especially bearing in mind that achieving the exquisitely invariant size of mammalian embryos (and organs) likely involves the sensing, integration, and reaction to, several inputs.

Kat Hadjantonakis, Sloan Kettering Institute (USA)

Nature has kindly provided free access to the Snow and Tam paper until  June 2016; the Lewis and Rossant paper is freely available.

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by Cat Vicente

This post is part of a series on forgotten classics of developmental biology. You can read the introduction to the series here and read other posts in this series here.

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This interview first featured in Development.

Abigail Tucker is a professor at King’s College London, UK and her lab works on various aspects of craniofacial development – from basic, evolutionary and clinical biology perspectives. This year, Abigail will be awarded the first Cheryll Tickle Medal by the British Society for Developmental Biology (BSDB). We chatted with Abigail about her research, her commitment to public engagement and the challenges and rewards of working with emerging model systems.

This year you will be awarded the first Cheryll Tickle Medal by the BSDB. What does it mean to you to receive this prize?

It really is fantastic. Throughout a scientist’s career there aren’t a lot of moments when people come up to you and say ‘that was really excellent science’. There are many awards that you can win when your career is beginning, like PhD or poster prizes and then at the end of your career there are lifetime achievement awards. So it is very nice to have a prize in the middle of my career. To have that recognition, to know that people appreciate the kind of research that I do, is really a great feeling.

This medal is awarded to female scientists. Do you think there is the need for awards that specifically recognise the contributions of women in science?

It would be great if there wasn’t the need for this award, and I think things are changing, but women still face problems that men don’t, particularly with regards to having children and taking that time out. I think we want to encourage women not to worry and to know that taking time out is not going to disadvantage them, but I do hope that at some point the BSDB will find that there isn’t the need for prizes that specifically recognise women. I recently read the Chair’s message in the BSDB newsletter, about how this medal is slightly controversial. It will be interesting to hear other people’s opinions when I give my talk, and find out whether there is support for this initiative.

How did you first become interested in developmental biology?

I did my undergraduate degree in biology at the University of Oxford, and one of the course topics that I studied was developmental biology. I absolutely loved it. It was an extremely interesting subject and it helped that it was taught by really enthusiastic people. I was quite lucky that at that time at Oxford there were lots of wonderful developmental biologists working on all kinds of model organisms. Because of that I decided to stay and do a PhD in developmental biology.

You studied tail bud determination in Xenopus during your PhD, but you now work on craniofacial development. How did your research interests change during your career?

After my PhD I wanted to try a different animal model, specifically the mouse because I was quite interested in genetics. I visited several labs looking for mouse projects and Paul Sharpe had a tooth project that was not at all what I was thinking of. At the time I was more interested in general patterning of the embryo, rather than specific organs. It sounded like a really interesting project though and it turned out extremely well. This project also moved me towards craniofacial development. This is a really interesting area to work on, because there are so many different organs crammed into your head. A kidney is just a kidney, but a head includes the sensory organs, the brain, the skull vault, the jaw, and all the teeth and glands inside it. It is extremely complex and I like that a lot.

What are the scientific questions that interest you at the moment?

We have previously done some work looking at the lineage of different structures in the head and the germ layers that they come from. Now, we are examining whether the origin of a tissue matters in a disease situation. When you tell someone that a specific structure is derived from endoderm or neural crest, their reaction is, ‘and why should I care?’ Actually, it makes a difference. The cells respond differently depending on their origin.

The lab is divided in two halves. There are people who are interested in more evolutionary aspects, asking, ‘why does something develop like this?’ The other side of the lab, mostly clinicians, wants to know what happens when development goes astray. In areas such as the ear or the jaw, we have been able to combine these two aspects together. We now know that things go wrong because of the way the structure evolved in the first place.

Your lab is physically located in a hospital. Does this increase the pressure to introduce a clinical angle into your work?

There is definitely pressure to have a more clinical side to our work, and from a funding point of view it is much easier to get funding for the clinical questions than the evolutionary ones. However, one of the big positives of working in a hospital is that you can actually talk to the clinicians who are working with the patients. You can ask them what the big questions are that they would like to have answered, and that are important to patients. If you are going to be working on a scientific problem you want to make sure that you are asking the right questions, and that your answers will have an impact. We are trying to encourage these interactions between scientists and clinicians by giving honorary contracts to clinicians so that they are members of the department. About half of my graduate students are clinicians who have decided to do a PhD, and they bring that approach to our research.

Your lab works with a wide range of organisms, from more established systems like mouse and chick to curious creatures like snakes, geckos, chameleons and opossums. Why do you use such a variety of systems and what are the advantages and disadvantages?

It is great working with non-model organisms, but everything is a lot slower. When you want to look at the expression of a gene in the snake you have to clone it first, so you always have to add an extra couple of months to any experiment. I hope that other scientists appreciate that experiments are not as quick as they are in other systems. We have had a corn snake colony here at the hospital for over 10 years. They are common pets – so easy to get hold of and nice and friendly. However, they only breed twice a year. So when a reviewer says, ‘could you just repeat that experiment?’, I reply, ‘yes, but we will have to wait until next year when we have eggs again’. That is not ideal. In fact, I have started writing the details of the breeding seasons in our methods sections, so that reviewers appreciate that it is quite difficult to do certain experiments immediately.

There are some questions that you need to go outside the model organisms to answer. The mouse has a really strange derived pattern of tooth development. It only has molars and incisors and it doesn’t replace its teeth. Its incisors are also continuously growing, which is interesting in its own right, but very different from us. If you want to know what is happening in patients missing their second set of teeth, then mouse is not really the model to use. We have to move to something like the mini-pig, that has a full complement of teeth, and we have also recently looked at fruit bats and opossum. There are questions that have not been addressed in the past because scientists were focusing on model organisms. Once you move out into non-model systems you find that the number of unanswered questions suddenly increases dramatically, and that there is enough work to keep you busy for many years.

How do you choose the organisms that you work on? Do you try to find a system that will help you answer your question or does the availability of the organism play a role?

A bit of both. When we wanted to compare marsupial and placental mammal ear development we were very lucky to find the opossum. There are only two or three opossum colonies in the world, and one of them is based in Mill Hill, here in London. That is fantastic. More recently, we wanted a reptile system and we ended up choosing the Madagascar ground gecko. This is not a normal pet gecko that you can easily get hold of, but its eggs have hard shells, which means that you can window an egg as you do in the chick. Being able to do this kind of experiment was worth going through the effort of getting that particular lizard. We actually had a colony here for a while, but because they have hard shells the females very easily get calcium depleted, especially if you are trying to breed them a lot to have access to eggs. After some time, we set up a collaboration with a group in Prague. They have around 2000 Madagascar ground geckos, so it is much easier to collect the eggs from them, rather than trying to raise the animals here.

You are involved in a variety of outreach projects, including science evenings and festivals, and even collaborated with Channel 4 and the BBC. What do you think is the value of such initiatives and would you encourage other scientists to do the same?

I really like talking to the public about my research and I’ve had great feedback. People are really interested when they understand what you are trying to do. It is exciting to share your findings and all the amazing things you can do in science with a different audience that will not read your papers. My lab and I try to participate in three or four activities every year and when I ask for volunteers I am always inundated with replies. I think this is great because it means there is a will on both the side of the scientists as well as the public to come to these events.

Some scientists worry that outreach activities take time away from research, but funding bodies are requesting these initiatives more and more and you can get involved at different levels. I was recently at a local school’s careers day where I talked about working as a scientist. This is a very easy thing to do, whereas if you go to a big festival you have to design a stand, with props and hands-on activities. I really enjoyed our most recent stand about cell death in developmental biology – the idea that cells actually die to shape different organs. There are several good examples throughout the body and it is a concept that people are surprised about – it isn’t something that they thought could happen. We also have an activity about making bioteeth. We discuss what you can learn from animals that replace their teeth all the time, what cells and signals are needed and about the possibility of creating bioteeth from stem cells. This is a lot of fun.

In 2011 you were awarded the King’s College Supervisory Excellence Award. Is mentoring an important part of what you do?

It is. I think it is really important that PhD students have a project that they really like, using techniques that they can do. They should come away from their PhD not only with knowledge of their particular area but also other skills that they have learnt along the way – a whole package. Then they can say, ‘I have a PhD but I can really go out into the world and do many different things’. It is really important to mentor someone through that process.

My PhD supervisor, Jonathan Slack, was supportive but generally had a hands-off approach, but there were lots of people in the lab, like Betsy Pownall and Harv Isaacs, who I could chat to and ask silly questions. I think I am a bit more hands-on. I meet my students every week to discuss what’s been happening and I make sure that everybody knows how to do the techniques. They are shown once or twice what to do and then they carry on at their own pace, without someone looking over their shoulder the whole time. I try to be very encouraging when things are not working out. In science, lots of things can go wrong, so from a PhD project point of view, it is key to have different avenues of ongoing research. Then if one thing doesn’t work, you have another way of looking at the problem. I have also found that PhD students have different interests and you need to tailor a project to the particular student while they progress through their PhD. Flexibility is quite important in mentoring.

What is your advice for young scientists?

I think that old papers are not read as much as they probably should be. When I was doing my PhD, I spent quite a lot of time translating 100-year-old papers from German into English (very badly, I’ve got to say!). It is amazing how many things have already been done and it is really important to know what has been done so that you can start asking new questions. At a recent meeting, someone presented work that made me think ‘I have read this before, but in a paper from the 1970s’. Part of the problem is that the older papers are really long. Normally you quote the paper, or a review that referred to it, but when you read the original you have all the details and you know all the experiments that were carried out. I think it is really important to have as good knowledge of the subject as possible.

What would people be surprised to find out about you?

I was once bitten by the head of a decapitated snake!

(2 votes)

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