Each of our cells has the same genetic information and thus the same potential to become a part of a heart, brain, or a finger. Somehow though, during development our cells manage to figure out exactly which type of cell they should be and which body parts they should help compose. The key to making this work is precise control over gene expression, such that as a single cell divides to make trillions, the correct genes are turned on and off at precisely the right times and places. When gene regulation fails, developmental disorders and diseases like cancer can occur.

Today, transcriptional regulation in animals is understood to involve a complex integration of cis-regulatory elements (enhancers), cell signaling pathways, nucleosome occupancy, and higher order chromatin architecture that all work in concert to direct gene expression. In the McKay Lab we are interested in how spatial and temporal regulatory information is integrated during development, and how that integration produces the distinct cell types and body parts of animals.

Central to the process of differential gene regulation are relatively small genomic regions called enhancers. Enhancers, as their name implies, have long been known to increase gene expression, often over long distances. In extreme cases an enhancer can act on a gene that is over 1 million bases away, such as in the case of the enhancer that regulates the Sonic hedgehog gene¹.

Enhancers mediate gene activation by serving as landing pads for proteins (transcription factors) that recruit the machinery required for gene transcription. Enhancers are remarkable not only for their ability to regulate gene expression across long genomic distances, but also because they exhibit highly flexible sequence characteristics, they work independently of their orientation, and they can be transplanted to different parts of the genome and still retain their ability to activate nearby genes². The role and importance of enhancers has become increasingly apparent, especially as the links between human disease and mutations within enhancers have become much clearer^3-5.
One of the major current question in the field is how networks of enhancers direct the differential gene expression programs during development.

Inside eukaryotic cells, DNA is packaged into chromatin, the basic unit of which is the nucleosome. Wrapping DNA around nucleosomes succeeds in packaging two meters of DNA into a ten-micron nucleus. It also serves as a potential means of controlling access to the DNA sequence because nucleosomes typically block transcription factors from binding their target enhancers. For a transcription factor to bind DNA, its target site must be sufficiently depleted of nucleosomes or “opened.” Consequently, one hypothesis for how transcription factor binding is controlled (and hence for determining which enhancers are active) is through regulation of chromatin accessibility. According to this model, an enhancer with cell-type specific activity would be open in cells in which it is active, but closed in cells in which it is inactive (Figure 1).

During his postdoctoral work, our PI Dan McKay tested this idea by profiling the open chromatin regions during appendage development in the fruit fly Drosophila melanogaster⁶. Using a high-throughput sequencing method that identifies genomic regions of low nucleosome occupancy, called FAIRE-Seq, Dan found that, despite having different morphologies, transcriptional programs, and transcription factors that specify the distinct identity of each appendage (so called master transcription factors), the patterns of open chromatin were surprisingly similar between the cells of wings, legs, and halteres. Even more surprising was the finding that although these patterns were dynamic over time, they remained highly similar between the appendages. In other words, the same regions of the genome appeared to be opening and closing at similar times, even though the cells were in completely different parts of the animal. This indicated that the temporal control of chromatin accessibility might be a more significant driver of differential gene expression during appendage development than spatial control (Figure 2).

Dan’s 2013 paper raised a big question: If the transcription factors that specify the distinct identity of each appendage weren’t primarily responsible for directing chromatin accessibility, what exactly was? And on top of that, how were these changes in open chromatin being coordinated across spatially-separated tissues?

One of the phenomenal things about insects is that the timing of their development is precisely controlled by a steroid hormone called ecdysone. In Drosophila, levels of ecdysone increase at stereotypical developmental timepoints, particularly during major transitions like molting⁷. The work of Michael Ashburner in the 1970s revealed that these ecdysone pulses were responsible for activating a large set of genes, many of which were eventually found to be DNA-binding transcription factors⁸. Because ecdysone acts systemically, and it has a known role in controlling gene expression, we wondered if ecdysone, and in turn ecdysone-induced proteins, contributed to the coordinated changes in chromatin accessibility that Dan had observed.

Focusing our attention on wing development, our first step was to get a better sense of how chromatin accessibility was changing in the wing⁹. Our original FAIRE data had only looked at chromatin accessibility at two time points: a stage right before metamorphosis and a much later stage at the end of metamorphosis. Consequently, it was essential to get FAIRE-Seq data in the pupal wing at finer timepoints. With collaboration from the Buttitta Lab at the University of Michigan, we obtained FAIRE-Seq data that confirmed Dan’s observations; chromatin accessibility was changing significantly, with thousands of regions opening and closing over a relatively brief two-day period. Based on these results we knew that the pupal wing, which undergoes striking morphological changes as it develops, was going to be an excellent model system for us to examine how chromatin access is regulated.

Since ecdysone is a steroid hormone and is essential for even the earliest stages of fly development, we couldn’t remove it completely. Instead, we focused our attention on one of the transcription factors directly induced by ecdysone, Eip93F (E93). To ask whether E93 was involved in changing chromatin accessibility, we repeated our FAIRE-seq experiments in an E93 mutant fly. We found that many regions (~50%) that originally showed dynamic changes in accessibility, failed to change their state in the mutant. So, it appeared that we were on the right track and that E93, and by proxy ecdysone signaling, was required for directing many genome-wide changes in chromatin accessibility. Importantly, our data showed that E93 was required for both opening and closing of chromatin.

Although these data showed us that E93 was required for changes in chromatin accessibility, it didn’t tell us whether it was directly causing these changes. To help answer this question, we wanted to determine where E93 was physically bound in the genome. These days assaying protein-DNA binding by ChIP-Seq is a standard practice, but the method requires a significant amount of input to get good results. When working with cell culture this isn’t much of a problem, but it presents a serious challenge when working with tissues in tiny animals like Drosophila, because we needed over a thousand wings to have sufficient input. Over the course of a week, the lab worked together to dissect all the wings necessary for the experiment, and in the end the effort paid off. We found that not only was E93 required for many of the changes in chromatin accessibility, it actually bound to about half of these dynamic regions, arguing that in many cases E93 had a direct role in coordinating both opening and closing chromatin.

Next, we had to tackle whether the temporally dynamic chromatin regions we observed in our FAIRE data actually corresponded to functional enhancers. The best method for testing enhancer functionality is still to clone them upstream of a fluorescent reporter gene. This can work great, but makes it much harder to test many candidates with a high degree of throughput, as it can take months to establish and test the transgenic flies. This was right around the time I joined the lab as a first-year graduate student, and I got the chance to work on characterizing the function of several of the putative enhancers we had cloned. We were thrilled to find that the E93 dependent dynamic chromatin regions we had cloned successfully drove GFP expression, and that the timing of their activity correlated with the timing of the accessibility of the native enhancer.

The crux of this project was to finally test if the failures that we saw in enhancers opening or closing in E93 mutants correlated with a functional defect in our reporters. We found that in the absence of E93 there were dramatic changes in enhancer activity, and that these changes followed what we would expect based on the changes we saw in chromatin accessibility. For example, the nub^vein enhancer, which normally opens during pupal wing development, produces striking patterns of fluorescence along the wing veins when it’s cloned upstream of a GFP gene. However, in an E93 mutant fly, this region fails to open to the same degree. When we imaged the nub^vein enhancer reporter in the presence of E93 RNAi we saw complete loss of the normal vein pattern of expression (Figure 3).

What we found most exciting about this project is that it demonstrated that an extrinsic signal, ecdysone, which pulses at specific times in development, alters the accessibility of enhancers to binding by transcription factors. In other words, for a genome that contains far greater regulatory capacity than is used at a given point in time, hormone signaling can help to determine which subsets of the genome are accessible for use at given time in development. Thus, ecdysone-regulated chromatin accessibility provides a temporal-specific input, which is combined with spatial-specific input in the form of tissue-specific transcription factors. Amazingly, both forms of input are integrated by enhancers.

This has left us with a whole new set of questions to go after. What are the mechanisms that drive ecdysone-dependent changes in chromatin accessibility? Does E93 act alone? How is it that E93 is required for both opening and closing chromatin? How does chromatin accessibility fit into other aspects of gene regulation such as long-distance enhancer-promoter interactions? There’s a lot more to figure out, and these questions are actively pushing us to expand our research focus. Fortunately for me, that means there’s a lot of room to explore and opportunity to make some meaningful contributions to the field.

References

1. Lettice LA, Heaney SJ, Purdie LA, Li L, de Beer P, Oostra BA, Goode D, Elgar G, Hill RE, de Graaff E. (2003). A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet. 12(14):1725-35.

2. Shlyueva D, Stampfel G, Stark A. (2014). Transcriptional enhancers: from properties to genome-wide predictions. Nat Rev. 15:272-286.

3. Maurano M, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, et al. (2012). Systematic Localization of Common Disease-Associated Variation in Regulatory DNA. Sci. 337(6099):1190-1195.

4. Visel A, Rubin EM, Pennacchio LA. (2009). Genomic views of distant-acting enhancers. Nat. 461:199-205.

5. Sagai T, Hosoya M, Mizushina Y, Tamura M, Shiroishi T. (2005). Elimination of a long-range cis-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb. Dev. 132:797-803.

6. McKay DJ, Lieb JD. (2013). A common set of DNA regulatory elements shapes Drosophila appendages. Dev Cell. 27:306-318.

7. Richards G. (1981). The radioimmune assay of ecdysteroid titres in Drosophila melanogaster. Mol. and Cell. Endo. 21:181-197.

8. Ashburner M. (1974). Sequential gene activation by ecdysone in polytene chromosomes of Drosophila melanogaster. Dev. Bio. 39:141-157.

9. Christopher M. Uyehara, Spencer  Nystrom, Matthew J. Niederhuber, Mary Leatham-Jensen, Yiqin Ma, Laura A. Buttitta & Daniel J. McKay (2017). Hormone-dependent control of developmental timing through regulation of chromatin accessibility. Genes & Development. 31:862-875.

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Deciphering the Mechanisms of Developmental Disorders (DMDD) is a large-scale imaging and phenotyping  programme for genetically modified mouse embryos. For embryos at E14.5, the key imaging technique is High Resolution Episcopic Microscopy (HREM), and the resulting images are used to comprehensively phenotype the embryos using a systematic approach.

With a combination of lectures, demonstrations and hands-on sessions, this three-day workshop (20-22 October, The Medical University of Vienna) will introduce HREM technology and discuss the value of the resulting images when used to score morphological phenotypes. The HREM procedure will be described, while sample preparation and data generation will be demonstrated.

As an introduction to phenotyping, the workshop will cover the normal anatomy of E14.5 mouse embryos and the morphology, topology and tissue architecture of their organs as presented in HREM data. A special focus will be given to developmental peculiarities and norm variations in anatomy. A protocol for scoring abnormalities will be demonstrated, after which hands-on sessions will allow participants to practice scoring both wild-type and mutant embryos whilst receiving feedback.

More information (PDF link):

http://www.bioimaging-austria.at/web/media/programs/HREM_DMDDProgram%20JL.pdf

Register here:

http://www.bioimaging-austria.at/web/pages/training/by-cmi-technology-units.php

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I recently saw drawings by Maria Sybilla Merian at Kupferstichkabinett Berlin and the University Library Dresden. Merian, who lived from 1647 to 1717, is renowned for her exceptional illustrations of biological specimens and gained recognition as a scientist for her nature observations, for example, of insect metamorphosis.

Merian evidently was genius in choosing frame and magnification in her drawings, but her pictures lack indications of scale*, which are essential in today’s science images. Scales give the reader the key for aligning the image content with reality. To my knowledge, neither Merian nor her predecessors from Antiquity, Byzantium, or Renaissance included scales in their medical and natural science images*. Even in the beginning of the 20^th century, images were often considered a waste of space and scales unnecessary as scientists were familiar with each other’s apparatuses and objects. Today however we study invisible processes and structures that are unfamiliar to most of our colleagues and therefore have to include scales in our images.

We often include in images a familiar object of a standard size for scale: a penny placed on a rock, a person standing beside a large animal or in a landscape, a measuring tape next to a fossil (or an Earth worm!).

Using familiar objects for scale isn’t possible for tiny things. We don’t have a clear mental image of the size of a salt grain or sesames seed to reliably use them to scale for instance cells**. We therefore include scale bars in microscopy images. With ImageJ/FIJI files from any microscope system can be read in along with their scaling information (shout-out to Curtis and Melissa and the Bio-Formats project!). By using Analyze > Tools > Scale Bar we can add the scale bar with a user-defined length, width, color, position, and label. Now the audience can calculate the actual size of objects and relate image with reality.

Four tips for superb scale bars

• Length: Be kind to your audience and use simple units, such as 100um, 50um, 10 or 2um.
• Color: Scale bars should have a high contrast with the background. Avoid red, green, or blue bars, as these colors might be considered part of the image.
• Position: Lower left corner is a safe place. The upper space should be kept for important information like species, cell type, or gene name.
• Add scale bar last: In the process of writing your manuscript you may re-think the figure size. Also images are re-sized for posters and slides. It is therefore easierst to add only a very fine scale bar with FIJI and then re-draw it in Adobe Illustrator (or PowerPoint, as I I know that about half of you out there use PowerPoint for making figures and posters!).

And finally, do not miss this article by Monica Zoppe with an interesting idea on how to communicate subcellular sclales better!

* I’d be delighted to stand corrected, and if you find old scientific images with scale bars, or interesting scales, send them my way for my collection!

** a great tool to update yourself in comparable scales in biology is here: http://learn.genetics.utah.edu/content/cells/scale/.

I never cease to be amazed at the relative size differences of cells and how they vary over so many magnitudes!

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We are seeking outstanding candidates to lead a project studying Notch, ephrinB2, and TGF-b signaling pathways in arterial venous programming/reprogramming during development and disease processes. We take a conditional mouse genetic approach to manipulating gene expression in endothelial cell-specific and temporally controlled fashion. We also use cutting edge in vivo real time imaging technology, including an in-lab constructed two-photon microscope, which provides exceptional access to gene function in vivo at the cellular resolution along with blood flow measurement overtime in live animals. This basic approach is complemented by preclinical studies with our elegant mouse models of diseases, offering outstanding opportunities for translational research. The laboratory is well equipped with state-of-the-art capabilities at the molecular, cellular, and organismic levels. In addition to funding from the PI, we also have an excellent track record in sponsoring postdoc fellowships. We are interested in a well-trained, highly productive recent Ph.D. to continue our innovative breakthroughs in a rewarding training program. This postdoctoral research is an excellent platform for a highly productive Ph.D. with a strong motivation to become a future group leader. Experience with mouse techniques is a plus. UCSF offers outstanding postdoctoral career development opportunities. Please submit your CV, research interests, and the names of three references by email with a subject title “postdoc application” to:

Rong Wang, Ph. D.
Professor
UCSF
rong.wang@ucsf.edu

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Multiple postdoctoral positions are available in the field of quantitative stem cell biology at the Warmflash lab at Rice University. Our lab uses human embryonic stem cells to model early embryonic development with a particular focus on understanding the mechanisms of spatial patterning and morphogen signaling dynamics. Our work combines quantitative experimentation with data analysis and mathematical modeling. For more details, see our lab webpage here and examples of our work can be found in our recent publications: Warmflash et al. Nature Methods 2014, Sorre et al Dev Cell 2014, Nemashkalo et al. Development 2017.

Positions are available for:

1. Theoretically trained scientists interested in working closely with experimentalists. Experience with either mathematical modeling of biological systems or analysis of biological data is preferred but not required.
2. Experimental biologists interested in quantitative approaches and working closely with theorists. Experience with cell culture, microscopy, or molecular biology is preferred but not required.

Interested candidates should email a CV and a brief statement of past research accomplishments and future research interests to aryeh.warmflash@rice.edu.

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A Research Technician position is available in the research group of Mina Gouti at the Max Delbrück Center for Molecular Medicine in Berlin. The group is using human and mouse pluripotent stem cells to study the development and disease of neuromuscular system. Further information about research in the lab can be found at: https://www.goutilab.com

The successful candidate will have a B.Sc. or M.Sc. degree in Biology or other related discipline, extensive experience in molecular biology and cell culture. Excellent communication, organization and prioritization skills are required, as well as flexibility to the work schedule as stem cell maintenance involves weekend attention (on a rotating basis). Proficiency in writing and speaking English is essential. Knowledge of German language will be considered as an additional advantage.

Key responsibilities will include:

• Performing research projects involving molecular biology techniques, pluripotent stem cell culture and differentiation as well as mouse and chick embryological techniques.
• Maintenance of mouse and human pluripotent stem cell lines for the lab stock.
• Generation of new pluripotent stem cell lines using the Crispr/Cas9 system.
• Oversee the maintenance of mouse colony, monitoring and submission of animal protocols.
• Provide technical support to other lab members when required.
• Establish, maintain and improve research protocols and maintain lab records.
• Oversee the effective running of the lab by monitoring stock levels, ordering consumables and reagents, maintaining equipment and updating lab databases.
• Attending safety courses in order to support and maintain good laboratory practice and safety procedures.

Minimum Experience:

Two years of lab experience working with molecular biology techniques. Previous experience with maintenance of a mouse colony and/or pluripotent stem cell culture will be an additional advantage.

The salary will be according to the TV-L9a scale and the contract will be initially for two years with the possibility of renewal. Applicants should send their CVs along with names and emails of at least two referees to Dr Mina Gouti (mina.gouti@mdc-berlin.de).

Deadline : 31st of August 2017

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Blog post written by Isabelle Vea – 2017 Embryology Student

All 24 of the 2017 Embryology students came to Woods Hole to learn from the best scientists in the developmental biology field. We were immersed in a unique setting to interact with established and promising investigators. In general, each invited lecturer came and spent from a few days to a couple of weeks at the Marine Biological Laboratories and was dedicated to interacting with us. Through our interactions with the faculty we quickly learned that it was more than just learning knowledge and techniques. For instance, the course directors carefully planned lunches and dinners with one faculty and two of the students allowing us to discuss informally about all sorts of topics.

In this post, I would like to share some of the interactions I had with the course faculty that are not related to embryos, yet were extremely meaningful.

Science and art

I always thought that science required creativity and so for me, art/crafts and science is a natural combination. But is it possible to combine both in our daily lives? Isn’t science already a lot? One of my most memorable discussions was with Bob Goldstein from UNC Chapel Hill, who managed to integrate his artistic views into the academic world.

Bob creates posters for scientific seminars in his department using screen printing. It was refreshing to be able to discuss screen printing techniques, inks etc. with Bob. We also discussed using arts and craft as a medium for talking about science at outreach events.

I do think it is possible to combine research with other hobbies or non-scientific activities. The bonus (and actually what Bob taught me through meeting him) is to be able to find other researchers with the same artistic interests.

If you are an artistic scientist, give a shout out in the comments! And if you are interested in discovering scientists with an artistic mind, check out #sciart on social media platforms.

Leadership

As graduate students and postdocs, our primary concern is to find the next research position. As a postdoc myself, I am still struggling to figure out what type of researcher I want to become in the long term. I have always wanted to know how one scientist decides on becoming a leader in his department or institution. Unfortunately, I have never had the opportunity to ask such questions in my home institutions. Here at the course, asking these questions seemed natural and many discussions took place informally in a pub or the hallway.

I was particularly interested to hear from Claudio Stern about his leadership experiences. Claudio Stern from UCL is involved in service to the scientific community, he is part of the scientific council at the Institut Pasteur in Paris and the previous president of the International Society of Developmental Biology. We discussed how you decide to become a leader in academia, and what opportunities may lie beyond your own lab. I learned that at some point in our science careers, we may ask ourselves whether we would like to help improve our colleagues’ work environment and to do so, we need to be able inspire them.

Enthusiasm in research

Despite my undivided love for invertebrates and the excellence of every module, my favorite week was the zebrafish/frog one. Into the second week of the course, I had been overwhelmed by C. elegans powerful tools to examine cellular mechanisms and going into vertebrate species was quite intimidating. I initially thought that my lack of knowledge in vertebrate anatomy would be detrimental to learn the techniques suggested during the module but something special happened.

The zebrafish lecturers (Elke Ober from University of Copenhagen and Tatjana Piotrowski from Stowers Institute) were very present during our lab time. They were not only physically here but kept checking on our experimental progress throughout the week and transferred a lot of their enthusiasm to us.

I had decided to perform a simple experiment that would back up my very risky one. As expected my risky experiment failed but I had managed to obtain time lapse images of the simple one. The night before show and tell, I asked one of the lecturers if there were still time to set up a new experiment: transferring cells of an embryo that I would have injected with fluorescent dye, into another embryo and see where the cells develop. I had never transferred any cells from one organism to another and the task seemed impossible to do with less than 24 hours left. But Elke just looked at me with excited eyes: “Yes! You should try! I will help you.” I could not not try.

Next thing I knew, I was injecting embryos with fluorescent dyes and transferring cells at 1 am in the very last hours of the module and both Elke and Tatjana were there as moral supports! The next day we checked the embryos, some of them survived and it worked! It was the most rewarding result of the course, not only because it worked but because I was inspired by their enthusiasm.

For sure, on a daily basis, experiments are not always successful (a big proportion of mine actually failed during the course), but just having one experiment work and a supportive and passionate community makes your day.

Overall, each faculty member came to Woods Hole with something to share with us. They taught us what they know about embryos but to me, they also conveyed their passion, shared their life experience and how this can be relatable to us, as budding independent investigators. And for this, the course was invaluable.

Isabelle Vea

Isabelle Vea is a Marie Skłodowska-Curie Fellow at the University of Edinburgh interested in the evolution of scale insects.

Twitter: @thecochenille

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A Wellcome Trust/Royal Society funded Research Assistant position is available in Dr Kyra Campbell’s research group. This is a fantastic opportunity to join the Campbell group, who are focused on identifying the molecular mechanisms underlying epithelial cell plasticity during development and disease. We study how this fundamental property is orchestrated during morphogenesis of the Drosophila midgut, and also in exciting Drosophila cancer models that we have recently generated.
We are looking for a motivated and enthusiastic candidate who will play a central role in the lab. You will be involved in all aspects of an ambitious research programme combining molecular biology and Drosophila genetics with high-resolution microscopy on our own dedicated multiphoton confocal, working closely with Dr. Campbell. In addition to carrying out research, you will also be expected to support the research of the laboratory, for instance by providing technical assistance, maintaining and keeping records of reagents and Drosophila stocks and as well as general laboratory organization.
Applicants should have a good honours degree or equivalent in a discipline relevant to studying animal development and cellular behaviours, and must have previous experience in the use of model genetic organisms, and molecular biology techniques. Previous experience in generating CRISPR mutants or Drosophila transgenics will be an advantage. This is a unique opportunity for you to carry out cutting-edge microscopy and develop your skills in an exciting multidisciplinary environment.
Candidates must be highly enthusiastic and committed to the project in addition to displaying outstanding motivation and commitment to research in a fast-moving and competitive field. Excellent organisational and interpersonal skills along with the ability to work effectively with other members of the research team are also essential.

Please visit this website to apply:

https://jobs.shef.ac.uk/sap/bc/webdynpro/sap/hrrcf_a_posting_apply?PARAM=cG9zdF9pbnN0X2d1aWQ9MzMwNjJBRkQ4MDQ5MUVFNzlDOEU1REY1REJEQTg5MDImY2FuZF90eXBlPUVYVA%3d%3d&sap-client=400&sap-language=EN&sap-accessibility=X&sap-ep-themeroot=%2fSAP%2fPUBLIC%2fBC%2fUR%2fuos#

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To interview Jim Smith I took a train to London and visited the Francis Crick Institute for the first time. The building had opened in 2016 and, by the time I visited, most if not all of the labs had settled in. Architecturally it was quite stunning, especially looking down from one of the higher floors and particularly so on a bright spring day. We sat down in one of the many open areas and chatted for an hour about Jim’s life and work both inside the lab and at the helm of large research institutions and funding agencies. I left thinking how positive it was for the field to have a developmental biologist with such energy and enthusiasm in such high places.

This interview by Aidan Maartens originally appeared in Development, Volume 143, Issue 15.

Jim Smith is Director of Science at the Wellcome Trust and a group leader at the Francis Crick Institute, where he was formerly Director of Research. A Fellow of both the Royal Society and the Academy of Medical Sciences, he was knighted for his services to medical research and science education in 2016. His lab works on mesoderm induction in the early vertebrate embryo. We met Jim in the Crick to hear about his life in science, his visions for the Crick and the Wellcome Trust, and his advice for early career scientists.

Let’s start with your first paper, which describes an investigation into the patterning of the chick limb from your PhD with Lewis Wolpert. How did this work come about?

When I went to university I was interested in maths, physics and chemistry, and at Cambridge you could do those three subjects without having to choose between them. But I had to do one more subject, and my director of studies convinced me to try biology, which I’d never done before because I’d done my O-levels a year early and there wasn’t time in the curriculum. So I gave it a go, and loved it. I was sent down the developmental biology pathway through lectures by John Gurdon and Peter Lawrence, and was introduced to Lewis Wolpert’s work by Peter. I joined Lewis’s lab to do a PhD at a very exciting time – they had just grafted mouse polarising regions into chicken limb buds and seen that you got duplicated limbs, which was a really dramatic illustration that there are universal molecular signals in limb development.

Now, that first paper – at the time I shared an office and a lab with Cheryll Tickle, and Lewis set me to work on the zone of polarising activity (ZPA), this special instructive region of the posterior part of the limb bud. Following on from wonderful work by Cheryll and Dennis Summerbell, the rationale for my experiments was to ask whether you needed cell division in order for the ZPA to influence development. So I irradiated these limb buds, first with X- and then γ-rays, and found that even without dividing the cells were still able to signal, but also that the more radiation you gave them, the weaker the signal was in terms of which extra digits it produced. At the time, I thought it was rather obvious and not was worth publishing or mentioning, but when Lewis heard about it he was much more interested and said we should write it up for Nature right away. Six weeks later, we had a thin envelope back saying it had been accepted – it was the easiest paper of my life, and it’s been downhill ever since.

And did you keep in touch with the limb field in your later career?

I did and I do, though of course there is so much literature to keep up with these days. I remember being at a meeting in Switzerland and bumping into Cliff Tabin, who took me somewhere – maybe his hotel room – and showed me the first in situ hybridisation data for Sonic Hedgehog. My mind was completely blown! In Lewis’s lab we had mapped out where the ZPA was by grafts and so on, we knew where it was at different stages, and these in situ data just overlapped perfectly. It was probably the most exciting thing I’ve ever seen – it was extraordinary.

After your PhD you went to Harvard for a short postdoc with Chuck Stiles – was this your first brush with growth factors?

Although I had always wanted to go to America, ending up with Chuck was a bit of an accident, but a happy one because I wanted to learn cell biology and biochemistry. Lewis’s lab was great to teach you to think, but (with all due respect) much of what you did was graft bits of tissue around, and I knew that to work out what the polarising signal was I’d need to know a little bit about cell biology and biochemistry. So in Chuck’s lab we did some stuff on the regulation of the cell cycle, and I learned cell culture and cell fusion. We discovered – in another paper that got published surprisingly easily – that growth factors remain active when stuck to substrates. But perhaps the most important thing was the recognition that growth factors might be important not only to make cells grow, but also for embryos and patterning as well. I published a paper in a supplement of the Journal of Embryology and Experimental Morphology (now Development) in 1981 called ‘Growth factors and pattern formation’, which was quite prescient I guess, though it remains relatively uncited. All this work got me thinking about how to assay for the activities of these factors in embryos.

I enjoyed living in the States – I wish I had been able to stay there longer. I’d never had more disposable income in my life before, or indeed since – I remember going into record shops and just being able to buy whatever I wanted! Lab-wise, the differences were extraordinary. Lewis’s lab was on the top floor of the Windeyer building of the Middlesex Hospital Medical School, and it was really just an extended hut – if the weather was hot, you didn’t need to put the chicken embryos in an incubator because it went up to 38°C anyway. But this did illustrate to me that you can do great science, fun science, in an environment that might look unpromising. And Lewis was a fantastic supervisor – he kept out of the way when he had to, gave advice when it was necessary, and supported me and continues to support me today.

Back in England for a postdoc with Jonathan Slack, you started your career-long affiliation with Xenopus. What do you think of the state of Xenopus as a model, and its future?

Xenopus is a very powerful model organism that you can still do great work with, and I claim – and will fight anyone who disagrees with me – that we have learned more about the generalisable aspects of early vertebrate development from Xenopus than from any other species. But I do think that people worry too much about model organisms, and Xenopus people are no exception in being defensive over their model. In an ideal world, you would work on a model that best allowed you to answer the question you are interested in. The trouble is that it takes a certain amount of investment and infrastructure to work on any model, which raises the activation energy for shifting to another. This means it’s very helpful to work in an environment that has as many organisms around as possible, which was what we had at Mill Hill in the nineties. If we had a problem that would be better approached in another animal, we’d just go and collaborate. The Crick will I hope foster the same sorts of collaborations, but also beyond developmental biology.

First with Jonathan Slack and then in your own lab at Mill Hill, you helped to identify the molecules responsible for induction of the mesoderm, and later the transcriptional networks these molecules regulated. What are the key open questions in how mesoderm induction works today?

The way I like to think about it is reflected in the title of a talk I gave recently – ‘The first ten hours in the life of a frog’. Mesoderm induction happens during those first ten hours or so, and it’s becoming clear that everything in this time is coordinated and interdependent, so if you want to understand mesoderm induction you cannot look at it in isolation. You have to look at it in terms of fertilisation, chromatin structure and dynamics, the early activation of transcription and transcription factor cascades, and the cell cycle, which we are working on quite a lot at the moment and which is proving to be very interesting. And intercellular signalling – we still don’t quite know how signals travel between cells, the details of how the signal transduction pathways activate the genes, or how the different pathways interact with each other. We don’t really understand the cell movements, why it is that particular cells move earlier than others, and why they move where they move. There’s still so much to find out, and it will certainly see me out as a problem.

If you want to understand mesoderm induction you cannot look at it in isolation

And where do you think developmental biology as a field is going?

I think we’re getting down to a deeper understanding of the spatial and temporal aspects of development. What I’d like to do is to develop simple real-time in situ hybridisation, to watch genes turning on and off in real time in a living embryo – not snapshots of fixed embryos. If you just watch things happen, you’ll get a really good idea of the dynamics of the processes. I think what it comes down to is technology – a lot of what we do will be driven by new advances. As new technologies come along, we’ll be able to ask new questions, some of which we can’t conceive of at the moment. Technology is highly under-rated: as I think Mike Levine said in a previous Development interview, the low-hanging fruit in developmental biology has been hoovered up mercilessly by the old farts – my generation – and we were very lucky. The future will lie in the ability to ask new questions with new technologies.

As well as a productive research career, you have held top administrative jobs throughout your career. As head of the National Institute for Medical Research (NIMR), you were involved in the development of The Francis Crick Institute, where you were Director of Research and where your lab is now based. What was the extent of your involvement, and, a few months in, is it too early to say whether the initial aims are being met?

I think it might be helpful to go back and ask why I do these leadership jobs in the first place. One of the things about early scientific success, which I was fortunate enough to have, is that people think you will be good at other things besides being good at science. So people ask you to do stuff, and if you’re not strong enough, as I wasn’t, you just say yes, and end up wrapped up into these leadership positions. Not that I’m complaining, you understand!

So I went to the Gurdon Institute to be Director from 2000 to 2008, and that was a very valuable experience. It was a small-ish place with terrific, collegial people working there, who made it very easy to do my job. And then I moved back to the NIMR as director, having worked there previously for 16 years from 1984. Coming back, it was a torrid time for the institute, because its members did not know what was going to happen to it and were very anxious as a result. We were aware that there would be this thing into which NIMR would move, and as the idea took shape, it was my job to shepherd NIMR into this new world. It was an interesting and fun task to work together to get the momentum and enthusiasm going for the move. By this time, Paul Nurse (then at The Rockefeller University), Richard Treisman (then Director of the CRUK London Research Institute) and I were working together quite closely on this, and we made sure, I hope, that everyone in the two founding institutes played as much of a part as they could in the design of the building and the way it would work. In designing an institute, the building itself is important, but just as important, or more so, are the people you bring in and the mindset that they bring in with them.

Richard and I spent a lot of time on building design, with a great deal of help from Steve Gamblin and John Diffley, and with the architects of course, and together designed the layout you can see today. The building’s lines of sight, its break-out areas, its central staircase, all reflect our aim for a design that would encourage people who work on different things to meet, interact, and talk with each other. And is it working? It’s been about six months, and the answer I think is yes – people seem to be happy and to like the building. I hope the mix of people we’ve brought together will mean we’ll have more collaborations than we had at the two founding institutes.

Was it hard to say goodbye to Mill Hill?

Well, of course I was sorry to leave – I had known the place for a third of a century, and I’d done my best work there, for sure. It was a quirky building in a quirky place, miles from anywhere – but it worked, and people loved it. It was a real wrench for many people to leave, but as this all coincided with its centenary, we had some really fantastic send-off parties! One hopes that the spirit and the collaborations will happen here as they happened there.

Your recently took up your job as Director of Science at the Wellcome Trust. What do you hope to achieve there?

Well, it’s quite a long list. First, I want to make sure that we fund the best science, and keep science at the centre of everything Wellcome does. We need to make sure the people we fund are supported properly, regardless of where in the country they work, and irrespective of their gender, social background, sexual preference, disability or religion. We have a drive at Wellcome focussing on inclusion and diversity, led by Lauren Couch, and that’s really important to me. We know for instance that 50% of graduate students in biomedical sciences are women, for example, but once you get to my exalted heights it’s something like 16% – we are losing some of our best scientists for no other reason than that they are women, and we have to stop that.

Second, I want to make sure that science is an attractive career with an appropriate career structure. We need to make sure that people are trained – for example in data science and statistics – at the right stages of their careers so that they have the best chance to advance. It’s also important that molecular biologists are aware of clinical medicine, and that people understand how pharmaceutical companies work, and how things operate in government. This will be crucial – not least because we need more people with a scientific background moving in to areas like law or journalism or government.

Third, while of course I want to emphasise and support basic science, it’s also important that when a basic scientist does something that can be translated, it is translated, and Wellcome’s Innovations division led by Steve Caddick can help with this. Everything depends on basic science but you can’t just do basic science and ignore the translation. It behoves people like me particularly to make sure that translation happens.

Fourth, I think it’s important to make sure that the UK is a good place to do science. At Wellcome, Simon Chaplin leads the Culture and Society division, which helps ensure that science is recognised and celebrated as being the best way to understand the way the world works, and to integrate science into our everyday lives.

It’s a lot, what I’ve just described – basic science, the right facilities, equality, infrastructure, careers, translation, research culture – but I think all these aims tie together.

Everything depends on basic science but you can’t just do basic science and ignore the translation

How do you see the prospects for funding of basic versus applied research in this country?

I’ve been Deputy Chief Executive at the Medical Research Council, and am now Director of Science at the Wellcome Trust, and when I speak to people in high office there is a clear understanding, belief and acceptance that basic science is the only way to go. But, as I touched on earlier, there is also the expectation that the basic science will be translated. Scientists cannot simply work in their basic science bubble – it’s important, as well as interesting and fun, to be around clinicians, chemists, pharmaceutical companies. As an example, the Crick has a fantastic interaction with GlaxoSmithKline that is not only advancing our understanding of particular problems, but also advancing our understanding of the environment in which both kinds of science work. This breaks down the illusion that they are different kinds of science – we are all in the end trying to work out how life works and how to make the world better, and the more you put people in bubbles, the worse off they will be. I do feel quite strongly about this.

How will institutions like the Wellcome Trust and the Crick adapt once Britain has left the European Union?

Both organisations are in a privileged position because people listen to us; for instance, Paul Nurse has been very visible in the debate about the effect of Brexit on science. In the immediate term, we care about our staff: in the Crick, about 30% of total staff and 56% of postdocs are from non-UK EU countries – we need to establish their right to remain in the UK. The postdoc stage is a very mobile time in your career: all of a sudden, young researchers go all over the world, and very frequently return to their home countries. That experience is incredibly valuable both to the country that sends them out and the country that receives them. So we are working hard to ensure that any migration system after Brexit should recognise that the UK in general, like the Crick, will benefit hugely from international researchers. I think that we should use Brexit to introduce a more streamlined system to cover all highly skilled research staff, whether EU or non-EU, and in particular we need to help people early in their careers to come to the UK – this has been difficult because the immigration system uses salary as a measure of seniority and skills, but postdoc salaries aren’t always enough to qualify them. And then of course there is the funding – access to EU funding and the European Research Council framework has been very valuable, if occasionally bureaucratic – and conversations are currently under way as to how we’ll maintain access to this.

You have a long history with Development, first publishing with us in 1979, and taking the reins from Chris Wylie to be our Editor-in-Chief from 2003 to 2009. How did the journal change during your tenure, and where do you see the journal’s present and future?

I looked it up – I think I’ve published 68 papers in Development, so it’s probably my main journal. Chris made some huge changes to the journal, turning it upside down, and Development is still his journal really: he gave us the structure, the format, the look. When I came in I saw my main job as not screwing up what Chris had done! With Jane Alfred, who joined as Executive Editor during my tenure and with whom I worked very well, we did make a few changes. It was stem cell time, or as Doug Melton and I both like to call it, ‘applied developmental biology’, so we got Ken Chien, Ken Zaret and Austin Smith in as editors. We introduced the ‘Research reports’ section, and I was keen to make sure that the review process was quick and decisive. I also wanted to make sure the papers were interesting – for a while there were too many papers with a generic title such as ‘The role of gene X in organ Y in species Z’, and I didn’t like that sort of title; we tried to make them more question-driven. I think we also had the initial discussions for Development’s community blog, the Node, and I’m quite proud of that even though I didn’t take it forward personally.

As for the future – I am quite taken by preprints, and I think Development’s two-way integration with bioRxiv is terrific. I am also keen on the Wellcome Open Research journal, and the planned Gates Open Research, both using the F1000 publishing platform – they’re interesting models to keep an eye on. We’re at quite an interesting time where we’re circling around trying to decide what the best way forward is for publishing.

And this year you were knighted – congratulations! What does the recognition mean to you?

Well it was fantastic for the field – with Ottoline [Leyser], Mandy [Amanda Fisher] and me all being recognised in one go. But yes of course I was pleased, and proud I suppose – I wished my parents were still alive to see it. I guess it sounds kind of hokey but it makes you think about all the people that work and have worked with you, the postdocs and students without whom I couldn’t have achieved much. I’ve been tremendously lucky in having great people in my lab, many of whom have become firm friends – part of the fun of doing science is that you meet people and make friends. The knighthood’s a hoot – my kids love it, I love it, but you can still call me Jim!

Do you have any advice for young scientists today?

I’ll repeat what I said earlier: if you can become expert in a technology it is not going to do you any harm at all. Enjoy yourself, remember how lucky you are to be doing what you’re doing, be generous with reagents and data, and magnanimous about authorship where necessary. The truth will always out, and the minuscule risk of sharing stuff and being scooped is far outweighed by the opportunities that will come along and the friends you will make – as I’ve said, one of the best things about science is the friendships you make along the way. But most importantly, I’d say to take your career into your own hands. Far too many people are passive in their careers, and wait for stuff to happen to them, but if you just sit back and wait, it won’t happen. Other people won’t do it for you.

Is there anything that Development readers would be surprised to find out about you?

Well I was thinking about this – I don’t think so, actually. Thanks to Twitter, I’m probably an open book – so people can find out anything about me, whether it’s the music I like or my love for running, by following me @ProfJimSmith.

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A paper published online yesterday in Nature (and ‘leaked’ a week ago by the MIT Technology Review) describes the use of CRISPR in human embryos to correct a mutation that causes hypertrophic cardiomyopathy. The work has hit the headlines and sparked debate about its utility and implications.

Collated below are responses from the field (or at least, those of them on Twitter!) and links to opinion pieces. If we missed any links, let us know and we’ll update.

We’d also love to hear your thoughts on the work – use the comment section below.

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