In the internet age, what’s the first thing you do before spending money on anything? Right: Go online and read reviews.
Well, the same behavior applies with buying antibodies. We look to publications like “reviews,” to ensure antibodies have produced reliable data in similar experimental contexts.
While sifting through publications is the gold standard for finding antibodies, however, there are some limitations. In this article, I’d like to outline these limitations and show how independent antibody reviews could address them.
1. Latency Between Data Generation and Publication
Problem: It takes an average of 9 months from manuscript submission to publication. This delay in data availability due to the (essential) peer-review process could lead other labs to waste valuable resources testing an antibody that has already been validated.
Solution: The submission of independent reviews immediately following successful data generation would ensure that data about successful antibody usage was shared within the research community without delay.
2. Only Positive Results Are Published
Problem: For every beautiful, sharp and crisp IF image, there were probably 2-3 antibodies that were tested and didn’t work. However, such negative data are usually never published and are forever hidden in the hard drive of a lab computer.
Solution: Independent reviews can capture cases where antibodies didn’t work, to help other scientists make more informed decisions—the same way we avoid restaurants with horrific reviews.
3. Validation Data May Not Be Shown
Problem: Most labs have validated antibodies targeting their protein of interest through knock-out or knock-down experiments. Yet the validation data are not always included in the publication because it’s “not part of the story,” and are often only known to the reviewers and lab members.
Solution: The sharing of antibody validation data from every lab through reviews would generate an invaluable database of validated antibodies.
4. Limited Space for Detailed Protocol
Problem: Many journals have word limits for their publications, which in turn caps how much protocol detail you can put into the Materials & Methods. And as we all know, to conduct a successful experiment, even the tiniest detail matters.
Solution: Unbound by editorial constraints, in each antibody review full experimental protocols could be submitted to facilitate reproducibility.
5. Some Data Are Locked Behind Paywall
Problem: Approximately 76% of publications are behind paywall, and thus, the majority of published antibody usage data are not available to all scientists.
Solution: The adoption of independent reviews aligns with the recent movement towards open science, and ensures that every successful usage of antibodies is known to the entire research community.
In fact, we feel so strongly about independent antibody reviews that we’ve actually built them into BenchSci.
At BenchSci, our goal is to drive discovery by ending reagent failure. Our machine-learning technology analyzes open- and closed-access publications and presents published figures with actionable insights. At the same time, we also recognize the limitations discussed in this article, which is why we also incorporated independent antibody reviews into the platform.
With the recent emphasis on research rigor and reproducibility by the NIH, I would like to advocate for the submission of independent antibody reviews to facilitate a collective effort to authenticate key biological resources, which, in turn, would benefit the research community as a whole. If you agree, consider signing up for BenchSci free and contributing reviews.
Fully-funded postdoc positions are available in a new lab group starting at the NIH main campus in Bethesda, Maryland. Research in the McJunkin lab has two major long-term goals: 1) to define the biological functions of miRNAs during embryogenesis and 2) to elucidate mechanisms of miRNA turnover. Using C. elegans as a model organism to address these questions, we will combine the strengths of classical forward genetics with CRISPR-Cas-9-mediated genome editing, next-generation sequencing, cell biology, and biochemical techniques. Because embryonically-expressed miRNAs exhibit a sharp decrease in abundance at the end of embryogenesis, our efforts to simultaneously study the biology of these miRNAs and the mechanisms of miRNA decay has the potential to uncover regulatory modules that couple miRNA decay to developmental timing.
The NIH main campus is a vibrant and collaborative research environment boasting over four hundred research groups and an active postdoc community. Bethesda, Maryland is part of the Washington, D.C. metropolitan area, and the NIH main campus is easily accessible by the Washington, D.C. subway system.
Applicants must have completed a Ph.D. within the last three years. Expertise in molecular biology and strong verbal and written communication skills are required. Experience in either RNA biology or C. elegans research is desirable. International scientists and U.S. citizens are equally eligible for these fully-funded positions.
For more information, please see our website (bit.ly/mcjunkin). To apply, please send a cover letter describing which aspect of our research program you are interested to pursue, a CV, and contact information for three references to mcjunkin@nih.gov.
Jayaraj (Jay) Rajagopal is a Principal Investigator at the Center for Regenerative Medicine at Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. A Howard Hughes Medical Institute Faculty Scholar, his lab works on the development and regeneration of the lung. He uses stem cell and animal models to develop novel insights that hopefully will provide inspiration for therapies to help treat human lung disease. He was awarded the Dr Susan Lim Award for Outstanding Young Investigator at the 2017 International Society for Stem Cell Research (ISSCR) meeting in Boston (MA,USA), where we met him to talk about how a fish tank started a life-long fascination with the lung, the transition to running his own lab, and his optimism for the future of both basic stem cell research and its clinical translation.
You’re here in Boston to collect ISSCR’s Susan Lim Young Investigator award: what does the award mean to you?
It really was an incredible honour. I looked over the past recipients and the vast majority of them are either friends or people whose work I admire. Additionally, Susan Lim and her husband Deepak Sharma are just wonderful people – it was great to meet them, and especially their daughter who is interested in becoming a physician. Most of all, it represents a chance to be embedded in a rich community of scholarship that promotes education and younger researchers.
What got you interested in science in the first place?
That started very early for me: I was always intrigued by animals. I spent my summers in India as a child and when all my cousins were in school I’d be out on the farm, capturing animals and things like that. The other early influence was my father, who was a doctor and would talk with me about interesting cases. His perspective was great because he introduced these diseases as fascinating mysteries. For as long as I can remember, those two things – animals and medicine – were what I wanted to devote my professional life to.
How did you become interested in developmental biology and the development of the lung in particular?
I went to college at Harvard and studied molecular biology, and actually specifically avoided developmental biology! Having read The Eighth Day of Creation by Horace Freeland Judson, molecular biology seemed so exciting. I worked with Jack Szostak and Jenn Doudna at the time when self-splicing RNAs were new. We could synthesise the RNA molecules in vitro, put them in a solution and test their enzymatic activity with exquisite precision. The whole process was a lot of fun and appealingly very understandable. Then I went to medical school and loved the human biology and physiology, as well as being able to interact with and treat patients. But at some point I stepped back and asked myself: what do I love? I realised that, at heart, I like cells and tissues, and how they come together functionally to create a living animal, essentially exactly what I was fascinated by as a kid in a more mature guise. Developmental biology just seemed like the natural thing to do.
My interest in the lung also traces back to when I was young. I had a fish tank and even as a very young kid I was mesmerised by it: these animals could breathe underwater, but if you let your tank get dirty – like many kids do – many fish can also breathe air. In medical school I learned about the lung’s physiology, and how beautifully it works to bring oxygen to the bloodstream. When I was looking for a lab to join in Boston, there wasn’t anyone studying the lung in the way that I wanted to. Doug Melton was just getting interested in the pancreas, moving from his more basic work in the frog, and I thought that since the lung and the pancreas came from the same tube, I could help him figure out how to make a pancreas, and then once I was done with my training in his lab, I’d move a little anterior in the tube and make a lung. Doug thought it was a great idea, and we hit it off immediately. The best laid plans often change though. When induced pluripotent stem cells (iPSCs) came out, I immediately started working on making iPSCs into β-cells, and that got me hooked on stem cells. Doug really was a fantastic mentor to me, broadening my perspectives, encouraging me to explore the newest ideas and systems, while maintaining my fundamental interests.
What were your aims when you first started your lab?
As part of my interview at the Center for Regenerative Medicine at Massachusetts General Hospital I gave a chalk talk describing my ideas, but my actual research program ended up only very loosely related to that chalk talk. Essentially, I didn’t really know what I was going to do, except in very vague terms, and although I was empowered with new experimental tools and an understanding of the basis of experimentation, I was left with pretty much the same interests I had as a child: how do organs come to be?
When my lab started I was initially not so interested in the iPSC differentiation paradigms I had explored in Doug’s lab. Rather, I was enamoured of the developmental biology of the lung and particularly of tissue regeneration – it was so beautiful, and that’s what I focused on, primarily in the mouse because the biological tools were much more rigorous. Yet at the same time, I had always had this keen interest in human basic biology and in medicine – so I sort of put myself in Doug’s shoes again and eventually realised I would have to return to iPSCs. We reinvigorated that aspect of the lab, and then moved on to developing systems to grow adult lung stem cells, and I think we now have a way to use an actual human lung explant to do what I’ve always wanted to do: investigate the developmental biology of a regenerating human mini-organ.
What is it about the lung that is so fascinating as a developmental system?
For me one reason is evolution, which was another interest of mine since I was a kid. Back to my fishtank: it’s a mystery how fish came out of the water. How did the first lungs arise? The question of how it came about is fascinating. It’s also a fascinating organ in terms of its physiology, which I was introduced to during my medical studies. And something really appealing about the lung is that it is an organ par excellence for understanding regeneration. You have to breathe – which means there are physical forces and gas fluxes, and you inhale allergens, infections, toxins, dust and so on. All of the cardinal ways in which the environment could possibly perturb a tissue are captured in the lung. We’re really interested in how a perturbation in a tissue wrought by one of these injuries is resolved. I do often wonder whether there are some forms of simple equations that you could write to understand how cells come together to generate ensemble properties of tissues. It’s a very tall order, but there has got to be at least partially ordered ways of thinking about it, some ‘laws’ of regeneration.
And the lung is turning out to be a lot more complex than we previously thought. Doing single cell sequencing in collaboration with Aviv Regev we find two things: firstly, that there’s a whole new set of cells with interesting physiological properties; and secondly that many cells have specific immune signatures. The epithelium was considered to be pretty monotonous, and to interact with a panoply of weird different immune cells (you can see I’m not an immunologist!). Now it looks like there may be considerable crosstalk of particular epithelial cells types to particular types of immune cells. We also learned there are many subtypes of known cells, totally novel cells important for disease, and even new specialised structures in the airway.
For me it seemed like everything came together in the lung: aesthetics, evolution, developmental biology, the clinical aspect, and how the organ interacts with the environment. Somehow you just find your groove if you keep doing what you like, and the lung is a perfect lens with which to ask all the questions I’ve ever wanted to ask. I understand the developmental biology and some of the therapeutic issues, and then we are collaborating with people from other disciplines who look at the problem through different lenses. Some are computational biologists, physicists with new imaging techniques, immunologists, and I’m interested in collaborating with a whole suite of other biologists, including neuroscientists, evolutionary biologists and mathematical modellers. I don’t think that any single type of biologist is going to get close to sorting out the ‘laws’ of tissue behaviour unless they work together. It’s one of the most fun things in science: to head into totally new domains. It’s also a good way to make new friends! I get bored relatively easily and so like constantly hopping from one aspect of tissue biology to another: from evolution to signalling to force transduction to hypoxia. And I suspect many of these topics will become reincarnated in the lab as a new idea makes one of them seem appealing again. My tendency to dalliance works well for the postdocs as they can take their own projects with them to their own labs.
The lung is a perfect lens with which to ask all the questions I’ve ever wanted to ask
Many speakers at this meeting have emphasised the importance of developmental biology for stem cell research – how do you see the relationship between the two fields?
One way stem cell biology has helped developmental biology is that developmental biologists were so interested in embryogenesis, but tended not to think about the adult organism. Stem cell biology made developmental biologists think about the adult. The idea of stem cells is also just useful to convey enthusiasm, and that enthusiasm is incredibly important. Even in my own case, stem cells drew me into the problem of lung development and made me think about it differently. Stem cells are super interesting – but they are only one aspect of tissue function. There was a quote from Jean Rostand on the wall of Doug Melton’s lab which said ‘Theories come and go, but the frog remains’. I think this serves to remind us that there are tissues, organs and animals. Those exist, and all these different ways of doing science and naming cell functions are just different lenses with which to look at them, none of them complete in their own right and always evolving. As we analyse cells more deeply in the lung epithelium, we are finding that none is associated with a unitary specific function, but they all have many distinct activities. Stem cells aren’t just for replication and differentiation anymore. We have shown that they signal and I am sure they sense and perform necessary metabolic activities too.
It’s also important not to let the translational side eclipse everything else. The constant translational need, which is important, can become a drumbeat that moves you away from basic biology. Stem cells have this immediate connotation of being of use in a practical fashion, which is part of what makes them wonderful, but developmental biology has always come from the first principles of ‘I would just like to understand something’, and I think we cannot lose that because most of our truly game-changing ideas are a result of curiosity-driven basic biology.
Finally, stem cell research is an easy paradigm to communicate to patients and their families. It’s much harder to educate society at large about the interest and importance of basic biology. But I think we have to do that, especially with the modern political climate – there can’t be anything more important than to just explain to people why new knowledge is important.
So do you think the stem cell field as a whole is good at engaging with the public?
First of all, I think what the ISSCR does is spectacular, and I would in particular point out people like George Daley, Len Zon, David Scadden and Doug Melton, who are all great communicators, not just to the public at large, but also to our politicians. From my own perspective and background, I think we need to think about educating patients themselves, and to remember that they are vulnerable. I was a pulmonologist, and if I had a patient with, let’s say, idiopathic pulmonary fibrosis, they would walk into the office short of breath. More or less the one thing I could do for them was to give them oxygen – that is where the treatment ended. So you can imagine my inbox was full of messages from people who couldn’t get a new functioning lung with a lung transplant. These patients all wanted ‘stem cells’. I’m usually very straightforward in my response to them: although I empathise with what they have to go through because I’ve seen it first hand, I tell them that currently, there are no stem cell therapies for the lung, and that I would be very careful because there are a lot of people squirting stem cells into people without the proper science. But at the same time I try to give them the optimism of research, because I really do believe in it, and I am only getting more optimistic about it these days. I really think there is going to be a renaissance in terms of therapies produced through iPSCs and organoid models, and I try to fill patients with that kind of optimism. Unfortunately, you can’t give patients a timetable when they are desperate for a cure, but I can honestly say the research keeps moving faster and faster than I could ever have imagined.
At one point in my career, we wanted to make iPSCs from cystic fibrosis patients so that we could model the disease. I talked to some of my clinician friends, and they agreed to ask some of their patients to contribute, and the result was unbelievable – within a couple of weeks, we were turning people away. It’s overwhelming to see that kind of enthusiasm from patients: even if you tell them that this donation is very unlikely to help them personally, they still want to contribute. It’s also reciprocal: one of my graduate students working on a cystic fibrosis-related project asked me if he could meet a patient. My clinical friends again had a patient lined up to meet him before you could imagine it, and that patient spoke to my laboratory. It just blew them away and made their research so much more meaningful. If you are a PhD scientist working on a disease at the bench, you’re missing something. If you’ve come to meet patients, when an experiment fails 90 times, there is another reason you’re repeating it – it’s not just that you want the answer, but there’s a person that needs your help.
Being a PI was just intrinsically so much more fun for me than being a postdoc
When you started your lab, what was the transition to being a PI like?
I have to say that I found my post-doctoral fellowship very hard. I came from clinical medicine, and was used to knowing what to do – even if you couldn’t save every patient, you knew you could do your job well, and in a well-defined way. In science, it didn’t work that way and, quite frankly, it took me a long time to learn how to fail, and to appreciate the importance of problem solving. I am actually one of those scientists that did not love bench work, but rather I preferred to look at and think about data, talk to colleagues about new ideas and dream up future experiments. I had also always known, since I had been a Chief Resident in Internal Medicine at Massachusetts General Hospital, that mentoring was my absolute favourite thing. So it turned out that being a PI was just intrinsically so much more fun for me than being a postdoc, for almost every single reason. Again, I’d found my groove – being a laboratory head is the job I was ‘supposed’ to do, and it has only gotten better and better and better. I can’t imagine a job that is more fun, and I think the core value I treasure about it, perhaps even more than the study of living things, is the freedom it provides me.
One great thing about lung science for me is that, unlike haematopoiesis, neuroscience or immunology, it is so understudied, and so it’s just a great place for me to train young scientists. I’m so pleased to say that the first four scientists to have graduated from my lab all have their own labs. I don’t think I’ll ever have a very big lab – I like to put a lot of energy into every single postdoc and student, and hopefully have all of them leave and still love biology, no matter what they decide to do. That said, I’m hoping every single one will have their own laboratory if that is what appeals to them. Also, thanks to the Harvard Stem Cell Institute and my relationship to the undergraduate Stem Cell and Regenerative Biology Department at Harvard University, we always have undergraduates in the lab. It’s just fantastic to have people at every single stage of their education and career. Having undergraduates in my lab also means my postdocs and graduate students have a mentee, which is also a crucial part of growing as a scientist.
Do you have any advice for someone thinking about a scientific career today?
There have been editorials written by very prominent scientists that have said that we are training too many PhDs; I completely disagree with this! If anything I would say we are training too few, because while you can look at a PhD as a means towards one particular end, you could also look at it as a pure form of education that trains you to think and problem solve, and also to communicate in various ways. In some sense it’s a liberal arts education in terms of problem solving. But if you gravitated towards writing you could become a wonderful editor, if you gravitated towards ethics, politics or law, you can go into those roles. You can go into clinical medicine: a doctor who understands science is very valuable, just like a scientist who understands medicine. I remember in my own time, it used to be considered wrong to go to a company; now there are brilliant scientists who want to go to a company from day one. I love being a PI, and it’s a path I want to encourage but I’d like to see my young people in diverse spheres of human activity that captivate their imagination. The more people we have doing different things, but bound by a respect for scientific inquiry, the better.
I would say to a young person: explore and try to figure out what you love, and don’t worry too much about exactly where you’ll be 20 years from now because, in my view, no one really knows. Life is an experiment with no controls – at some level we’ll never know whether we’ve taken the right path – but if you’re constantly doing something you’re excited about, work becomes play. If you can live a life where work is always play, you have sealed the deal professionally. On top of that, you have to think about work-life balance – different paths have different constraints, and it’s important to talk to people who have lives that you’d want to emulate at work and also at home. Similarly with money: different people have different thresholds concerning what they are comfortable earning, and it’s important to think about this (but money can’t buy you love). I’d also advise people to ask for advice and help from people they respect. Mentors who listen and empathise, and who have a solid sense for your abilities can be invaluable for you as they were for me. I’ve found many people believed in my ultimate success and that was enormously encouraging at times when I did not think I could rise to the level of my own scientific bar.
Is there anything that Development readers would be surprised to find out about you?
Well the things I love outside of the lab are music, reading, the arts, travel and my family. I guess they’re all about exploration, and that might be the common theme. It’s a pretty interesting life to be able to combine all of these things.
Perhaps the other thing is that I’ve never left Boston since coming here for college, where in fact I met my wife in my freshman year! I’ve always found Boston to be supportive – people often think of it as an intense and competitive environment, but I’ve found it to be completely the opposite. Whenever I’ve asked for help, I’ve gotten it!
The DORA Community Manager position is an opportunity for a Ph.D. or Master level fellow to gain experience in scholarly publishing and policy in Washington, DC. The DORA Community Manager will be headquartered at the American Society for Cell Biology (ASCB), which is located in Bethesda, MD. This position will report to the Director of Public Policy and is a 24 month assignment.
Essential Functions
Documenting best practices in Research Assessment
Research and document examples of best practice of research assessment for different situations from a range of organizations, in particular DORA signatories.
Website and outreach
Regularly blog, post to social media and send newsletters to signatories about issues related to DORA and progress on documenting best practices in order to keep awareness of this issue high.
Work with relevant staff to maintain DORA website and ensure that it is a regularly updated source of valuable information.
Management of DORA signatories and data
Assure the quality of the current data on institutional signers of DORA and recruit additional institutions, for example to improve the international coverage.
Work with the Steering Committee to target and recruit new institutional subscribers.
Committee Management and Strategic Partnerships
Develop strategic partnerships with groups who are working in highly related areas and can help to amplify the DORA message or assist in its activities.
Provide monthly updates to the Core Steering Committee.
Support the activity of the Core Steering Committee including creation of agendas for quarterly meetings.
Liaise with individual members of the Core Steering Committee as necessary and with staff who are involved DORA nodes in other parts of the world.
Competencies
Technical Capability in communications, data management, and analytics
Strategic Thinking
Communication Proficiency
Project Management
Attention to detail
Creative problem-solving ability
Required Education and Experience
Master’s or Ph.D. in the sciences preferred
Knowledge of scholarly publishing, assessment of research
Strong written and verbal communication including the use of social media
FOR IMMEDIATE CONSIDERATION:
Please e-mail your resume and one page cover letter with salary requirements to jobs@ascb.org
Checkpoints ensure that mouse oocytes with DNA damage arrest in meiosis I, preventing non-viable embryo formation, however the mechanisms which activate this checkpoint have so far eluded researchers. This week we feature a paper published in the latest issue of Development that reveals that the unique ability of mouse oocytes to sense DNA damage by rapid kinetochore checkpoint activation. First author Simon Lane and his PI Keith Jones of the University of Southampton, told us more.
Keith Jones and Simon Lane
Keith, please can you give us your scientific biography and the main questions your lab is trying to answer?
KJ I am Head of Biological Sciences, and Chair of Cell Biology at the University of Southampton. In the mid 1990s I worked at the Medical Research Council Experimental Embryology & Teratology Unit in London, examining the way in which sperm-driven changes in intracellular calcium at fertilization were regulated and how they affected embryo quality, helping to establish a link between early events of fertilization and long term embryo quality.
Between 1998 and 2008 I held an academic position in the Institute for Cell and Molecular Biosciences at the University of Newcastle-upon Tyne, UK. My lab has helped develop the use of Fluorescent Proteins to study the process of meiosis in real-time. This approach led to recent developments in the understanding of how the meiotic divisions are regulated. In 2008, until 2012, I moved to University of Newcastle, Australia, where Simon joined me as a PhD student. In 2012 I moved back to the UK and Simon followed me, then as a postdoc having successfully defended his thesis.
My lab is focused on understanding how the oocyte makes the transition in meiosis from a mature egg.
Simon, how did you come to join the Jones lab?
SL After receiving an interesting lecture on fertilisation in ascidian eggs I applied for a summer placement in the cell biology labs in Newcastle University. There I met Keith who was about to move his lab to Australia and was recruiting PhD students. I didn’t hesitate at the opportunity to do a PhD in a subject that was very interesting and in such an exciting part of the world!
Can you give us a brief summary of why you decided to ask the questions in your paper and the previous research that led you to this story?
KJ Along with the John Carroll lab (then UCL, now Monash) we made the original discovery of the ability of oocytes to arrest in meiosis I a few years ago.
The current work is an extension of that initial study. The first study was all about reporting the phenomenon. The present one, published in Development, is a more detailed investigation of the mechanism by which arrest is achieved.
Can you give us the key results of the paper in a paragraph?
KJ In a nutshell it shows that oocytes have a profound ability to arrest in meiosis I in response to DNA damage, and that the mechanism by which this achieved is unusual. It’s a process that involves the kinetochore, rather than the sites of DNA damage, and it doesn’t involve the usual DDR kinases ATM and ATR. We also show that the response is specific to the first meiotic division, as it is absent in mature eggs.
Imagining the kinetochores, from Figure 6, Jones, et al. 2017
You suggest three models for MI oocyte sensitivity to DNA damage, how might you proceed to test your preferred model?
KJ The paper shows the response specific to the first meiotic division. We are therefore pursuing the role of various proteins known to play specific functions during the first but not the second meiotic division.
Possible models to explain meiosis I-specific arrest, from Figure 9, Jones, et al. 2017
In the paper you talk about potential implications for human oocytes: how well do you think the mouse model translates and do you have any plans to test this research in human cells?
KJ We already know that follicular fluid collected from the ovaries of women who have endometriosis is able to cause arrest of mouse oocytes during in vitro maturation. The mechanism we believe is that ROS levels are higher in endometriosis, a phenomenon associated with inflammation, and the increased free radicals have the ability to damage DNA.
When doing the research, did you have any particular result or eureka moment that has stuck with you?
SL I like the feeling when you are working late to complete an experiment but then you see something new and interesting and you think to yourself, I might just be the first person who has ever seen this. The experiment where the Mad1 response to DNA damage is completely different between oocytes and eggs was like that.
DNA-damaged mature eggs can complete meiosis II, from Figure 8, Jones et al. 2017
And on the flipside: any moments of frustration or despair?
SL There are many of these moments (more frustration than despair), it’s a part of the process I guess. So many things have to come together at once to get each experiment working so it keeps you constantly on your toes!
What are your career plans following this work?
SL I’m currently in the process of applying for fellowships.
And what is next for the Jones lab?
KJ I’d really like to figure out how the kinetochore function in meiosis. This seems a little dull at first, yet the structure of the chromosomes and how the segregate in meiosis I are unique, with co-segregation of sister kinetochores happening only in this division. Understanding how this co-segregation is achieved and how the meiotic spindle microtubules interact with the fused sister kinetochores are probably the most fundamental unknowns in meiosis.
Finally, what do you two like to do when you are not in the lab?
KJ My partner likes to tell me that my work is my only hobby! I think, although am not certain, this is a windup. I enjoy walking, good wines (I have been really surprised at the excellent sparkling wines made in Hampshire- next to Southampton), cooking, and BBC4 podcasts-take these in any combination. My work takes me round the world so I consequently do enjoy travel.
SL I keep fit with boot-camp style training and also like to experiment with 3D printing and electronics projects.
The Reprogramming and Hematopoiesis lab is currently seeking a highly motivated postdoctoral fellow!
Reprogramming and Hematopoiesis lab
Cellular reprogramming can be achieved experimentally in different ways, including nuclear transfer, cell fusion or expression of transcription factors. We aim to uncover how hematopoietic stem cell and effector cell identity is established employing cellular reprogramming logic. Ultimately our work may allow the generation of patient-specific hematopoietic cells for regenerative medicine and immunotherapy. To explore these aims, we use a variety of approaches, including cellular reprogramming through gene transduction (Pereira et al, Cell Stem Cell, 2013) and single cell gene expression profiling during embryonic development (Pereira et al, Developmental Cell, 2016). Hematopoiesis is a core area of research at the Medical Faculty at Lund University. Within this broader research area the Division of Molecular Medicine and Gene therapy harbors an ensemble of international research groups with a focus on understanding both normal and malignant hematopoiesis and to develop new strategies for therapeutic intervention. Our lab is generously funded by the Wallenberg Centre for Molecular Medicine and the Knut and Alice Wallenberg Foundation.
Candidate Profile
The candidate should be an enthusiastic and motivated scientist willing to join a young international research group in a highly dynamic and multidisciplinary environment (with English as main language). Candidates with a passion for cell identity and epigenetics as well as immunology and/or hematopoiesis who recently completed their PhD thesis or currently finishing up are encouraged to apply. The successful candidate will join a research program at the interface between the fields of cellular reprogramming and stem cells, hematopoiesis and oncoimmunology. Excellent verbal and written communication skills in English are required.
Research at Lund University
Lund University is Scandinavia’s largest institution for education and research and consistently ranks among the world’s top 100 universities. The Lund Stem Cell Center hosts 15 research groups in experimental hematology and is one of Europe’s most prominent in the field of hematopoietic research. This environment has all facilities and equipment essential for the project including an outstanding animal facility, technical platforms for flow cytometry and cell sorting, a human ES/iPS core facility, viral vector technology and single cell genomics facility. This creates a very interactive environment with weekly seminars and annual retreats for students, postdocs and PIs.
Experimental Approaches
Key approaches will include flow cytometry, high-content automated image acquisition and analysis, single cell gene expression and chromatin profiling, cellular transplantation, Crispr/Cas9 and small molecule screening and the generation and characterization of new mouse models.
Start of Position and Application Deadline
The position start date is flexible from October 2017. Application deadline: 31st October 2017.
How to apply
Please send a letter of motivation, your curriculum vitae, and the contacts for three references to:
Pereira, C.F.**; Chang, B.; Gomes, A.; Bernitz, B.; Papatsenko, D.; Niu, X.; Swiers, G.; Azzoni, E.; Brujin M.F.T.R.; Schaniel, C.; Lemischka, I.R.; Moore, K.A. Hematopoietic Reprogramming In Vitro Informs In Vivo Identification of Hemogenic Precursors to Definitive Hematopoietic Stem Cells. Developmental Cell 2016, 36 (5), 525-39. **corresponding author.
Pereira, C. F. **; Chang, B.; Qiu, J.; Niu, X.; Papatsenko, D.; Hendry, C. E.; Clark, N. R.; Nomura-Kitabayashi, A.; Kovacic, J. C.; Ma’ayan, A.; Schaniel, C.; Lemischka, I. R.; Moore, K., Induction of a hemogenic program in mouse fibroblasts. Cell Stem Cell 2013, 13 (2), 205-18. **corresponding author.
A new study carried out by the University of Oxford has used flat worms to look at the role of migrating stem cells in cancer
Researchers from the Aboobaker lab in the Department of Zoology used the worms (planarians) which are known for their ability to regenerate their tissues and organs repeatedly. This process is enabled by their stem cells, which constantly divide to make new cells.
Cell migration – or the movement of cells from one part of the body to another – is a key function of cells in our bodies. New stem cells are constantly required to maintain tissue and organs functions, and they are expected to migrate to where they are needed. However, control of these movements can fail, and cancers can form when these cells migrate to places they aren’t supposed to be.
By understanding how stem cells are programmed to move, what activates them and how they follow a correct path, researchers may be able to design new treatments for cancer.
‘We already knew that these worm stem cells have a lot in common with our own stem cells, but we knew nothing about how they migrate and if this process relates to how our cells migrate,’ says Dr Prasad Abnave, first author of the study, published in Development.
‘We wanted to establish if the same mechanisms had been evolutionary conserved or not, we hoped that they would be, as this would make an excellent model for studying all aspects of stem cell migration.’
However, before the team could start working with the worms, they had to overcome a small problem. ‘Perhaps a little counterintuitively, the sheer abundance of stem cells in planarians makes it difficult to study migration,’ said Professor Aziz Aboobaker.
‘In order to trace the movement of cells you need to create a field for them to move into so you can be sure of the direction and speed at which their moving, but if the cells you are interested in are already everywhere that is difficult to do.’
Luckily the team were able to draw on over 100 years of previous work. In one particular experiment that used x-rays to kill planarian stem cells, it was found that the animals survived the treatment if part of the worm was kept under a lead shield, as ‘presumably the stem cells under the lead shield migrate to the rest of the animal and everything is fine.’ said Abnave.
With the help of Dr Mark Hill at Oxford’s Department of Oncology the group were able to design an apparatus that allowed them to use X-rays to leave behind a thin strip of stem cells. These cells could then be observed as they migrated through the rest of the organism to where the original stem cells had been killed.
‘This collaboration gave us a great opportunity to apply previous experience gained in studying cancer cells to a study involving cells in a whole organism. It will provide a useful tool to improve our understanding of stem cells, and their potential role in cancer,’ said Mark.
‘It sounds simple, but it took a long time to design an apparatus and techniques with which we could study many worms at once. That was key in being able to study how migration was controlled and for performing high quality experiments that could really generate reproducible results,’ said Aboobaker.
Professor Gillies McKenna, the Director of the CRUK / MRC Institute for Radiation Oncology and Biology commented: ‘This project is an example of why Oxford is such a rewarding place to do research. People from different departments and disciplines bringing their expertise together to tackle a problem neither could do alone but together shedding new light on both fundamental biology and also on cancer.’
By studying how the worms respond to injury, the team found that stem cells migrated very precisely to the affected area. However in the absence of damaged tissue the cells sat still and did not migrate.
Using a technique called RNA interference the team were then able to remove the function of regulatory genes already known to be important in cell migration (and to play a role in human cancers) and found that they were all also required for migration of planarians stem cells. These genes included proteins known as transcription factors that are important because they act as ON/OFF switches for hundreds of other genes.
‘This was a very satisfying result as it confirmed our suspicion that our simple worms will be very useful for understanding stem cell migration, now we have proven the system we can look intensely for new mechanisms that control or interact with cell migration and have a real expectation that we find will also be true for our migrating cells” said Abnave. One advantage of our worms is that they are easy to work with and we can make rapid progress.’
Next the team hopes to look for new genes that control stem cell migration using the system they have developed.
Our latest monthly trawl for developmental biology (and other cool) preprints. See last year’s introductory post for background, and let us know if we missed anything.
This month features butterfly eyespots, brain development in vivo and in silico, lots on cell commitment in embryos and dishes, a diverse selection of modelling preprints, and, right at the end in our ‘Why not…’ section, some algorithmic science art inspired by sand-bubbler crabs!
Gene neighbourhood integrity disrupted by CTCF loss in vivo. Dominic Lee, Wilson Tan, George Anene, Peter Li, Tuan Danh, Zenia Tiang, Shi Ling Ng, Motakis Efthymios, Matias Autio, Jianming Jiang, Melissa Fullwood, Shyam Prabhakar, Roger Foo
High-Resolution Dissection of Conducive Reprogramming Trajectory to Ground State Pluripotency. Asaf Zviran, Nofar Mor, Yoach Rais, Hila Gingold, Shani Peles, Elad Chomsky, Sergey Viukov, Jason D. Buenrostro, Leehee Weinberger, Yair S. Manor, Vladislav Krupalnik, Mirie Zerbib, Hadas Hezroni, Diego Adhemar Jaitin, David Larastiaso, Shlomit Gilad, Sima Benjamin, Awni Mousa, Muneef Ayyash, Daoud Sheban, Jonathan Bayerl, Alejandro Aguilera Castrejon, Rada Massarwa, Itay Maza, Suhair Hanna, Ido Amit, Yonatan Stelzer, Igor Ulitsky, William J. Greenleaf, Yitzhak Pilpel, Noa Novershtern, Jacob H. Hanna
Loss of MECP2 leads to induction of p53 and cell senescence. William E Lowry, Minori Ohashi, Peiyee Lee, Kai Fu, Benni Vargas, Denise E. Allen, Elena Korsakova, Jessica K Cinkornpumin, Carlos Salas, Jennifer C Park, Igal Germanguz, Konstantinos Chronis, Edward Kuoy, Stephen Tran, Xinshu Xiao, Matteo Pellegrini, Kathrin Plath
Pan-arthropod analysis reveals somatic piRNAs as an ancestral TE defence. Samuel H. Lewis, Kaycee A. Quarles, Yujing Yang, Melanie Tanguy, Lise Frezal, Stephen A. Smith, Prashant P. Sharma, Richard Cordaux, Clement Gilbert, Isabelle Giraud, David H. Collins, Phillip D. Zamore, Eric A. Miska, Peter Sarkies, Francis M. Jiggins
Repeat associated mechanisms of genome evolution and function revealed by the Mus caroli and Mus pahari genomes. David Thybert, Maša Roller, Fábio C. P. Navarro, Ian Fiddes, Ian Streeter, Christine Feig, David Martin-Galvez, Mikhail Kolmogorov, Václav Janoušek, Wasiu Akanni, Bronwen Aken, Sarah Aldridge, Varshith Chakrapani, William Chow, Laura Clarke, Carla Cummins, Anthony Doran, Matthew Dunn, Leo Goodstadt, Kerstin Howe, Matthew Howell, Ambre-Aurore Josselin, Robert C. Karn, Christina M. Laukaitis, Lilue Jingtao, Fergal Martin, Matthieu Muffato, Michael A. Quail, Cristina Sisu, Mario Stanke, Klara Stefflova, Cock Van Oosterhout, Frederic Veyrunes, Ben Ward, Fengtang Yang, Golbahar Yazdanifar, Amonida Zadissa, David Adams, Alvis Brazma, Mark Gerstein, Benedict Paten, Son Pham, Thomas Keane, Duncan T. Odom, Paul Flicek
ATR is a multifunctional regulator of male mouse meiosis. Alexander Widger, Shantha K Mahadevaiah, Julian Lange, Elias ElInati, Jasmin Zohren, Takayuki Hirota, Marcello Stanzione, Obah Ojarikre, Valdone Maciulyte, Dirk de Rooij, Attila Toth, Scott Keeney, James MA Turner
PlantCV v2.0: Image analysis software for high-throughput plant phenotyping. Malia A Gehan, Noah Fahlgren, Arash Abbasi, Jeffrey C Berry, Steven T Callen, Leonardo Chavez, Andrew N Doust, Max J Feldman, Kerrigan B Gilbert, John G Hodge, J Steen Hoyer, Andy Lin, Suxing Liu, César Lizárraga, Argelia Lorence, Michael Miller, Eric Platon, Monica Tessman, Tony Sax
Segmented plants with help from Rasberry Pi, from Tovar, et al.’s prperint
Raspberry Pi Powered Imaging for Plant Phenotyping. Jose Tovar, John Steen Hoyer, Andy Lin, Allison Tielking, Steven Callen, Elizabeth Castillo, Michael Miller, Monica Tessman, Noah Fahlgren, James Carrington, Dmitri Nusinow, Malia A. Gehan
Segmenting Calcium flashes in Reynolds, et al.’s preprint
Mapping nonapoptotic caspase activity with a transgenic reporter in mice. Peter Nicholls, Thomas Pack, Nikhil Urs, Sunil Kumar, Gabor Turu, Evan Calabrese, Wendy Roberts, Ping Fan, Valeriy Ostapchenko, Monica Guzman, Flavio Beraldo, Vania Prado, Marco Prado, Ivan Spasojevic, Joshua Snyder, Kafui Dzirasa, G. Allan Johnson, Marc Caron
Multi-platform discovery of haplotype-resolved structural variation in human genomes. Mark J.P. Chaisson, Ashley D. Sanders, Xuefang Zhao, Ankit Malhotra, David Porubsky, Tobias Rausch, Eugene J. Gardner, Oscar Rodriguez, Li Guo, Ryan L. Collins, Xian Fan, Jia Wen, Robert E. Handsaker, Susan Fairley, Zev N. Kronenberg, Xiangmeng Kong, Fereydoun Hormozdiari, Dillon Lee, Aaron M. Wenger, Alex Hastie, Danny Antaki, Peter Audano, Harrison Brand, Stuart Cantsilieris, Han Cao, Eliza Cerveira, Chong Chen, Xintong Chen, Chen-Shan Chin, Zechen Chong, Nelson T. Chuang, Deanna M. Church, Laura Clarke, Andrew Farrell, Joey Flores, Timur Galeev, Gorkin David, Madhusudan Gujral, Victor Guryev, William Haynes-Heaton, Jonas Korlach, Sushant Kumar, Jee Young Kwon, Jong Eun Lee, Joyce Lee, Wan-Ping Lee, Sau Peng Lee, Patrick Marks, Karine Valud-Martinez, Sascha Meiers, Katherine M. Munson, Fabio Navarro, Bradley J. Nelson, Conor Nodzak, Amina Noor, Sofia Kyriazopoulou-Panagiotopoulou, Andy Pang, Yunjiang Qiu, Gabriel Rosanio, Mallory Ryan, Adrian Stutz, Diana C.J. Spierings, Alistair Ward, AnneMarie E. Welsch, Ming Xiao, Wei Xu, Chengsheng Zhang, Qihui Zhu, Xiangqun Zheng-Bradley, Goo Jun, Li Ding, Chong Lek Koh, Bing Ren, Paul Flicek, Ken Chen, Mark B. Gerstein, Pui-Yan Kwok, Peter M. Lansdorp, Gabor Marth, Jonathan Sebat, Xinghua Shi, Ali Bashir, Kai Ye, Scott E. Devine, Michael Talkowski, Ryan E. Mills, Tobias Marschall, Jan Korbel, Evan E. Eichler, Charles Lee
Assessment of the impact of shared data on the scientific literature. Michael Milham, Cameron Craddock, Michael Fleischmann, Jake Son, Jon Clucas, Helen Xu, Bonhwang Koo, Anirudh Krishnakumar, Bharat Biswal, Francisco Castellanos, Stan Colcombe, Adriana Di Martino, Xi-Nian Zuo, Arno Klein
A persistent lack of International representation on editorial boards in environmental biology. Johanna Espin, Sebastian Palmas-Perez,Farah Carrasco-Rueda, Kristina Riemer, Pablo Allen, Nathan Berkebile, Kirsten Hecht, Renita Kay Kastner-Wilcox, Mauricio Nunez-Regueiro, Candice Prince, Maria Constanza Rios-Marin, Erica P. Ross, Bhagatveer Sangha, Tia Tyler, Judit Ungvari-Martin, Mariana Villegas, Tara Cataldo, Emilio Bruna
Here are the highlights from the current issue of Development:
Making a move: EMT holds the key to planarian regeneration
During development and wound healing, progenitor cells are required to migrate to different locations before they can differentiate into terminal tissue types. This cell migration often involves epithelial-to-mesenchymal transition (EMT), a process by which cells delaminate from an epithelium and become motile. On page 3440, Aziz Aboobaker and colleagues investigate how neoblasts, the adult stem cell population present in planarians, are able to migrate to sites of damage in order to regenerate tissue after irradiation. Using a shielded X-ray irradiation assay, they show that neoblasts require β-integrin and the activity of a matrix metalloproteinase to interact with the extracellular matrix and move through the tissue, just as in EMT. In addition, they show that migration requires EMT-associated transcription factor orthologs, such as snail-1, snail-2 and zeb-1. Strikingly, the differentiation status of cells also affects their ability to migrate. Finally the authors report that, even in the absence of wounding, a notum-dependent signal from the brain, which normally lacks resident stem cells, draws in migrating neoblasts to maintain tissue homeostasis. Together, these results suggest that EMT-related mechanisms controlling cell migration are conserved among bilaterians and provide insights into how progenitor populations move to a site of wounding before regeneration begins.
How mouse oocytes give DNA damage the SAC
Cells in embryos and adult tissues have mechanisms that allow them to identify and respond to DNA damage, thereby ensuring that deleterious mutations cannot arise and persist in individuals. On page 3475, Keith Jones and colleagues investigate the mechanism by which mouse oocytes arrest upon DNA damage. This response involves activation of the spindle assembly checkpoint (SAC), which normally prevents the onset of anaphase until all chromosomes are correctly attached to the spindle. In this study, the authors find that, within minutes of DNA damage, SAC-associated proteins are not recruited to the sites of damage along chromosome arms, but instead become concentrated at the chromosome kinetochores, which act as a platform to generate the SAC signal. SAC activation is dependent on the activity of aurora kinase and MPS1 kinase but, interestingly, does not rely on PI3K-related kinases important for the DNA damage response in other systems. Furthermore, the authors show that the arrest response is unique to oocytes in meiosis I and does not occur in oocytes undertaking meiosis II. These results uncover a new mechanism by which DNA damage is dealt with in oocytes and provide clues into how the formation of genetically abnormal embryos is prevented.
Imp and Syp call time on Drosophila neuroblasts
Drosophila neurons are born from progenitors, known as neuroblasts, in a temporally controlled manner. Given that the timing of birth affects the type of neuron that is generated, this process must be tightly regulated over time so that a diverse array of neuronal progeny is produced. The RNA-binding proteins IGF-II mRNA-binding protein (Imp) and 15 Syncrip/hnRNPQ (Syp) are known to exhibit temporally graded expression patterns in neuroblasts, and have thus been shown to regulate the process of neuronal fate specification. Now, on page 3454, Tzumin Lee and colleagues uncover a role for Imp and Syp in neuroblast decommissioning, as well as in neuron differentiation. ‘Decommissioning’ is the process by which neuroblasts shrink and exit the self-renewing progenitor state before forming terminally differentiated neurons. The authors find that Imp and Syp are crucial for this two-stage ‘decommissioning’ process. Imp regulates shrinkage of the neuroblast so that this event does not occur prematurely, while Syp acts subsequently to promote the accumulation of Prospero in the nucleus, leading to cell-cycle exit. Together, these results provide a mechanism by which neuroblast decommissioning occurs in the Drosophila brain and enhance our understanding of how neural stem cells are controlled during development.
PLUS:
An interview with Jayaraj Rajagopal
Jayaraj (Jay) Rajagopal is a Principal Investigator at the Center for Regenerative Medicine at Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. His lab works on the development and regeneration of the lung, using stem cell and animal models to develop novel insights that hopefully will provide inspiration for therapies to help treat human lung disease. In 2017, he was awarded the Dr Susan Lim Award for Outstanding Young Investigator at the International Society for Stem Cell Research (ISSCR) meeting in Boston (MA,USA), where we met him to talk about how a fish tank started a life-long fascination with the lung, the transition to running his own lab, and his optimism for the future of both basic stem cell research and its clinical translation. Read the Spotlight article on p. 3389.
On the evolution of bilaterality
Bilaterality – the possession of two orthogonal body axes – is the name-giving trait of all bilaterian animals. These body axes are established during early embryogenesis and serve as a three-dimensional coordinate system that provides crucial spatial cues for developing cells, tissues, organs and appendages. How bilaterality evolved and whether it evolved once or several times independently is a fundamental issue in evolutionary developmental biology. Recent findings from non-bilaterian animals, in particular from Cnidaria, the sister group to Bilateria, have shed new light into the evolutionary origin of bilaterality. In their Hypothesis article, Grigory Genikhovich andUlrich Technau compare the molecular control of body axes in radially and bilaterally symmetric cnidarians and bilaterians, identify the minimal set of traits common for Bilateria, and evaluate whether bilaterality arose once or more than once during evolution.
The PAR proteins: from molecular circuits to dynamic self-stabilizing cell polarity
PAR proteins constitute a highly conserved network of scaffolding proteins, adaptors and enzymes that form and stabilize cortical asymmetries in response to diverse inputs. They function throughout development and across the metazoa to regulate cell polarity. In recent years, traditional approaches to identifying and characterizing molecular players and interactions in the PAR network have begun to merge with biophysical, theoretical and computational efforts to understand the network as a pattern-forming biochemical circuit. In their Review article, Charles Lang andEdwin Munro summarize recent progress in the field, focusing on recent studies that have characterized the core molecular circuitry, circuit design and spatiotemporal dynamics.
Can injured adult CNS axons regenerate by recapitulating development?
In the adult mammalian central nervous system (CNS), neurons typically fail to regenerate their axons after injury. During development, by contrast, neurons extend axons effectively. A variety of intracellular mechanisms mediate this difference, including changes in gene expression, the ability to form a growth cone, differences in mitochondrial function/axonal transport and the efficacy of synaptic transmission. In turn, these intracellular processes are linked to extracellular differences between the developing and adult CNS. During development, the extracellular environment directs axon growth and circuit formation. In adulthood, by contrast, extracellular factors, such as myelin and the extracellular matrix, restrict axon growth. In their Review article, Brett Hilton andFrank Bradke, we discuss whether the reactivation of developmental processes can elicit axon regeneration in the injured CNS.
The new Center for Stem Cell & Organoid Medicine (CuSTOM) at Cincinnati Children’s Hospital Medical Center (CCHMC) is launching a major new initiative to recruit outstanding tenure-track or tenured faculty at the Assistant to Associate Professor level.
CuSTOM (https://www.cincinnatichildrens.org/research/divisions/c/custom) is a multi-disciplinary center of excellence integrating developmental and stem cell biologists, clinicians, bioengineers and entrepreneurs with the common goal of accelerating discovery and facilitating bench-to-bedside translation of organoid technology and regenerative medicine. Faculty in CuSTOM benefit from the unique environment and resources here to accelerate their studies of human development, disease and regenerative medicine using organoid platforms.
CCHMC is a leader in organoid biology and one of the top ranked pediatric research centers in the world, providing a unique environment for basic and translational research. Among pediatric institutions CCHMC is the third-highest ranking recipient of research grants from the National Institutes of Health. CCHMC continues to make major investments in research supporting discovery with 1.4 million square feet of research space and subsidized state-of-the-art core facilities including a human pluripotent stem cell facility, genome editing, high-throughput DNA analysis, biomedical informatics, a Nikon Center of Excellence imaging core and much more.
We invite applications from innovative and collaborative investigators focused on basic or translational research in human development and/or disease using stem cells or organoid models. Successful candidates must hold the PhD, MD, or MD/PhD degrees, and will have a vibrant research program with an outstanding publication record.
Applicants should submit their curriculum vitae, two to three page research statement focused on future plans, and contact information for three people who will provide letters of recommendation to CuSTOM@cchmc.org. Applications must be submitted by January 5, 2018.
The Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati are Affirmative Action/Equal Opportunity Employers. Qualified women and minority candidates are especially encouraged to apply.