You may have heard the name CABANA floating around the EMBL training programme, but you may not know exactly what it is. Here we present a handy guide to the project, its origins and where it stands now almost three years on from its launch.
CABANA is a capacity strengthening project for bioinformatics in Latin America. It aims to accelerate the implementation of data-driven biology in the region by creating a sustainable capacity-building programme focusing on three challenge areas – communicable disease, sustainable food production and protection of biodiversity.
Want to know more about the project? Check out this video from the CABANA consortium.
With just over a year left of the project, funded by the Global Challenges Research Fund (GCRF) – part of the UK Aid Budget, the capacity building element of the project is ramping up. A big part of the project is running a series of training events for the Latin American audience, something that began with the centralised events team within EMBL-EBI, but is now increasingly being operated in Latin America by the partners themselves.
CABANA has virtualised its training programme for the rest of 2020 and has committed to a fully virtual 2021 programme too. Check out the latest events on offer, or visit the new virtual training portal for the e-learning options.
Follow the CABANA project on Twitter or Facebook for the latest news and updates.
Partnering with industry has been a core part of EMBL-EBI’s mission right from the very beginning and a significant number of our users come from this sector. As we celebrate an incredible 25 years of industry collaboration next year, let’s hear from Andrew Leach, the new Head of Industry Partnerships at EMBL-EBI to find out a bit more.
Industry Partnerships: What does this mean at EMBL-EBI?
Industry Partnerships at EMBL-EBI is about helping to connect public and industry science. We aim to foster and facilitate collaboration, knowledge exchange and networking between scientists and technologists at EMBL-EBI and their counterparts working in industry. We work across multiple sectors and with organisations from very large multinationals to very small start-ups.
Tell us more about the opportunities for scientists in industry to interact with EMBL-EBI.
EMBL-EBI’s Industry Programme is a subscription-based programme for global companies who are using EMBL-EBI’s data and resources as part of their research and development. Representatives from the member companies meet regularly in a forum where we share details of the latest innovations in EMBL-EBI’s services and research. The programme also organises a series of knowledge exchange workshops that explore new emerging areas for R&D. These events are open to any employee of the member companies. The programme also provides a great opportunity for scientists to meet their peers in a pre-competitive, science-oriented environment to discuss the latest developments.
We are always keen to hear of opportunities to explore new strategic partnerships with industry. Open Targets is an excellent example; this ground-breaking public-private consortium was established in 2014 with the overall goal of improving how we identify and prioritise drug targets. Open Targets currently involves six partners: EMBL-EBI, the Wellcome Sanger Institute, GlaxoSmithKline, Bristol Myers Squibb, Takeda and Sanofi.
We also have a proud history of research collaborations that bring together expertise from academia and industry to work on a common research problem or to address a particular data or technology challenge. One particular advantage of collaborating with EMBL-EBI is that we have tremendous flexibility in the way that collaborations can be set up, from small projects lasting a few months, to much larger projects. Key to success is active participation and commitment from everyone involved.
What about smaller companies?
Every company has to start somewhere and we are committed to engage with small and medium-sized enterprises (SMEs) and start-up enterprises. These are very often the drivers of innovation, and we find that such organisations make extensive use of the resources available at EMBL-EBI. We actively work with organisations such as OneNucleus, the UK Trade and Investment agency (UKTI), the InnovateUK Bioinformatics knowledge-transfer network and the ELIXIR SME and Innovation Forum to showcase the opportunities at EMBL-EBI. Of course, we are also very keen to hear from any smaller company interested in collaborating more directly with us on a particular problem.
What can be achieved by connecting with industry?
Having worked in industry myself (for many years at GSK), I know that industry science is often just as cutting-edge as in traditional academic circles – but historically it has been much less visible due in part to commercial sensitivities together with the fact that publication was not seen as a key goal in industry. These attitudes are changing now; there is a real drive within industry to collaborate externally and especially with leading academic groups and institutions. Industry can bring “real world” applications of the resources and research that we do at the EMBL-EBI; it can be very rewarding to see how the work we do can translate into practical applications. Plus, it can be a way for students and post-docs to get some insights into what a career in industry looks like, and potentially for industry to identify potential recruits for the future!
What would you like to see in the future for Industry Partnerships at EMBL-EBI?
I would like to see our connections with industry continue to grow and strengthen. We have historically had very strong connections with the Pharma and biotech sectors and it would be good to see us strengthen our relationships in other areas of bioscience and also with relevant data science and technology sectors. Of course, we are always keen to create new large-scale strategic partnerships such as Open Targets but we also recognise that a smaller-scale, one-on-one collaboration for example between an SME and an EMBL-EBI Principle Investigator can be equally fruitful. We also want to make further steps to encourage entrepreneurs; this includes working with Jo Mills (Entrepreneurship and Innovation Centre Manager) who with her team is creating a new Startup School for genomics and biodata. This will support early-stage ideas and provide knowledge and confidence to develop them into future products or services.
We always welcome opportunities to explore new partnerships and ventures.
Event report by Suzanna Prosser, Lunenfeld-Tanenbaum Research Institute, Canada
Gender imbalance is a longstanding issue in academia, with men still more likely to progress to the highest levels. Institutional and individual biases, attitudes, and self-limiting beliefs are only some of the factors that allow this situation to persist. The Gender Roles and their Impact in Academia virtual conference served as a timely reminder of these issues, whilst also highlighting current thinking, research and practices surrounding gender, diversity, equality and academia. It was only fitting that the conference commenced on the second Tuesday of October, which is designated as Ada Lovelace Day, an annual celebration to raise the profile of women in STEM.
The opening lecture was delivered by Melvin Konner (Emory University) whose 2015 book ‘Sex, Evolution and the End of Male Supremacy’, upset a lot of people if the vitriolic reviews and commentaries it received are anything to go by. The premise Melvin presents in his book is a very simple one: “women are not equal to men; they are superior in many ways, and in most ways that will count in the future”. He explained that the similarities between men’s and women’s brains are far greater than the differences, but historically women have been believed not to have the capacity to lead. The consequence of this is that their voices have been excluded from the places where they would be most beneficial. We are now, however, living in a time where women are managing to trickle up to prominent leadership roles throughout the world, although sadly the tides of change continue to move slowly.
The notion that men are superior to women has perpetuated in part due to biological evidence perceived in such a way so as to support this thinking. Against this, Gemma Puixeu (IST Austria) very eloquently argued that while biology can justify the differences between the sexes, it cannot justify gender binarism nor gender inequality. Acknowledging that there are many other players aside from chromosomal sex defining systemic sex, allows us to appreciate that gender expression is multifactorial, leading to a continuum that is influenced by non-biological factors. Indeed, gender binarism can only be explained by cultural enforcement. For gender inequality, traditional evidence states that sexual selection is stronger in males, as male traits are superior and that evolution is male-driven. On the other hand, alternative evidence says that there is no power inequality between the sexes, and questions what are male and female traits, and why we value them differently. Furthermore, one sex does not evolve in spite or at the expense of the other. So, if male supremacy is not explained by biology, why has science failed us? First, it is subjective – if performed by men, it is for men and suffers from unconscious bias. Second, arguing women are subordinate by nature justifies socio-politico-economic interests.
Talks by Cordelia Fine (University of Melbourne), Ijeoma Uchegbu (University College London) and Stephen Curry (Imperial College) covered why gender diversity matters in the work place, strategies to approach equity and diversity in academia, and how to ensure science is built by men and women. Evidence provides overwhelming support for diversity on teams and panels leading to better decision-making processes, outcomes and productivity. Indeed, diverse teams make superior decisions as they focus more on facts and process them more carefully. Depending on field, over 50% of graduate students are female, however often less than 10% of professors are women. Reasons why women fall out of the academic pipeline are varied but, as Heather Metcalf (Association for Women in Science) explained, intersectionality is a crucial dimension, with reasons being very different for women of different backgrounds.
Women are frequently encouraged to adopt more male-associated traits, such as confidence. However, Suzanne Doyle-Morris (InclusIQ) informed us that women that display overt confidence tend to be penalized with negative labels such as bossy, difficult, and strident. And the inherent confidence women possess to occupy space in fields dominated by men often goes unacknowledged. Furthermore, over-valuing confidence disadvantages people from groups, genders and cultures in which self-promotion is criticised, and risks hiring and promoting the wrong people. Instead, panels need rigorous training in preparation for conducting evaluations so as to see through confidence to get to competence. It is important to value competence over confidence, as competence as a trait works for a wider range of people when looking for leaders in academia. In addition to hiring committees, this is particularly important in research funding decisions, as obtaining funding serves as an indicator and requirement for career success. However, systemic inequality also exists in grant allocation, to the detriment of women. Claartje Vinkenburg (CJ Vinkenburg Advies) described how panel members believe in their own ability to objective evaluate proposals based on merit, but that panel members’ implicit associations and explicit expectations around the ‘ideal scientist’ and ‘ideal career’ affect how they evaluate and discuss applications. In addition, the requirement to ‘sell science’ (high risk, high reward) creates an additional layer of gendered complexity to the decision process.
In the final keynote lecture of the conference, Jo Handelsman (Wisconsin Institute for Discovery) discussed gender bias in academic science. Unconscious bias describes the underlying attitudes and stereotypes that people unconsciously attribute to others that affect how they understand and engage with them. Unfortunately, many scientists believe they don’t display unconscious bias as they are trained to be objective, however study after study proves this to be untrue. In one such study, participants were more likely to hire whichever application had a man’s name on it, then provided post-choice justifications, like citing whichever strength was present, for their biased behavior. Worryingly, those who believe they aren’t biased are those that apply biases the most. Fortunately, there are tangible steps that can be taken to overcome unconscious bias, including: promotion of self-awareness of biases, understanding the nature of bias, providing opportunities to discuss bias to create accountability, and the provision of training sessions to promote bias literacy. Indeed, earlier in the meeting, Ansgar Büschges had described the use of unconscious bias training as a prerequisite for participation in faculty search committees at the University of Cologne for the active recruitment of women. In addition, the identification of hiring criteria before the evaluation of candidates can abolish bias in selection participants. Jo also advised female scientists to give their referees as much information as possible about themselves (accomplishments, career goals etc.), as the less information people have available the more likely they are to fall back on biases.
Gender imbalance in science hasn’t occurred due to not having suitably qualified women, but rather the structures that are in place which prevent them from taking their rightful place in the higher echelons. Instead of helping women do better, we need to eradicate the barriers that prevent them from succeeding and provide them with the same level of support and mentorship that men receive. We need affirmative action, targets and quotas to reach gender equality, alongside a rethinking of criteria and assessment. While the problem is a chronic under-representation of women in research, men need to be part of the conversation. Indeed, the drive for gender equality is not an attack on men to prevent them from succeeding, but the provision of space to allow women to succeed as they deserve.
The recent virtual EMBO|EMBL Symposium on Organ Development and Disease in 3D Culture saw the highest number of registrations we have had since we launched the format. A total of 880 researchers from around the world got together online to discuss recent developments in the formation and maintenance of organoids and their use in disease studies and regenerative medicine.
Out of the 200 digital posters that were presented at the three poster sessions, four were distinguished with a poster prize by a committee appointed by the scientific organisers. Here are the winners:
Organoids model transcriptional hallmarks of oncogenic KRAS activation in lung epithelial progenitor cells
Authors: Aaron Moye (1), Antonella Dost (1), Marall Vedaie (2), Linh Tran (5), Eileen Fung (5), Dar Heinze (2), Carlos Villacorta-Martin (2), Jessie Huang (2), Ryan Hekman (2), Julian Kwan Kwan (2), Benjamin Blum (2), Sharon Louie (1), Sam Rowbotham (1), Julio Sainz de Aja (1), Mary Piper (4), Preetida Bhetariya (4), Roderick Bronson (3), Andrew Emili (2), Gustavo Mostoslavsky (2), Gregory Fishbein (5), William Wallace (5), Kostyantyn Krysan (5), Steven Dubinett (5), Jane Yanagawa (5), Darrell Kotton (2), Carla Kim (1)
Presenter: Antonella Dost (1)
Mutant KRAS is the most common oncogenic driver of epithelial cancers. Nevertheless, the molecular changes induced by KRAS activation in primary epithelial cells beyond activation of proliferation remain elusive. Here, we determined transcriptional changes at single-cell resolution after KRAS activation in distal lung epithelial cell populations. We developed a new in vitro organoid system to define the early oncogenic KRAS transcriptional program and model early-stage lung adenocarcinoma (LUAD) using primary murine lung cells. Alveolar epithelial progenitor (AT2) cells expressing oncogenic KRAS lost their mature identity and acquired a transcriptional program similar to lung development and progenitor cells. Similar changes were observed in an early-stage LUAD mouse model, in human induced pluripotent stem cell derived AT2 cells, and in stage I lung cancer patient samples, validating our organoid model. While these events have been observed in advanced lung cancers in mice and humans, we show that KRAS induced dedifferentiation occurs in early-stage lung cancer. This work provides a new organoid tool to rapidly recapitulate lung cancer progression in vitro and a window into the transcriptional changes that immediately follow oncogenic KRAS expression in epithelial cells, revealing candidate targets for early intervention of KRAS-driven lung cancer.
(1) Boston Children’s Hospital, United States of America (2) Boston University, United States of America (3) Harvard Medical School, United States of America (4) Harvard T. C. Chan School of Public Health, United States of America (5) University of California Los Angeles, United States of America
Using human pluripotent stem cell-derived organoids to investigate regional-specific features of the small intestine
Authors: J Guillermo Sanchez, Heather McCauley, Jacob Enriquez, James Wells, Cincinnati Children’s Hospital, United States of America
Presenter: J Guillermo Sanchez
The gastrointestinal tract is the largest endocrine organ in the body. Specialised nutrient sensing cells, called enteroendocrine cells, are embedded in the intestinal epithelium and secrete over 20 hormones that regulate processes such as satiety, gut motility and gastric emptying. Directed differentiation of human pluripotent stem cells into human intestinal organoids has been used to study and mimic intestinal development; however, most of these models generate intestinal tissue which resembles duodenum and proximal jejunum (Spence, et al 2011). The intestine displays distinct regional functions along the proximal-distal axis, with the ileum being important for unique enteroendocrine hormone secretion, bile acid resorption and interactions with the microbiome. It is known that major signaling pathways such as Wnt, FGF and BMP can affect the regional identity of the developing GI tract. Consistent with previous studies (Munera, Tsai) we found that manipulation of the exposure time of intestinal spheroids to these signaling pathways generated distal intestinal tissue by expression of epithelial markers, nutrient transporters, and hormone expression. These distally-patterned human intestinal organoids retain their regional identity after transplantation in vivo, and can be used to generate epithelial-only enteroid cultures. It remains unknown how diverse cellular types and functions are established along the proximal-distal axis of the small intestine. This model enables us to compare the early transcriptional changes involved in conferring regional-specific features, including enteroendocrine cell allocation, to the GI tract.
Poster currently not available
Recapitulating the somitogenesis in vitro to identify novel causative genes for congenital bone diseases
Somites are periodically formed though the segmentation of anterior parts of presomitic mesoderm (PSM) in embryos. This periodicity is controlled by the segmentation clock gene Hes7, which exhibits a wave-like oscillatory expression in the PSM. The periodical somite formation is a crucial event for body segment formation and abnormal somitogenesis leads to congenital bone diseases.
Spondylocostal dysostosis (SCD) is a bone malformation disease which is characterised by morphological abnormalities of vertebrae and ribs. Mutations in several somitogenesis-related genes, including HES7, are already known as the cause of SCD. As for 75% of SCD patients, however, the causative gene and at what stage of bone development the abnormality occurs are still unclear.
Thus, the aim of this study is to establish a method to recapitulate the somitogenesis in vitro and to identify novel a causative gene of SCD.
To recapitulate the somitogenesis in vitro, we previously reported a simple and efficient method to generate mouse embryonic stem (ES) cell-derived PSM-like tissues (Matsumiya et al., Development, 2018). In these tissues, Hes7 oscillation was synchronized among neighboring cells, the anterior-posterior axis was self-organised, and somite-like structures were observed. We are currently developing a similar method to recapitulate the human somitogenesis by using human induced pluripotent stem (iPS) cells instead mouse ES cells. Furthermore, by using human iPS cell lines that lack the candidate gene of SCD for the in vitro somitogenesis, we are trying to identify a novel causative gene of SCD.
Poster currently not available
(1) EMBL Barcelona, Spain (2) RIKEN Center for Integrative Medical Sciences, Japan
Heme oxygenase 1 upregulation is induced by stress via alpha-synuclein aggregation in transgenic mice and in Parkinson’s disease derived brain organoids
Excessive accumulation of alpha-synuclein (a-syn) predisposes to the development of Parkinson’s disease (PD), a disorder characterised by neurodegeneration in the substantia nigra and concomitant motor impairments. It was previously shown that stress-induced release of glucocorticoids accelerates the progression of PD and that the glucocorticoid receptor (GR) is downregulated in several neurodegenerative as well as in stress-related diseases. The impact of altered a-syn protein levels on GR dysfunction and stress-related protein expression is largely unexplored, but may have severe implications for PD manifestation and disease progression. Therefore, we examined the effect of chronic stress in two models overexpressing human a-syn: a transgenic mouse model (h-a-synL62) and brain organoids derived from iPSCs of a PD patient. Wildtype mice that underwent daily restraint for 6 weeks presented typical chronic stress induced features, such as GR-deficiency and increased a-syn protein levels in prefrontal cortex and hippocampus. Importantly, these molecular alterations were reproduced in forebrain organoids generated from healthy donors after treatment with the synthetic glucocorticoid Dexamethasone for 2 weeks. In contrast, glucocorticoid exposure had no effect on GR expression and normalised the level of a-syn in h-a-synL62 mice and PD brain organoids. Accordingly, heme oxygenase 1 (HO-1), an antioxidant protein that can be induced by soluble oligomers and protofibrils and that triggers proteosomal degradation of a-syn, was upregulated. Together, our work provides a new link between a-syn overexpression, GR-deficiency and oxidative stress and their contribution to the development and progression of PD. Further, we established and validated a human 3D tissue culture model that can be used to study stress related diseases, offering replacement of research animals exposed to disturbing procedures.
Event Report by Apoorva Baluapuri, University of Würzburg, Germany
As it happens frequently in life, there is always something good that comes out of a bad situation. The scientific world seems to be in the midst of such a situation, where all possibilities to share exciting discoveries and network among peers in person have disappeared, thanks to a 200 nm wide particle of protein. However, the good thing that has come out of it was the ability to virtually participate in conferences and talks at a reduced cost, and also without raking in carbon footprint.
The 14th Transcription and Chromatin conference at EMBL showed how such virtual hosting can be done in an excellent manner. While the new format took some getting used to, such a minor inconvenience was a small price to pay for making the new science accessible to researchers around the world – and many of them who would not have joined a conference in a different continent in person, tuned in from the comfort of their homes and offices.
In fact, thanks to the intuitive features of Zoom, many more questions were asked following the talks at the conference, with intense rigour and enthusiasm particularly from the younger participants. Due to the considerations of time-zone differences, the meeting was restricted from 14:00-22:00 CEST (approx.) and consisted of 15-20 minutes long talks, which turned out to be very fruitful in terms of keeping things concise while maintaining the interest.
The titular opening session was dedicated to mechanisms of transcription in eukaryotes. The range of speakers truly covered every end of the spectrum in all respects. While seasoned scientists like Patrick Cramer (Max Planck Institute for Biophysical Chemistry, Germany) showcased the lessons learnt in transcription initiation, promoter-proximal pausing and elongation from Pol II structural biology, young scientists like Kinga Kamieniarz-Gdula (Adam Mickiewicz University, Poland) also dazzled with new insights into transcription termination.
Similar trend was noted in the area of chromatin topology with Ana Pombo (Max Delbrück Center for Molecular Medicine, Germany) showcasing Genome Architecture Mapping which found variable 3D topology in brain cells at both short and long genomic distances, and integrated it with single-cell RNA-Seq data to get cell-type specific gene expression. Display of new technologies was relentless with Kyle Eagen (Northwestern University, USA) showing how BRD4-NUT (which recruits P300 histone acetylase) drives interactions to form a specific nuclear subcompartment, and how a PROTAC against it abolished the subcompartment interactions.
In times when scientists are mostly working from home, Steve Henikoff (Fred Hutchinson Cancer Research Center, USA) took the concept to a new level by showcasing a new protocol for CUT & RUN called CUT&Run @ Home, which can actually be performed in your own garage. This was truly inspirational!
Working from home has reached a whole new level! Steve Henikoff is superexcited running his experiments using the CUT&Tag@home setup (PC: Jorja Henikoff). If you want to set this up, here is the link to CUT&Tag@home protocolhttps://t.co/wxnsfc5fc2pic.twitter.com/GJ6fD4BCBI
However, regulation of X chromosome was not left behind, and Asifa Akhtar (Max Planck Institute of Immunobiology and Epigenetics, Germany) H4K16ac and X chromosome regulation. It was shown in really exhaustive detail how histone acetylation is not just a way to open the chromatin structure, but it’s also a much more elaborate and elegant system controlling gene expression in both Drosophila and mouse.
As usual, what was very obvious was the affinity of the speakers towards incredible puns and double entendre! While Alistair Boettiger (Stanford University, USA) mentioned that he thinks of TADs as more like “dancers”, rather than architects of nucleus, Karolin Luger (University of Colorado Boulder, USA) showed cool structural data indicating how SPT16 CTD “hugs and protects” exposed DNA binding surfaces on nucleosomes.
When it comes to transcription in the 2020s, the phenomenon of phase separation cannot be ignored. Thanks to Bob Kingston (Harvard Medical School, USA), who showed the functional role for phase separation in a system, where PRC1 subunit CBX2 CaPS domain drives phase separation in cells; and David Gilmour (The Pennsylvania State University, USA) who explained the consequences of too short and too long consensus Pol II CTDs, it was clear that the phenomenon has clear and present relevance in transcription.
However, the core mechanistic session related to Pol II was not neglected either: Steve Buratowski (Harvard Medical School, USA), showed that Pol II CTD phosphorylation cycle is all about time and not distance on genes. Using single molecule imaging system, he showed two modes of Pol II association on promoters: short duration via Mediator in contrast to long duration via PIC. Amazingly, he found time to talk about Elongation Factor dynamics as well. It turns out that elongation exchange can happen on moving Pol II as well, and was shown for SPT5 that it actually disassociates while Pol II remains bound, with a new SPT5 binding event being recorded later.
That being said, this conference was not just about basic science and mechanisms – but included lessons learnt from applying the mechanistic understanding into the translational aspects of science. For example, Ali Shilatifard (Northwestern University Feinberg School of Medicine, USA) showed that inhibiting Super Elongation Complex (SEC) by small molecule inhibitors reduces Pol II speed (in terms of kb/min by FP-4sU-Seq, and not pSer2 Pol II ChIP-Seq – no sloppy work shown at this conference !!) and helps in recovery of MYC driven tumours in mice.
Towards the last session of the conference, there was a nice mix of talks covering transcription elongation and termination, with Hanneke Vlamming (Harvard Medical School, USA) (one of the few post-doctoral researchers who delivered the talks!!) showing that for Pol II, the elongation potential is encoded in DNA sequence. She also indicated that mRNA sequences are not only easier to transcribe for Pol II, but also for maintaining steady state RNA and protein levels. At the same time, Torben Heick Jensen (Aarhus University, Denmark) showed the effects of depleting Integrator, indicating that Integrator depletion causes decrease OR increase of transcriptional read-through, depending on the genes if they are multi or mono-exonic. What seemed really striking was also the report that heat shock triggers increased elongation rates of Pol II while inducing premature termination – as shown by Jesper Svejstrup (now at University of Copenhagen).
Finally, the conference wrapped up with Shelley Berger summarizing the new findings from her lab changes in foraging behaviour of ants based on epigenetics, with the cool finding that HDAC inhibitors induce changes in “caste” of ants.
In many ways, this conference was a first for a lot of people. The ease with which young scientists could ask questions in Zoom and interact with the speakers on Slack was definitely the highlight – but left some scope for improvement in terms of how poster presenters interacted with the audience. In the words of a few presenters, it seemed extra work to upload the data in parts when some of the other conferences allowed them to upload just the PDFs of their posters. Nevertheless, the Zoom sessions were still adequate for the individual poster sessions.
What was truly enjoyable and an upgrade from in person socialising at conferences was the Social Mixer Event! It was an amazing experience to meet so many new people (and say hello to a few old acquaintances) during the speed networking. Hope this is a recurring theme in the years to come.
This bring us to introspect the utility of virtual conferences when the emphasis to reduce the carbon footprint has been on the rise. Maybe alternating between virtual and in-person conference, or a hybrid model with virtual and in-person talks in the future would be that way to go.