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On the occasion of World Cancer Day (4 February), we meet two of the trainers of the virtual EMBL Course: Cancer Genomics (17 – 21 May 2021) – Tobias Rausch and Alexey Larionov.
Tobias Rausch (TR) received his PhD in “Computational Biology and Scientific Computing” at the International Max Planck Research School in 2009. He then started to work at the European Molecular Biology Laboratory (EMBL) as a bioinformatician. His primary research interests are population and cancer genomics, structural variant discovery and omics computational methods development. (https://github.com/tobiasrausch).
Initially educated as a clinical oncologist in Russia, Alexey Larionov (AL) switched to experimental oncology upon completion of his PhD. Initially he worked as a postdoctoral researcher in Edinburgh University studying transcriptomics of breast cancer, with a focus on markers and mechanisms of endocrine response and resistance. Working with data-rich methods (qPCR, micro-arrays, NGS) he became interested in data analysis and switched to bioinformatics. Since completing his MSc in Applied Bioinformatics, Alexey has worked as a bioinformatician at Cambridge University, focusing on NGS data analysis and heritable predisposition to cancer. Seehttp://larionov.co.ukfor more details.
What is your research focus?
TR: Computational genomics.
AL: Heritable predisposition to cancer
Why did you choose to become a scientist?
TR: When I started at EMBL I saw myself as a software engineer who loves to design, develop and implement algorithms to solve data analysis problems. With the advent of high-throughput sequencing, this engineering background gave me a competitive edge as a data scientist, and that’s how it happened!
AL: It was interesting…
Where do you see this field heading in the future?
TR: Nowadays cancer genomics is a data-driven team science, but it is a long way from obtaining data to obtaining insight. In the age of analytics we all have to wrap our heads around multi-domain data with spatio-temporal resolution, ideally in real-time.
AL: I assume that the question is about translational cancer research in general. I expect that in the near future the field needs better integration of different types of biological data and better collection of relevant clinical data.
How has training influenced your career?
TR: I think training is essential to get you started. Training is like a kind person who takes your hand and guides you through unknown territory. It goes along with mentorship and I was lucky enough to have good training and good mentorship already as a student.
AL: Since my initial clinical and bioinformatics degrees, cancer research has changed so much that I would not be able to even understand current papers if I hadn’t taken regular in-depth training in different aspects of computing and bioinformatics.
How has cancer research changed over the years?
TR: I hope I am still too young to answer that :-). I leave that question for Bert Vogelstein or Robert A. Weinberg.
AL: Cancer research has become much more complex and powerful because of the development of new methods; specifically significant progress in bioinformatics, sequencing and human genomics.
Which methods and new technologies will be addressed in the course?
TR: We try to give an overview of how high-throughput sequencing can be applied in cancer genomics. We cover a range of technologies (short-read and long-read sequencing), data types (RNA-Seq, DNA-Seq and ATAC-Seq) and data modalities (bulk and single-cell sequencing), and last but not least – we take a deep dive into cancer genomics data analysis.
AL: In my sections of the course, I will discuss established methods for the analysis of bulk RNA sequencing, focusing on differential gene expression. Then I will touch on the new methods being developed for the analysis of long-read RNA sequencing.
What learning outcomes should participants expect to take home after the course?
TR: To come back to my previous answer: I hope after the course, cancer genomics won’t be an unknown territory anymore for the participants. I hope we pave the way and then it’s up to the students to make something out of it.
AL: In my section of the course, participants will learn:
1) Bioinformatics algorithms and tools for QC, alignment, and gene expression measurement in bulk short-read RNA-sequencing data
2) Current approaches to analysis of long-read RNA-seq data, comparing the Oxford Nanopore and PacBio sequencing technologies.
Arsenic (As) and antimony (Sb) are two metalloids that, due to anthropogenic and natural causes, pose an environmental threat, considered as priority pollutants by the World Health Organisation and the United States Environmental Protection Agency. Although the safety guards recommend a maximum of 10 μg/L of As and Sb in drinking water, these values are exceeded in many regions worldwide, with no remediation approach that is simultaneously effective, clean and economically sustainable [1,2]. The ancient bioenergetic enzyme arsenite oxidase (Aio), from microorganisms Rhizobium sp. NT-26 (NT-26 Aio) and Alcaligenes faecalis (A.f. Aio), is currently being studied for its use as a biosensor and in bioremediation processes. Both Aio enzymes contain a large subunit (AioA) that harbours a molybdenum centre and a [3Fe-4S] cluster, and a small subunit (AioB) that possess a Rieske [2Fe-2S] cluster and have demonstrated to oxidise AsIII, as well as SbIII, into the easier to remove and less toxic forms of AsV and SbV, respectively [3,4]. Aiming to elucidate the catalysis mechanism of the enzymes, a combination of expression and purification of the proteins, crystallisation, structural analysis, enzyme kinetics and affinity tests were conducted. X-ray structures of the ligand-free form of the enzyme had been previously determined (PDB: 4AAY, 5NQD and 1G8K [3,5,6]). In our work, Aio crystals in complex with two different forms of the substrate analogue – Sb oxyanions, with a reaction kinetic 6500 times slower than AsIII  – diffracted up to ca 1.8 Å resolution. The structures show the reaction intermediates bound at the active site, with a μ-oxo bridge binding Sb to the Mo atom. Analysis of bond lengths and geometry of the ligands at the Mo active site allowed us to revisit the catalytic mechanism of As oxidation , contributing to the understanding and future biotechnological application of this family of enzymes in water treatment.
Since the beginning of 2020 we have seen the coronavirus SARS-CoV-2 causing a global pandemic with almost 34 million cases and over 1 million deaths worldwide [as of 01.10.2020] [1.] As a result, we have seen a surge in research efforts to develop effective treatments for the underlying disease, COVID-19. One approach is to target the main protease (Mpro) of SARS-CoV-2 as it is essential for virus replication in an early step of the viral life cycle [2.] Most efforts are centred on inhibiting the orthosteric binding site of the enzyme. However, considering allosteric sites on the protein allows for more selective drug design and widens the chemical search space. Here, we report an allosteric hotspot in the SARS-CoV-2 Mpro dimer by using novel atomistic graph theoretical methods: Markov transient analyses follow the propagation of a random walker on a graph and have been shown to successfully identify allosteric communication in catalytic proteins [3.] We further score the so identified allosteric hotspots against random sites in similar distances and thus identify a statistically significant putative allosteric site in the SARS-CoV-2 Mpro. We then simulate a binding event at this hotspot region using data from a recent XChem fragment screen by the Diamond Light Source [4.] which provides a starting point for rational drug design. This study uses highly efficient network theoretical models to shed light on allosteric communication and uncovers putative allosteric sites in the SARS-CoV-2 main protease. This provides a valuable contribution to the ongoing efforts to find a cure against COVID-19 by broadening the horizon for drug discovery efforts.
[1.] Official World Health Organization COVID-19
dashboard: https://covid19.who.int (Accessed: 01.10.2020).
[2.] Hilgenfeld, R. (2014). FEBS Journal, 281(18), 4085-4096.
[3.] Amor, B., Yaliraki, S. N., Woscholski, R., & Barahona, M. (2014) Molecular BioSystems, 10(8), 2247-2258.
[4.] Douangamath, A., Fearon, D., Gehrtz, P., Krojer, T., Lukacik, P., Owen, C. D., … Walsh, M. A. (2020) Nature Communications, 11, 5047.
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.
Since its opening in March 2010, the EMBL Advanced Training Centre (ATC) has served as a forum for the scientific exchange of new ideas, data, approaches and tools. An important component of this is the ATC Corporate Partnership Programme (CPP), which aims to connect companies with the latest developments in molecular biology and build successful long-term relationships between EMBL and corporate partners.
Supporting outstanding scientists
The support that industry partners provide through their membership in the CPP, ensures that outstanding scientists – from PhD students to established investigators – are not excluded from attending a course or conference, or working in an EMBL laboratory as a visiting scientist, because of a lack of funds to cover conference fees or travel expenses. Since 2010, CPP funding has provided fellowships covering registration fees and travel costs to more than 2,100 participants from over 90 countries, attending more than 350 EMBL or EMBO courses, conferences, or symposia.
In addition to the significant impact of their financial support, the engagement and collaboration of corporate partners is crucial in the development and delivery of EMBL’s courses and conferences. For example, of the 33 training courses held at EMBL Heidelberg in 2019, 11 were co-organised with CPP partners. Another example is the EMBL Conference ‘Expanding the Druggable Proteome with Chemical Biology’, which took place in February 2020. This conference, co-funded by the CPP, explored advances at the interface between academic and industry research. The scientific organisers included two CPP partners alongside academic leaders in the field (read the interview with one of the organisers Gerard Drewes here and check out the winning posters here).
Building mutually beneficial relationships
The strong involvement of EMBL scientists at all levels is another crucial factor in enabling the CPP to establish and develop mutually beneficial relationships with its corporate partners. The alliance of the CPP with its corporate partners is one facet of EMBL’s engagement with industry – in particular the life sciences business sector. This compliments the activities of EMBL’s technology transfer partner EMBLEM, the EMBL Course and Conference Office, the EMBL-EBI Industry Programme, and direct interactions with industry partners by EMBL group and team leaders and heads of core facilities.
With two new partners joining the CPP in 2019 and another already this year, the CPP has grown to 19 members, bringing together EMBL and global leaders in a range of business sectors, including biopharmaceuticals, diagnostics, information technology, research and clinical instrumentation, and laboratory products.
We look forward to seeing the programme continue to evolve and grow in future years, always striving to deliver outstanding value and maintain its impact on the future of science.
With events going digital, professional training has become increasingly convenient and accessible. While getting the latest scientific research developments from the comfort of your home has never been so easy, sitting alone in front of a screen significantly diminishes the chances of meeting new people and collaborators – a benefit of on-site meetings that is considered one of their most important assets.
Most meeting organisers realise that and offer various networking opportunities and socialising incentives as part of the programme. One of the methods we have implemented to facilitate social interaction at our onsite as well as virtual conferences is the so-called speed networking – a networking session where people swap conversational partners every 5 minutes with the aim to meet as many people as possible and exchange information about their research or the project they are currently working on. The session is normally scheduled for the first day of the conference so that participants can later go back to the people they have met during the speed networking session and continue the discussion.
What should you talk about during the speed networking?
5 minutes doesn’t seem like a long time, so it is important that you focus on the essentials. Start by introducing yourself then go into more detail. Are you looking for collaborators? Or maybe a new job or a postdoc position?
How can you do that in just 5 minutes?
Prepare a 20 second blurb about yourself
Keep aware of the time factor – there should be a countdown on your screen
Stick to the vitals
Make sure to take notes next to their name so that you can later go back to them for reference
Most importantly, have fun and relax! 🙂
What if you don’t finish your conversation within the allocated time slot?
Before the time is up, make sure you suggest the next step
Message them directly on the available discussion platform with a suggestion for a follow-up meeting
After the meeting, be sure to e-mail them with a suggestion for further exchange.