Best Poster Awards – Precision Health

140 researchers came together recently at the EMBL Advanced Training Centre in Heidelberg, Germany, for the EMBO Workshop: Precision Health: Molecular Basis, Technology and Digital Health (13 – 16 November 2019) to present and discuss the promises and challenges of precision health and the molecular insights necessary to enable a maintenance of wellness and prevention of disease.

Out of the posters presented, 4 were awarded a poster prize based on popular vote. Here we present the poster abstracts of four of the winners.

A computational modelling approach to characterizing postprandial glucose responses in individuals
Balazs Erdos from TiFN Wageningen and MaCSBio, Maastricht University, The Netherlands, PHOTO: Balazs Erdos

Balazs Erdos (1), (2)*, Bart van Sloun (1), (2), Shauna O’Donovan (2), Michiel Adriaens (2), Natal van Riel (3), Ellen Blaak (4), Ilja Arts (2)

The large variability in the dynamic properties of the postprandial glucose response curves in individuals suggest that it is not sufficient to use average values or single time point measures of postprandial glycemia in order to characterize individuals’ glycemic control. Instead, approaches that are capable of capturing the dynamic events are necessary. In this study, we develop personalized computational models based on ordinary differential equations, to describe the glucose and insulin dynamics of individuals in response to an oral glucose tolerance test. We observed that these personalized models are capable of capturing a wide range of glucose and insulin dynamics including normal, prediabetic and type 2 diabetic responses as well as responses from intermediate states.

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(1) TiFN, Wageningen, The Netherlands, (2) Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands, (3) Dept. of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands, (4) Dept. of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands

*E-mail: balazs.erdos@maastrichtuniversity.nl


Predict nephrotoxicity associated with cisplatin-based chemotherapy in testicular cancer patients

Sara Garcia (1), Jakob Lauritsen (2), Zeyu Zhang (3), Mikkel Bandak (2), Marlene Danner Dalgaard (1), Rikke Linnemann Nielsen (1), Gedske Daugaard (2), Ramneek Gupta (1)

In industrialized countries, testicular cancer (TC) is the most common solid tumor in men between 20 and 40 years old and besides being one of the most treatable types of cancer, the long-term side-effects of chemotherapy are worrisome, since they are largely irreversible. Their severity is normally related to the total amount of chemotherapy received, which makes that an important factor to a successful treatment. The standard treatment for TC is 3 cycles of cisplatin, etoposide and bleomycin (BEP), being that the number of cycles can vary between 4-5 or more if the prognosis of the patient is intermediate or poor. Some of the late side-effects include nephrotoxicity, which can be measured by the drop in glomerular filtration rate after the patient follows chemotherapy. Materials and Methods: Integrative machine learning models were built using a dataset of 400 Danish individuals in order to identify clinical and/or genomics features and classify patients at higher risk of developing nephrotoxicity given a treatment of BEP-cycles. Results: First, only clinical features, such as age at the time of treatment, dose of cisplatin, patient’s prognosis, and number of cycles, were considered, and relevant features were selected to use in the classifier (AUC 0.66, SD 0.02). The classifier was then optimized by adding genomics markers, which helped improving the prediction (AUC 0.75, SD 0.02). Conclusions: Therefore, it is proposed a machine learning algorithm which, by helping predicting nephrotoxicity in advance, can benefit to improve chemotherapy efficacy in TC patients. These data driven models can also be applicable to other cancers, such as ovarian, bladder, and lung cancer where more elderly patients are at risk of nephrotoxicity and identification upfront will have direct clinical implications.

Poster currently not available

(1) Technical University of Denmark, Denmark, (2) Copenhagen University Hospital, Denmark, (3) University of Chinese Academy of Sciences, China


Loss of N-glycanase 1 alters transcriptional and translational regulation
Petra Jakob from EMBL Heidelberg, Germany, PHOTO: Petra Jakob

Petra Jakob (1), William Mueller (1), Sandra Clauder-Münster (1), Han Sun (2), Sonja Ghidelli-Disse (3), Diana Ordonez (1), Markus Boesche (3), Markus Bantscheff (3), Paul Collier (1), Bettina Haase (1), Vladimir Benes (1), Malte Paulsen (1), Peter Sehr (1), Joe Lewis (1), Gerard Drewes (3), Lars Steinmetz (1)

N-Glycanase 1 (NGLY1) deficiency is an ultra-rare, complex and devastating neuromuscular disease. Patients display multi-organ symptoms including developmental delays, movement disorders, seizures, constipation and lack of tear production. NGLY1 is a deglycosylating protein involved in the degradation of misfolded proteins retrotranslocated from the endoplasmic reticulum (ER). NGLY1-deficient cells have been reported to exhibit decreased deglycosylation activity and an increased sensitivity to proteasome inhibitors. We show that the loss of NGLY1 causes substantial changes in the RNA and protein landscape of K562 cells and results in downregulation of proteasomal subunits, consistent with its processing of the transcription factor NFE2L1. We employed the CMap database to predict compounds that can modulate NGLY1 activity. Utilizing our robust K562 screening system, we demonstrate that the compound NVP-BEZ235 (Dactosilib) promotes degradation of NGLY1-dependent substrates, concurrent with increased autophagic flux, suggesting that stimulating autophagy may assist in clearing aberrant substrates during NGLY1 deficiency.

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(1) EMBL Heidelberg, Germany, (2) Stanford University, United States of America, (3) Cellzome, Germany


Data integration for prediction of weight loss in clinically controlled dietary trials

Rikke Linnemann Nielsen (1), Marianne Helenius (1), Sara Garcia (1), Henrik Munch Roager (2), Derya Aytan (3), Lea Benedicte Skov Hansen (1), Mads Vendelbo Lind (2), Josef Vogt (1), Marlene Danner Dalgaard (1), Martin I Bahl (3), Cecilia Bang Jensen (1), Rasa Muktupavela (1), Christina Warinner (4), Vincent Appel (5), Rikke Gøbel (5), Mette B Kristensen (2), Hanne Frøkjær (6), Morten H Sparholt (7), Anders F Christensen (7), Henrik Vestergaard (5), Torben Hansen (5), Karsten Kristiansen (6), Susanne Brix Pedersen (1), Thomas Nordahl Petersen (3), Lotte Lauritzen (2), Tine Rask Licht (3), Oluf Pedersen (5), Ramneek Gupta (1)

Diet is a key strategy in weight loss management. Advances in omics technologies research allow analyses of determinants of clinical interventions outcomes. We have previously reported diet-induced weight loss in non-diabetic middle-aged Danes in two clinically controlled dietary trials where the content of whole grain or gluten was changed. However, it remains elusive how predictable weight loss is at the individual level. We here classify weight loss responders and non-responders from the whole grain and gluten trials by integrating multi-omics data (host genetics, gut microbiome, urine metabolome) together with physiology and anthropometrics into random forest models. The most predictive models for weight loss included features of diet, gut microbial species and urine metabolites (ROC-AUC:0.84-0.88, model only with diet type ROC-AUC:0.62). Furthermore, we demonstrate that a model ensemble is robust to missing information of microbiome and metabolome profiles given features of physiology (including postprandial response), host genetics and transit-time (ROC-AUC:0.72).

Poster currently not available

(1) Technical University of Denmark, Denmark, (2) University of Copenhagen, National Food Institute, Technical University of Denmark, Denmark, (3) National Food Institute, Technical University of Denmark, Denmark, (4) Harvard University, United States of America, (5) The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark, (6) University of Copenhagen, Denmark, (7) Bispebjerg University Hospital, Denmark


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Meet the Trainer – María del Mar Vivanco

PHOTO: María del Mar Vivanco

Meet María del Mar Vivanco, Team Leader at CIC bioGUNE in Bilbao, Spain. Maria is one of the organisers of the EMBO Practical Course: Techniques for Mammary Gland Research (1 – 6 March 2020).

What is your research focus?

I am interested in cancer heterogeneity, why some cells respond to therapy while others do not, thus contributing to development of resistance and metastasis. In particular, I am intrigued about the complex effects of transcription factors, which are required for normal physiology of the mammary gland and are also implicated in tumorigenesis and development of resistance to therapy in breast cancer.

Why did you choose to become a scientist?

When I was young I had a variety of interests – psychology, physics, art, biology… However, I was intrigued by science and anything related to DNA and its regulation. Then I did my PhD at EMBL Heidelberg (Gene Expression Programme) and discovered the opportunities in research for identifying problems, looking for solutions and the thrill of finding some of the answers…and I was hooked!

Where do you see this field heading in the future?

Despite significant progress in cancer research and clinical advances, breast cancer still is the most commonly diagnosed cancer – one in eight women will develop this disease during their lifetime – and it claims the lives of more women than any other cancer, plus men can also get breast cancer. This highlights the unmet clinical need for improved strategies for prevention, early detection and more efficient and specific treatments in order to accelerate progress and help more patients survive the disease.

One of the features that characterises breast cancer is its heterogeneity, both among patients and within each patient tumor. This heterogeneity is found at molecular, phenotypic and functional levels, complicating diagnosis and challenging approaches to therapy. Currently, huge efforts are dedicated to understanding this heterogeneity at all levels, including at single-cell resolution, which is anticipated to open new possibilities for more efficient and specific anti-cancer therapies.

How has training influenced your career? 

Doing my PhD at EMBL marked the way I envision science, and this vision was reinforced and developed further at UCSF. Science can – and SHOULD – be fun. Later on, funding struggles and the current publishing madness have somehow taken a toll on the fun element, so I just have to remind myself sometimes that science is still exciting!

If you weren’t a scientist, what would you be?

An artist.

You are one of the organisers of the EMBO Practical Course: Techniques for Mammary Gland Research (1 – 6 March 2020). What is the greatest benefit of the course for the scientific community and what could the techniques in this course be used for in the bigger picture?

Some of the techniques practiced at this course are specific for the mammary gland and thus it provides a solid base for researchers starting in this field. In addition, there is a significant emphasis on imaging and comparison of mouse and human studies, the two major systems for looking at normal physiology and cancer research that, when combined, offer great insights into this heterogeneous disease. In addition, having the opportunity to work alongside other trainees contributes to the establishment of a network that may be helpful in the future. Cancer is a very complex problem, and having collaborators with different views and expertise will be very useful in your career.

Interested in this course? Submit your application by 8 December!

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Best Poster Awards – Cancer Genomics

The 4th EMBL Conference: Cancer Genomics (4 – 6 November 2019) brought together over 240 scientists in the field of cancer research to present the latest findings in cancer functional genomics, systems biology, cancer immunogenomics and epigenomics, as well as their translation and clinical impact.

123 posters were presented at the two poster sessions, out of which two were selected as the winners by popular vote. 

Infinite sites violations during tumour evolution reveal local mutational determinants

Jonas Demeulemeester is a postdoctoral researcher at the Francis Crick Insitute in UK. PHOTO: Jonas Demeulemeester

Authors: Jonas Demeulemeester (1), Stefan C. Dentro (2), Moritz Gerstung (2), Peter Van Loo (1)

The infinite sites model of molecular evolution requires that every base in the genome is mutated at most once. It is a cornerstone of (tumour) phylogenetic analysis, and is often implied when calling, phasing and interpreting variants or studying the mutational landscape as a whole. It is unclear however, whether this assumption holds in practice for bulk tumour samples. Here we provide frameworks to model and detect infinite sites violations, identifying 24,459 in total, including 6 candidate biallelic driver events, in 700 bulk tumour samples (26.3%) from the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes project. Violations generally occur at mutational hotspots and their frequency and type can accurately be predicted from the overall mutation spectrum. In melanoma, their local sequence context evidences how not only ETS, but also NFAT-family transcription factor binding creates hotspots for UV-induced cyclobutane pyrimidine dimer formation. In colorectal adenocarcinoma, violations reveal hypermutable special cases of the trinucleotide mutational contexts identified in POLE-mutant tumours. Taken together, we reveal the infinite sites model breaks down at the bulk level for a considerable fraction of tumours. These results warrant a careful evaluation of current pipelines relying on the validity of the infinite sites assumption, especially when scaling up to larger sets of mutations and lineages in the future.

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(1) The Francis Crick Institute, United Kingdom, (2) EMBL-EBI, United Kingdom


The other award-winning poster was:

Understanding the early impact of activating PIK3CA mutation on cellular and genetic heterogeneity presented by Evelyn Lau, UCL Cancer Institute, United Kingdom


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Meet the Trainer – Pavel Baranov

Meet Pavel Baranov, Professor of Biomolecular Informatics at the University College Cork, Ireland. Pavel’s research group focuses on the understanding of how proteins are synthesised and how their synthesis is regulated.

Why did you choose to become a scientist?

When I was a toddler, I wanted to be a firefighter. Within a couple of years, I decided that being an astronaut would be more fun. A few more years passed, and I began to dream of becoming a scientist. I guess at that point I stopped growing and started living my dream.

What is your research focus?

My research group studies RNA translation. Translation is at the core of biology. Cells spend most of their energy on protein synthesis and the ribosome is the most abundant molecular machine in almost all cells. Ribosomal RNAs and tRNAs are the most conserved molecules across all kingdoms of life, and it is now apparent that proteins evolved earlier than DNA. Life as we know it relies on two main type of molecules not found outside of living systems – nucleic acids and proteins. It is the process of translation that connects these two chemistries together. I could hardly think of a more fundamental, interesting and challenging cellular process than translation.

Where do you see this field heading in the future?

As translation brings two chemistries together it is far more complex than other molecular process such as transcription and replication. Because of its complexity and the lack of tools to study it, studying translation is very challenging. The tools are now being developed, e.g. variations of ribosome profiling techniques, real-time single molecule imaging, cryo-EM microscopy, etc. The main change that I foresee is that translation will draw the attention of many more biomedical researchers, for better or worse.

What is your number one tip for people looking for scientific training?

Independent practice is the key in my opinion. After taking a course you may get the impression that you can do something, but it could be a false impression – you don’t really know if you can unless you have done it.

If you weren’t a scientist, what would you be?

Science is not a job for me, it is a dream. If I were not able to make my living as a researcher, I would have to find something else to make earnings, but I would not give up on my scientific interests.

You are organising the EMBO Practical Course ”Measuring Translational Dynamics by Ribosome Profiling” (3 – 9 May 2020). What is the greatest benefit of the course for the scientific community and what could the techniques in this course be used for in the bigger picture?

The invention of ribosome profiling is the most significant development in the field of protein synthesis since the deciphering of the ribosome 3D structure. Ribosomal profiling is a popular technique for measuring the rate of translation in addition to measuring RNA levels, but this was somewhat possible even before. The unique ability of ribosome profiling is the detection of which open reading frames are being translated in RNA. The application of ribosome profiling revealed that even in eukaryotes the same mRNA molecule is often used for making more than one polypeptide, and that our current knowledge of the human genome protein coding repertoire is still far from complete. In addition to detecting translated frames, ribosome profiling could be used to detect ribosome pauses.  We recently learned that such pauses could be used to regulate gene expression and other biological processes.  This course will provide trainees with everything what is needed for mastering this powerful technology, from hands-on experience in generating ribosome profiling data to bioinformatics analysis and the use of public data resources.

Interested in this course? Submit your application by 9 February!

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Generating meaningful images – a report from Seeing is Believing 2019

By event reporters Liz Haynes @actin_crazy and Stephan Daetwyler @Daetwyler_St

Seeing is Believing event reporters Liz Haynes & Stephan Daetwyler, PHOTO: Liz Haynes/Stephan Daetwyler

The field of biology owes some of its most compelling discoveries to careful visual observation. From Van Leeuwenhoek’s use of new microscopes to describe microscopic “animalcules” in the late 1600s, to Ramon y Cajal’s pioneering 19th century work illustrating beautiful and complex neuronal architecture. Images inspire us, help us generate new hypotheses, and shed light into the tiny worlds yet unexplored. Indeed, these observations uniquely help us understand the structures and dynamics of life, something that would not be achievable with approaches like biochemistry alone.

The images are only as valuable as the amount of information that we can deduce from it.

Generating meaningful images, however, is not an easy task. There have always been limits to what we can observe, due to the properties of the sample or the techniques that we can apply to it. These are the boundaries that microscopists seek to push. A successful imaging experiment requires an amenable sample, a contrast agent to reveal the structures of interest, and a microscope that is capable of capturing an image at a relevant scale. Moreover, the images are only as valuable as the amount of information that we can deduce from it. Therefore, image storage, accessibility and analysis are crucial. Each one of these steps offers opportunities for optimisation and new technologies.

Co-organiser Jan Ellenberg opens the Seeing is Believing symposium, PHOTO: Liz Haynes & Stephan Daetwyler

The EMBO | EMBL Symposium “Seeing is Believing: Imaging the Molecular Processes of Life” (9-12 October 2019) presented us with exciting new developments in all of these fields, coupled with a drive to make new progress available as quickly as possible to the community through preprints, open-source initiatives, and resource sharing.

Advances in sample preparation

At the heart of every imaging approach is the sample. Even the best microscope is ineffective with dim or improperly prepared samples. At Seeing is Believing, we saw an emphasis on using expansion of samples to help overcome the resolution limits of microscopy and solve some traditionally difficult problems. In particular, we were impressed with expansion-based approaches to study centriole structure (Paul Guichard, Ultrastructural Expansion Microscopy) and resolve microtubules tightly packed within axons (Lukas C. Kapitein). By far, the biggest emphasis in sample improvement was on the development of new fluorescent probes and biosensors. Kai Johnsson presented design strategies for the improvement of live cell dyes, and introduced new MaP dyes that are SNAP and HALO compatible, and importantly require no wash to clear unbound probe. Periklis Pantazis presented a mechanosensor based on the Piezo1 stretch activated ion channel, allowing users to visualise mechanical stress within a live cell. Atsushi Miyawaki wowed the audience by meeting the challenge to “be better than a firefly” with a new variant of luciferase named AkaBLI, which his lab generated through targeted evolution. This improved luciferase allowed them to visualise neuronal activity within freely behaving mice and marmosets.

Advances in microscopy

New imaging methods on show at Seeing is Believing, PHOTO: EMBL Events

The features of our microscopes directly determine which questions we can address. Seeing is Believing highlighted exciting new development in building cutting-edge microscopy tools. Reto Fiolka presented a novel single-objective light-sheet microscope enabling imaging of live cells in microfluidics devices or 3D environments with 200 nm lateral resolution. Kevin Dean complemented novel light-sheet development by presenting an axially swept light-sheet microscope ideally suited for all clearing techniques that provides an unprecedented field of view enabling whole tissue imaging with sub-micron resolution. With her imaging approach, Alexandra Pacureanu surprised the audience with how X-ray holographic nano-tomography is capable of resolving the fine, dense and complex neuronal circuitry in large tissues or even organism providing a new route to understand how the nervous system processes information.

Nobel Prize winner Stefan Hell spoke on how to attain 1 nm resolution with super-resolution microscopy, PHOTO: Liz Haynes & Stephan Daetwyler

Further impressive advances were presented in fast volumetric imaging (Lars Hufnagel, light field imaging) and high-resolution imaging, e.g. MINFLUX by Stefan Hell, correlative EM imaging by Harald Hess and Lucy Collinson, GI-SIM/LLS-SIM by Dong Li, and 3D-STED deep in a tissue by Joerg Bewersdorf.

Advances in data analysis

All acquired data is meaningless if we cannot extract information from it. At Seeing is Believing, it became obvious how artificial neuronal networks have become important for image analysis. Applications range from segmentation to denoising an image (BGnet, W.E. Moerner and Noise2Void, A. Krull/Florian Jug). Particularly, the convolutional network architecture U-Net has become an important tool. To provide a user-friendly environment to apply those state-of-the art image analysis tools, Anna Kreshuk presented the iLastik platform as an easy to use tool. A new fundamental approach to handle, visualise and process the large amount of data coming from the microscopes was presented by Ivo Sbalzarini. Instead of using pixels to save an image, adaptive particles approximate the image content. Furthermore, Gaudenz Danuser gave a thought-provoking talk on how current perturbation-based approaches in cell biology can mislead us in our analysis. Danuser emphasised that the observed phenotype from a perturbation of a system (e.g. loss of a protein’s function) is not equal to the real function of the gene. For example, cutting a wire from the battery to the electronic board of radio would lead to the “phenotype” loss of sound. However, the function of the wire was simply to provide power to the radio, not to produce sound! As a better perturbation-free alternative, Danuser introduced a concept used in econometrics known as Granger causality.

Advances in biology

All of these new developments culminated in impressive new insights into biological processes. There were many talks on mitochondria and endoplasmic reticulum dynamics revealed by novel live-cell super-resolution techniques. Suliana Manley gave one of the most intriguing of those talks, on modes of asymmetric and symmetric mitochondrial division.

Co-organiser Jennifer Lippincott-Schwartz presents how RNA moves around the cell and is translated at different locations, PHOTO: Liz Haynes & Stephan Daetwyler

Jennifer Lippincott-Schwartz also gave a stunning presentation on how RNA granules can hitch a ride through an ANXA-11 mediated connection to lysosomes, and how ALS associated mutations in ANXA-11 break this connection. Furthermore, an intriguing new mRNA reading frame sensor (Moon and Sun tags) was presented by Sanne Boersma of the Tanenbaum lab to understand stochasticity of mRNA translation.

To conclude, the field of microscopy has grown so much that some may feel we have solved all the theoretical problems, and only engineering challenges are left – hardware improvements, new materials, new engineering solutions. At the closing dinner of the conference, however, Atsushi Miyawaki from RIKEN beautifully summarised how he felt about the future of microscopy, and of Seeing is Believing. Standing in the banquet hall of the Heidelberg Castle, he told us that castles in Japan remain unfinished. This state of incompletion is not due to any fault of the architects, but a feature of beauty, as it was believed that things that were incomplete had room to grow, and that growth is valuable. No matter how high our achievements are in the field of microscopy and image analysis, there will always be unforeseen avenues of growth. Attending Seeing is Believing has hopefully prepared us to follow those avenues, and to share what we find so we may all grow together.

For a more comprehensive summary of all talks presented at Seeing is Believing, and to get links to preprints, publications, and resources, visit our blog at https://seeingbelievingweb.wordpress.com/

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