Multiomics to Mechanisms Symposium – Best Poster Awards

The recent EMBO|EMBL Symposium: Multiomics to Mechanisms – Challenges in Data Integration (11-13 Sep 2019) addressed ways of integrating large-scale biological data across the different omics fields.

258 researchers from various fields gathered in Heidelberg last week to listen to 36 talks and engage with 146 poster presenters. Here we present the posters of 5 scientists who received best poster awards at the conference by popular vote.

Benchmarking of multi-omics joint  dimensionality reduction (DR) approaches for cancer study

Laura Cantini is a CNRS Research Scientist at IBENS in France.

Authors: Laura Cantini (1), Pooya Zakeri (2), Aurelien Naldi (1), Denis Thieffry (1), Elisabeth Remy (3), Anaïs Baudot (2)

Dimensionality Reduction (DR), decomposing data into low-dimensional spaces while preserving most of their information content, is among the most prevalent machine learning techniques in data mining. With the advent of high-throughput technologies, high-dimensional data have become a standard in biology, emphasizing the use of DR. This phenomenon is particularly pronounced in cancer biology, where consortia have profiled thousands of patients for multiple molecular assays (“multi-omics”), including at the emerging single-cell scale. DR approaches have been mainly applied to single omics data leading to cancer subtyping, tumor sub-clones quantification and immune infiltration quantification. Recently, DR approaches designed to jointly analyze multiple omics have been proposed. Integrative DR methods are based on various mathematical assumptions, ranging from extensions of CCA, tensors, or more general data fusion approaches, which makes difficult to chose which method to apply.
In this context, we here in-depth benchmark multi-omics DR approaches using: i) artificial multi-omics cancer data ii) multi-omics bulk data from 10 different cancer types downloaded from TCGA iii) multi-omics single-cell data from cancer cell lines In (i), the capability of the various methods to predict the clustering ground truth was found strongly sensible to the size of the clusters, with intNMF, RGCCA, MCIA and JIVE being the more robust methods. For (ii), MCIA, RGCCA, MOFA and JIVE more consistently identified factors associated to survival, clinical annotations and biological annotations. Finally in (iii), despite never being applied to single-cell data, tICA and MSFA outperformed other methods for their ability to cluster  single cells based on their cell line of origin. Overall, our results show that RGCCA, MCIA and JIVE perform consistently better across the three scenarios. This suggests that a mathematical formulation, based on the search of omic-specific factors whose inter-dependence is maximized, better approximates the nature of multi-omics data.

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(1) Institut de Biologie de l’Ecole Normale Superieure IBENS, France, (2) Aix Marseille University, INSERM, MMG, CNRS, France, (3) Aix Marseille University, CNRS, France

Single-cell transcriptome and chromatin accessibility data integration reveals cell specific signatures

Andrés Felipe is a PhD student at the German Cancer Research Center in Heidelberg, Germany.

Authors: Andres Quintero (1), Anne-Claire Kröger (2), Carl Herrmann (2)

The ability to integrate multiple layers of omics data will play an essential role in understanding the complex interplay of different molecular mechanisms that give rise to cellular diversity. In particular, single-cell multi-omics studies provide an enormously valuable source of information, allowing the characterization of different cell states under different biological contexts. However, the integration of distinct cellular modalities to disentangle the regulatory networks and pathways that explain cell identity is still a challenge.Here we introduce Integrative Iterative Non-negative Matrix Factorization (i2NMF), a computational method to dissect cell type associated signatures from multi-omics data sets. i2NMF takes full advantage of data sets with multiple modalities for the same sample or cell, defining cell type-specific features and discerning the shared and specific contribution of each omics type to the identification of different cell types. We applied i2NMF to an early human embryo single-cell multi-omics data set for which scRNA-seq and scATAC-seq profiles were available for every single cell, identifying master transcription factors at the morula and blastocyst stages. Finally, i2NMF is also able to integrate different modalities across multiple experiments. We used this functionality to extract cell-type specific molecular signatures from two complementary datasets of the mouse visual cortex, comprising scATAC-seq and scRNA-seq data. i2NMF was implemented on TensorFlow, presenting a scalable framework and allowing its efficient execution under multiple systems. Our results demonstrate that i2NMF is a useful tool to identify cell-type specific signatures and dissect their underlying molecular features.

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(1) German Cancer Research Center (DKFZ), Germany, (2) University Hospital Heidelberg, Germany

Linking signalling and metabolomic footprints with causal networks

Aurélien Dugourd is a PhD student in mechanistic modelling at JRC Combine, RWTH Aachen, Germany.

Aurélien Dugourd (1), Christoph Kuppe (1), Rafael Kramann (1), Julio Saez-Rodriguez (2)

Renal clear cell carcinomas (RCCC) are the result of a system-wide dysregulation of signaling and metabolic functions  originating from multiple factors. Characterizing cellular molecular machineries across multiple omic layers is a very powerful strategy to understand the cellular effects of such dysregulations. In this study, we performed metabolomics and phosphoproteomics from RCCC tissue in comparison to the non-cancerous kidney tissue in a cohort of 20 patients. In order to extract mechanistic information from these observations and to integrate both datasets, we developed a novel analysis pipeline. Phosphoproteomic abundance changes are used to estimate kinase activity changes across patients. Kinase activity estimations are then correlated with metabolite abundance changes. This points at possible interactions between signaling pathways and metabolism. We subsequently build a generic network integrating signaling pathways and metabolic reaction networks based on literature knowledge and databases. We use this signaling/metabolic network to identify paths across kinases and metabolic enzymes to link the correlated kinase activities and metabolites.
This provides potential mechanisms to explain the effect of deregulation of signaling on metabolism. Our approach was able to recover the structure canonical signaling pathway topologies and highlight specific connections between kinases and metabolite abundance deregulated in kidney tumor tissues. This pipeline allows to extract and compare mechanistic
information from metabolomic, phosphoproteomic (and potentially transcriptomic) data across many kidney cancer patients. This information can be used to select potential therapeutic targets to disrupt cancer specific cellular mechanisms, such as the SP1 kinase. Furthermore, the pipeline offers the advantage of being easily transferable in many different biological contexts.

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(1) RWTH Uniklinikum Aachen, Germany, (2) Heidelberg University, Germany

A network-based approach for the identification of multi-omics modules associated with complex human diseases

Maria Anna Wörheide is a PhD student at the Helmholtz Zentrum München in Germany.

Authors: Maria Anna Wörheide (1), Jan Krumsiek (2), Gabi Kastenmüller (1), Matthias Arnold (1)

Application of advanced high-throughput omics technologies have provided us with vast amounts of quantitative, highly valuable data. For complex, heterogeneous, and untreatable diseases such as Alzheimer’s disease (AD), the integration of different omics levels and their interconnections is desperately needed to understand the underlying molecular pathomechanisms and identify potential therapeutic targets. However, integrated, multivariable analyses of cross-omics data are not straightforward, and even if successfully applied, often lack a human comprehensible representation. Graph databases provide an intuitive and mathematically well defined framework to store and interconnect diverse biological domains in accessible network structures. Here, we propose a network-based, multi-omics framework
developed with the graph database Neo4j, that allows the large-scale integration and analysis of data on biological entities across omics, as well as results from association analysis with specific (endo) phenotypes. The backbone of this framework comes from known biological relationships and functional/pathway annotations available in public databases. It is augmented with experimental, quantitative data for single omics (e.g. tissue-specific gene expression) and across omics (e.g. eQTLs or mQTLs) derived in population-based studies. To identify modules within this network that are potentially relevant to a disease such as AD, we extend the
framework using large-scale association data for AD (e.g. from case-control GWASs). The resulting network is comprised of over 50 million nodes (entities), representing more than 30 different data types, and more than 80 million edges (relationships). We mined this comprehensive catalogue of biological information using established graph algorithms to
identify potentially disease-related modules of tightly interlinked entities, and were able to obtain several subnetworks significantly enriched for AD-associations.

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(1) Helmholtz Zentrum München, Germany, (2) Weill Cornell Medicine, United States of America

Mechanistic insights into transcription factor cooperativity and its impact on protein-phenotype interactions

Ignacio Ibarra is a PhD student in Judith Zaugg’s lab at EMBL Heidelberg, Germany.

Authors: Ignacio Ibarra, Nele Hollmann, Bernd Klaus, Sandra Augsten, Britta Velten, Janosch Hennig, Judith Zaugg (EMBL Heidelberg)

Recent high-throughput transcription factor (TF) binding assays revealed that TF cooperativity
is a widespread phenomenon. However, we still miss global mechanistic and functional understanding of TF cooperativity. To close this gap we introduce a statistical learning framework that provides structural insight into TF cooperativity and its functional consequences based on next generation sequencing data. We identify DNA shape as driver for cooperativity, with a particularly strong effect for Forkhead-Ets pairs. Follow-up experiments revealed a local shape preference at the Ets-DNA-Forkhead interface and a decreased cooperativity once the interaction is lost. Additionally, we discovered many novel functional associations for cooperatively bound TFs. Examining the novel link between FOXO1:ETV6 and lymphomas revealed that their joint expression levels improve patient survival stratification.
Altogether, our results demonstrate that inter-family cooperative TF binding is driven by position-specific DNA readout mechanisms, which provides an additional regulatory layer for downstream biological functions.

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Working on your own conference poster? Then check out 10 tips to create a scientific poster people want to stop by .

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14 tips for a smooth conference experience

The date of your first EMBL conference in Heidelberg is fast approaching. You are excited, have already bookmarked interesting abstracts in the conference app and are ready to make your travel arrangements. Here are 14 tips that will help you stay out of trouble and focus on the science.

1. Don’t try to book a flight to Heidelberg

Although it is one of the most popular tourist destinations in Germany, Heidelberg does not have an airport. The closest airports are Frankfurt International Airport, Stuttgart Airport and Airport Karlsruhe/Baden-Baden. More information on how to reach Heidelberg is available here.

2. Make sure you read the final logistical email (FLE) we send you

The information provided in this email is vital for your travel plans and conference schedule and will be your bible for the days you spend at the conference. It provides important attachments such as the programme, the onsite handout and the poster listing.

3. Try not to miss the shuttle bus

The EMBL campus is located on a hill outside of Heidelberg which makes it a beautiful and inspiring place to visit, away from the hustle and bustle of downtown Heidelberg. However, it also makes it more difficult to reach by public transport. Although efforts have been made to improve the public transport connection to the campus, there is still the need of conference shuttle busses that operate on a strict schedule (included in the FLE). So if you miss the shuttle bus, your only way up the hill may be by taxi. Please note that there are no UBER services in Heidelberg.

Our team has prepared an onsite handout with pictures of all bus stops so that you don’t miss the bus because you don’t know where the correct stop is. This information is provided in the FLE.

4. Get the app instead of the abstract book

When you register online, you will be asked if you would like to receive a printed copy of the abstract book. If you click yes, you will get your copy onsite, but make sure that you don’t lose it as this is the only copy you will get. Many participants diligently take notes in the abstract book during the sessions, only to go home one day realising they have lost their copy.

One way to avoid that is by using the app instead. It includes everything contained in the printed abstract book and more, and it also allows you to review the abstracts ahead of the conference and offers the option to export your notes directly to your email.

5. Share your dietary requirements

The EMBL canteen makes a special effort to cater to everyone’s needs by providing fresh food every day and appropriate substitutes for participants on vegetarian, vegan, lactose-free or gluten-free diets. In our registration system you have the option to indicate your preferences, but should you have special requirements based on food allergies or intolerances, please do not hesitate to reach out to us, so we can ensure you are well fed.

6. Send your flash talk slides well in advance

If you are presenting a flash talk, make sure to send us your slides well in advance to make sure they are looped on the screen in time. You will have only 2 minutes to present your poster in the flash talk, so you don’t want to waste any second with technical difficulties.

For some more tips on how to give a flash talk, watch this video.

7. Avoid asking for a certificate of participation during the registration

As much as we’d like to help you out, registration is not the best time to ask for a certificate of participation. These are normally sent out after the end of the event via email.

8. Hold on to your badge

Your badge is your access card to the conference venue and your coupon for the lunch and dinner buffets, so make sure you don’t lose it or leave it in your hotel room.

9. No cash policy on the EMBL Campus

If you arrive on campus outside of the conference times and you would like to get something to eat or drink, it might not be possible. EMBL has a no cash policy on its campus and the only way to purchase something from the cafeteria or canteen is via a special guest credit card. Therefore, it would be a good idea to grab something to eat on your way to the campus, especially for breakfast as we normally only have coffee available in the mornings.

10. Do not ask us for medicine

As much as we would like to help you with your headache or cold symptoms, we are not authorised to hand out any medicine. However, we have a list of pharmacies that are close to the conference venue which we are happy to share with you.

11. When you sign up for a social event, show up!

Most conference social events like dinners, lunches, parties take place in the EMBL Advanced Training Centre (ATC) and are open to all conference participants without prior registration. In the case that there are organised social events taking place outside of the conference venue such as tours or downtown dinners, these are usually restricted to a limited number of participants, and prior registration is necessary.

All the logistics are meticulously coordinated with the service providers and very often there are waiting lists for these events, so if you are unable to attend, please inform us, so that we can give your spot to someone who can.

12. Stay on the paths in the woods

The EMBL Heidelberg Campus is surrounded by a beautiful forest which offers a great opportunity for lunch-time walks or runs. However, before you set on exploring the woods, please familiarise yourself with the paths so that you easily find your way back. In the app you will find 4 different walking routes of various lengths.

13. Take down your poster on the last day

You have put in so much work in your poster that it is a shame to leave it with us. Make sure you take it down on the last day of the event as you may end up needing it for another conference.

14. Stay away from red push buttons on the emergency exit doors

Not all exit doors in the ATC Foyer may be opened. Look out for a silver button with a key on it to open the door without activating the emergency exit alarm.

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Meet the Trainer – Imre Gaspar

Meet Dr. Imre Gaspar, Senior Research Assistant in the Kikuë Tachibana Group at the Institute of Molecular Biotechnology in Vienna, Austria, which focuses on understanding how chromatin is spatially reorganised in totipotent cells.

What is your research focus and why did you choose to become a scientist?

I’m interested in the central dogma, that is how gene expression is regulated on the transcriptional and post-transcriptional levels and how these regulations allow development of an organism.

I became a scientist because I always fancied solving riddles – and as a scientist you get to work on solving the ultimate riddle that interests us, humans.

Where do you see this field heading in the future?

Right now, there is a boom of high-throughput and omics techniques in studying gene expression allowing us to create predictive quantitative models of regulatory networks, which will allow us to get mechanistic understanding of the processes underlying development, homeostasis and pathogenesis. Microscopy analysis is already essential for the latter and is also gaining importance also in the omics studies with the advent of high-throughput hybridisation techniques.

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

Being a microscopist, it was absolutely essential for my career to receive training in state-of-the-art imaging and image analysis technologies. Courses are important, of course, but I find that the best source of training a scientist can receive is core facilities, internal trainings, and of course close colleagues in the lab.

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

I have a degree in medicine, so I probably would have become a medical software developer – that profession is closest to the work of a scientist and having a background in medicine would allow me to contribute to the development of medical instrumentation.

You are organising the EMBO Practical Course ”FISHing for RNAs: Classical to Single Molecule Approaches” (15 – 20 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?

We are at the onset of quantitative analysis in biology: many labs have already implemented corresponding work-flows, but this principle should be spread widely, especially in the fields working on the understanding of gene expression. I expect that the single molecule techniques we will cover during the course will serve as mind-changers to help people embrace the concept of quantitative biology.

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Best Poster Awards – EMBO|EMBL Symposium: New Approaches and Concepts in Microbiology

It’s a well known fact that EMBL conferences present the most top-class science from around the world, not only from established researchers but also up-and-coming scientists. In this brand new series we will feature some of the award-winning posters from recent EMBL conferences and symposia. 

We begin with 4 of the poster prize winners at the EMBO|EMBL Symposium: New Approaches and Concepts in Microbiology (10-13 July 2019). 

De novo selection of peptides that confer antibiotic resistance

Michael Knopp is currently a PostDoc at the University of Uppsala and will join the Typas group at EMBL Heidelberg in October 2019.

Authors: Michael Knopp (1), Jonina Gudmundsdottir (1), Tobias Nilsson (2), Finja König (2), Omar Warsi (1), Fredrika Rajer (1), Pia Ädelroth (2), Dan Andersson (1)

The origin of novel genes and proteins is a fundamental question in evolutionary biology. New genes can originate from different mechanisms including horizontal gene transfer, duplication-divergence and de novo from non-coding DNA sequences. Comparative genomics has generated strong evidence for de novo emergence of genes in various organisms but experimental demonstration of this process has been limited to localized randomization in pre-existing structural scaffolds. This is bypassing the basic requirement of de novo gene emergence, i.e. lack of an ancestral gene. We constructed highly diverse plasmid libraries encoding randomly generated open reading frames and expressed them in Escherichia coli to identify peptides that could confer a beneficial and selectable phenotype in vivo. Selections on antibiotic-containing agar plates resulted in the identification of three inserts that increased aminoglycoside resistance up to 48-fold. Combining genetic and functional analyses, we show that the peptides are highly hydrophobic and that they insert into the membrane, reduce membrane potential, decrease aminoglycoside uptake and thereby confer high-level resistance. This study demonstrates that randomized DNA sequences can encode peptides that confer selective benefits, and illustrates how expression of random sequences could spark the origination of new genes.

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(1) Uppsala University, Sweden;  (2) Stockholm University, Sweden

Combinatoria genetics approach to prevent and disrupt biofilm-associated infection

Irina Afonina is a postdoctoral associate at the Singapore-MIT Alliance for Research and Technology (SMART).

Authors: Irina Afonina (1), Kimberly Kline (2), Timothy Lu (3)

Enterococci are opportunistic bacterial pathogens that cause a variety of infections including life-threatening endocarditis, chronic wounds, medical device and urinary tract infections. All of these infections are biofilm-associated, which are intrinsically more tolerant to antimicrobial clearance, and which therefore pose a major challenge in treating these infections. Biofilm formation is multifactorial, requiring multiple factors, which can vary depending on the environment or niche where the bacteria reside. Therefore, to understand the complexity of interactions and factors that contribute to enterococcal biofilms, we are combining CRISPRi technology with rapid DNA assembly to identify gene pairs involved in biofilm formation in different infection niches. We established a dual-vector inducible CRISPRi system for Enterococcus faecalis that targets planktonic and biofilm cells with efficiency resembling that of a gene knock out. We have shown that CRISPRi targeting of constitutively expressed gfp gene on the bacterial chromosome, fully quenches GFP signal within planktonic, early and late biofilm cells. Additionally, we have shown that silencing of the croR gene, required for bacitracin resistance, mimics a croR in-frame deletion phenotype, and both CRISPRi croR and croR show reduced minimal inhibitory concentration to bacitracin compared to uninduced or wild type strains. We are creating combinatorial libraries to identify pairs and quartets of genes of all of the two-component signal transduction systems encoded in E. faecalis, to address the hypothesis that different signals will drive unique biofilm programs in different environmental conditions. This research serves as a platform to rapidly identify combinations of genes involved in enterococcal pathogenesis, including antimicrobial resistance, virulence, and immune invasion.

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(1) SMART, Singapore; (2) Nanyang Technological University, Singapore; (3) Massachusetts Institute of Technology, USA

A conserved RNA seed-pairing domain directs small RNA-mediated stress resistance in enterobacteria

Nikolai Peschek is a PhD student in Prof. Dr. Kai Papenfort’s lab in the Department of Biology at the Ludwig-Maximilians-University of Munich, Germany.

Authors: Nikolai Peschek (1), Mona Hoyos (1), Roman Herzog (1), Konrad U. Förstner (2), Kai Papenfort (1)

Small regulatory RNAs (sRNAs) are crucial components of many stress response systems. The envelope stress response (ESR) of Gram-negative bacteria is a paradigm for sRNA-mediated stress management and involves, among other factors, the alternative sigma factor E (σE) and one or more sRNAs. In this study, we identified the MicV sRNA as a new member of the σE regulon in Vibrio cholerae. We show that MicV acts redundantly with another sRNA, VrrA, and that both sRNAs share a conserved seed-pairing domain to regulate multiple target mRNAs. V. cholerae lacking σE displayed increased sensitivity towards antimicrobial substances and overexpression of either of the sRNAs suppressed this phenotype. Laboratory selection experiments using a library of synthetic sRNA regulators revealed that the seed-pairing domain of σE-dependent sRNAs is strongly enriched under membrane-damaging conditions and that repression of OmpA is key for sRNA-mediated stress relief. Together, our work shows that MicV and VrrA act as global regulators in the ESR of V. cholerae and provides evidence that bacterial sRNAs can be functionally annotated by their seed-pairing sequences.

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Peschek, N. et al. A conserved RNA seed‐pairing domain directs small RNA‐mediated stress resistance in enterobacteria. The EMBO Journal (2019) DOI:10.15252/embj.2019101650

(1) Ludwig-Maximilians-Universität München, Germany;  (2) TH Köln, ZB MED, Germany

The interaction between replication factor DiaA and primary metabolite sedoheptulose-7- phosphate directly regulates DNA replication in Escherichia coli

Joanna Morcinek-Orłowska is a PhD Student at the University of Gdańsk, Poland.

Authors: Joanna Morcinek-Orlowska (1), Aleksandra Bebel (1), Justyna Galinska (1), Torsten Wladminghaus (2), Anna Zawilak-Pawlik (3), Monika Glinkowska (1)

To proliferate, bacterial cells duplicate their genomes and this process is coordinated with cell growth and division. During the last few decades, various biochemical mechanisms controlling initiation of DNA replication in the model bacterium Escherichia coli have been characterized in detail. However, it remains elusive what constitutes a signal for the growing cell to initiate the next round of chromosomal DNA replication. Here we present evidence that a primary metabolite sedoheptulose 7-phosphate (S7P) binds to a replication factor DiaA and regulates its activity in promoting oligomerization of the DnaA initiator protein. Furthermore, our results show that the cellular level of S7P and the ability of DiaA to interact with the metabolite both influence DNA replication in vivo. S7P is an intermediate in the pentose phosphate pathway, providing building blocks for synthesis of nucleotides and a starting point for production of the outer membrane components. Consequently, we propose a mechanism which links DNA replication with cell growth through primary metabolism.

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(1) University of Gdansk, Poland;  (2) LOEWE Center for Synthetic Microbiology-SYNMIKRO, Philipps-Universität Marburg, Germany; (3) Polish Academy of Sciences, Poland

Working on your own conference poster? Then check out 10 tips to create a scientific poster people want to stop by .

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Meet the Trainer – Anna Kreshuk

PHOTO: EMBL/Marietta Schupp

Meet Dr. Anna Kreshuk, a group leader in the EMBL Cell Biology and Biophysics unit, whose group uses machine learning to develop automated methods to help biologists speed up image analysis. Anna joined EMBL in 2018 and has since been very active in building up training opportunities in her research field.

What is your research focus and why did you choose to become a scientist?

My research is concerned with developing new machine learning-based methods of the analysis of biological images. I enjoy doing science, both for the thrill of finding new things and the joy of seeing others do that in their domain with the help of our tools.

Where do you see this field heading in the future?

I hope to see most of the routine image analysis automated in the future. This will hopefully raise new research questions in biology which can only be answered by imaging at scale, creating, in its turn, more exciting research questions for us.

How has training influenced your career?

We develop software for end users without computational expertise, who want to solve biological problems we don’t quite understand. Participating in training has provided a lot of insight to the user side of things, brought new collaborations and even new research directions for me and for my group.

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

A one-week course can be a great start, however, it’s important to find out how you can get support with the new technology in your everyday work. Try to stay in contact with your course buddies, but also look for online communities. For image analysis, for example, there is a great forum connecting all the popular tools.

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

My 7-year-old recently asked: “you say I can become anything I want to be, but then why didn’t you become an astronaut?”. Seriously though, I’d probably be a programmer, I love automating things.

You are organising the EMBL Course: Deep Learning for Image Analysis (20 – 24 January 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?

Deep learning has brought an enormous advance in computer vision. We can now analyse microscopy images in ways no one thought possible just 10 years ago. While the technology is getting more accessible every year, it’s still difficult even for computationally savvy biologists to apply state-of-the-art methods to their image analysis problems. This is exactly the gap we intend to close.

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