Looking back on a year of organising virtual events

Exactly one year ago, the Covid-19 pandemic hit Europe. All on-site events had to be cancelled and we had to rethink our entire program. Our Course and Conference Officers worked really hard to create a virtual equivalent of EMBL’s on-site training offering.  We successfully launched our first virtual conference and many more followed. 

The learning curve was steep and so was the stress level. But when the going gets tough, the tough get going. Two of our Conference Officers, Nathalie and Diah, share with us their experience from being in the eye of the storm, the lessons they have learned and some tips for organising a virtual meeting.

Conference Officers Nathalie and Diah
Conference Officers Nathalie (left) and Diah

How does organising a virtual event compare to organising an on-site event?

Diah: “It is a different world, but equally fun! Organising a virtual event is harder than people think and often more challenging. Not getting to see anyone in person and mastering all sorts of virtual platforms can be quite tough.”

Nathalie: “Some of the milestones we have are the same, for example: preparing the website, programme, opening registration, emails with participants and invited speakers, abstract review and selection… But a huge bulk of the work is totally different: instead of booking buses and ordering catering, we are setting up Zoom webinars and populating the virtual platform.

The massive change has been adapting to the new tasks we have to do and how we should do them consistently for all our events. In our team we have numerous working groups looking at areas of event organisation and creating guidelines, procedures and templates that will help us all. It really is a whole team effort!”

Read: Why do we charge fees for virtual events?

What kind of feedback do you get from participants, speakers and organisers?

Nathalie: “The feedback I have received from speakers and participants has been great: they are so happy we converted our event to virtual instead of cancelling/postponing it. Initially a few speakers were disappointed for the event to turn virtual but the same people commented afterwards that they were impressed with how well it went. What is wonderful is that it is still so beneficial for them in their continued research.”

Diah: “Very humbling! Many agree that onsite face-to-face events are somehow irreplaceable but at the same time they are amazed at the number of benefits virtual events offer too! They give you more flexibility: you don’t have to travel across the world. Also, some people feel more comfortable asking questions in the virtual format. ”

What is the most important lesson you have learned about organising virtual events?

Nathalie: “It’s been necessary for us to turn to virtual events but the lessons we have learned are that virtual events are effective, valuable and have many advantages! We’ve noticed that participants feel more comfortable asking questions during Q&A, that virtual talks have had a wonderful response, that virtual networking works well and you can meet different people from all over the world just at your desk!

On a bigger scale, virtual events mean less travel and a lower carbon footprint and they are more inclusive as they allow some people to participate who couldn’t have done so before. This is hugely important and is a very positive outcome of this difficult situation and it will have an impact on how events are organised in the future.”

What do you miss most about on-site events?

Diah: “The buzz when everyone arrives and the ATC is full of people is very exciting – after all the planning, everyone is there! And my favourite moment is the end of the conference: everyone is smiling and happy and you wave goodbye to the buses that leave EMBL. That sense of relief and accomplishment at the same time. I miss that!”

Nathalie: “Parties! One of the best things about the onsite events is meeting the speakers and participants you’ve been in touch with for months and when it comes to the conference party, it is really fun to see everyone let their hair down and enjoy themselves! And taking silly pictures at the Photobooth with people is something I loved and a really cute memento of the conference. That is a small thing I miss too!”

What in your opinion makes virtual events better than on-site events?

Nathalie: “The inclusiveness: more participants can take part as there is not the same financial barrier (travel, accommodation) and people can join from anywhere in the world.”

Diah: “Virtual events are resilient. There is no need to cancel an event because of the weather or a disaster. Participants can attend the event from anywhere!”

Conference Officer Diah wearing a face mask in an empty auditorium during a virtual event
Conference Officer Diah working a shift in an empty Auditorium

A common criticism is that networking doesn’t work well in the virtual world. What is your experience with virtual social events?

Nathalie: “I think it is great to see how Zoom breakout rooms allow people to mix in small groups or 1-to-1. Particularly the speed networking translates very well.”

Diah: “It’s my favorite part of the programme and I am amazed at how well it has been accepted and running so far. We have had live-streamed concerts and participants love it. At one conference some of the scientific organisers even stayed for the whole duration of the social session and wanted to continue mingling even after it had finished.”

Read our blog on virtual speednetworking.

Top tips to keep in mind while organising a virtual event?

Nathalie: “First of all – be open-minded. There are so many new technologies out there and different things you can try!

Have clear guidelines and templates: you use so many different apps and systems that saving time when setting things up can be a lifesaver!”

Diah: “I would also say: Test, test and test. Glitches are always likely to happen, so be prepared and stay calm.”

Read our blog for more tips on how to organise a virtual event

How do you see the future of EMBL Events?

Nathalie: “I hope we will embrace this new world of virtual events and have effective hybrid events in the future: allowing for face-to-face interaction for those who want to come on-site, but also giving the opportunity for those who prefer to join virtually and get the benefit of being part of the event without having to leave their home!”

Diah: “I think hybrid events will take a central place in the format of EMBL Events in the future. But whatever the format will be, we will keep improving and finding the best way to support the scientific community.”

Looking back in general, what are your thoughts?

Diah and Nathalie: “It has been very rewarding during the last year to see how we at EMBL have been able to adapt to the situation we have found ourselves in and been able to ensure that we can still provide a platform for scientific exchange. The aim of EICAT is to provide excellent training to scientists, and, despite the challenges, this is being achieved virtually for the first time! We are really proud of being able to provide opportunities for this exchange of knowledge and research.

Personally, this time has also been one of continuous learning for all of us on the team. We have developed our skills and experience in a number of ways and massively increased our knowledge of online platforms and tools! It has truly been a time of teamwork as we have adapted into the virtual event world and we are grateful to everyone involved: our marketing team, our Photolab technicians, designers and scientific organisers. It has been a challenging but very valuable learning experience!”

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Meet the EMBL Events Team: Jane

PHOTO: Jane Reynolds

Today’s interview is with EMBL-EBI’s Jane Reynolds. Jane is one of the event organisers in the team, and joined in December 2020. Jane’s focus is on the on-site and virtual training courses.

At EMBL since: December 2020
Number of organised courses: 1

 Favourite place in Hinxton area? Having joined EMBL-EBI just before Christmas, I haven’t been able to explore Hinxton yet. I did enjoy a virtual tour of the conference centre though, which gave me an insight of where the course dinners take place.

What is the first thing you do before a course starts and the first thing you do after a course finishes? Before an event starts, I remind myself of the hard work and preparation that’s already been done and that the best thing I can do from here on in is be present and ready to deal with anything that might arise. After an event finished? Well, it sounds a bit dull but I usually make a quick list of things that could be improved (as well as those that went really well). Particularly working in new formats, it’s often only by running an event that you notice the small changes that can be made to improve the experiences of delegates or speakers. I like to capture these while they are fresh in my mind.

What are the challenges/differences of organising a virtual course? One of the major changes has been how big chunks of work have shifted closer to the start date of an event; for example, delegates tend to sign up later to online events than in-person events, even if they are advertised for the same length of time as usual, so the timeframe for dealing with the administration related to this is shorter.  The work definitely has a different rhythm to it and the tools and systems have changed but the reason we’re doing it is the same.  Remembering this has helped me to adapt.  Although I have to say I am really looking forward to meeting delegates (and my new colleagues!) in person when the time comes.

You’ve been working from home since you started your role at EMBL-EBI; how has this been for you? As well as working from home, I’ve been lucky enough to start a new role in the past year, and it’s been an interesting (hopefully once-in-a-lifetime!) experience.  Luckily the Training Team at EMBL-EBI have been wonderful in sharing their knowledge with me and given me a very warm virtual welcome.

If you weren’t a EMBL-EBI events organisers what would you be? Probably a teacher of some kind.  Before I started working in events and engagement, I worked as an English Language Assistant, which I really enjoyed, so ideally I’d combine teaching and travel.

PHOTO: weekend city break in Copenhagen May 2020

What is the strangest/funniest thing that has ever happened in a course? My birthday is in July and in my past jobs this has been the busiest time – either at Graduation events or summer events – so I have often spent it working, but never in an office!  I’ve been organising table plans in Liverpool Cathedral, at a Massive Attack concert in a disused train depot or hosting tours of new exhibitions…one of my favourite things about working in events is that there is rarely a dull moment!

If you were a superhero what power would you like to have?  I love learning languages but it’s hard to find the time…so definitely the ability to speak and understand different languages without having to learn verb tables!

What is your favourite TV show? Like everyone I’ve watched a lot more TV than usual over the past year, but The Sopranos – which has stood up to a rewatch or two – remains my favourite.

Upcoming events that Jane is organising: Cancer genomics 2021 – virtual 

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Best Poster Awards – EMBO|EMBL Symposium: Organoids 2020

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

PHOTO: Antonella Dost

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.

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(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

PHOTO: Guillermo Sanchez

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

PHOTO: Marina Matsumiya

Authors: Marina Matsumiya (1), Mitsuhiro Matsuda (1), Nao Otomo (2), Yoshiro Yonezawa (2), Shiro Ikegawa (2), Miki Ebisuya (1)

Presenter: Marina Matsumiya

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

PHOTO: Silke Frahm-Barske

Authors: Silke Frahm-Barske (2), Sebastian Diecke (2), Franz Theuring (1)

Presenter: Silke Frahm-Barske

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.

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(1) Charité – University Medicine Berlin, Germany
(2) Max-Delbrück-Center, Germany

Working on your own conference poster? Then check out these 8 tips for preparing a digital poster that stands out from the crowd.

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14th EMBL Conference: Transcription and Chromatin

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.

A word cloud composed of the titles of the talks from Day 1 showcases the range of topics in focus.

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!

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.

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Expanding the Druggable Proteome with Chemical Biology – Best Poster Awards

The 2020 conference season at the EMBL Advanced Training Centre kicked off with the EMBL Conference: Expanding the Druggable Proteome with Chemical Biology (5 – 7 February 2020). Meet the three poster prize winners from the conference – Patrick Zanon, Enric Ros and Rens de Vries.

Identification of novel antibiotic targets using covalent inhibitors and residue-specific proteomics

PHOTO: Patrick Zanon

Authors: Patrick Zanon (1), Stephan Hacker (1)

Bacterial resistance towards all marketed antibiotics poses an imminent threat to global health. In order to overcome this antibiotic crisis, drugs with novel mechanisms-of-action are desperately needed. Covalent inhibitors are especially promising in this regard as they are already prevalent as antibiotics (e.g. β-lactams and fosfomycin), allow targeting protein pockets that are hard to address with non-covalent interactions alone and hold the promise to overcome some mechanisms of resistance development.[1] Furthermore, covalent inhibitors are uniquely suited to identify new binding pockets on proteins using residue-specific proteomics and in this way to broaden the scope of targetable protein targets.
The vast majority of covalent inhibitors so far either hijack the enzymatic activity of the protein by modification of catalytic serines and tyrosines or address cysteines through their inherent outstanding nucleophilicity. Nevertheless, the number of potentially addressable proteins in the bacterial proteome is significantly limited by the requirement for these amino acids to be present in target proteins. By developing electrophilic groups that are selective for other amino acids (e.g. lysine), we strive to expand the number of exploitable interaction sites for covalent inhibitors in the bacterial proteome. Furthermore, to assess the reactivity and selectivity of covalent inhibitors and to streamline the discovery of novel antibiotic targets, we develop new methods for residue-specific activity-based protein profiling.[2,3] In this way, we are convinced, that we will be able to make important contributions to overcome the antibiotic crisis.

[1] R. A. Bauer, Drug Discov. Today 2015, 20, 1061–1073.
[2] K. M. Backus et al., Nature 2016, 534, 570.
[3] P. R. A. Zanon, L. Lewald, S. M. Hacker Angew. Chem. Int. Ed., doi: 10.1002/anie.201912075.

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(1) Technical University of Munich, Germany

Incorporating 1,2,4,5-tetrazines into proteins: A method for targeted drug release

PHOTO: Enric Ros

Authors: Enric Ros (1), Antoni Riera (1), Lluís Ribas de Pouplana (1)

Bioorthogonal reactions, namely reactions that can take place under biocompatible conditions, are having a major impact in the development of new research tools and novel therapeutic strategies. In the latter case, the discovery of the reaction commonly referred to as “click-to-release” (CtR), which triggers the liberation of a given cargo (normally a drug or a fluorophore), has led to several applications in drug delivery. This reaction happens between a 1,2,4,5-Tetrazine (Tz) fragment and certain alkenes or alkynes and, in order to achieve drug delivery specifically at the site of action, one of the two reactant counterparts should be conjugated to a biomolecule acting as a carrier, ideally a protein.
We have synthetized the previously unreported 3-bromo-1,2,4,5-tetrazine and used its excellent reactivity to attain chemoselective protein labelling onto lysines. Due to the chemical features of the formed amino-Tz. The resulting labelled lysines can undergo fast CtR reactions with trans-cyclooctenes, thereby releasing a desired cargo under physiological conditions. To showcase the applicability of this approach, we have labelled the monoclonal antibody Trastuzumab (anti-Her2) and demonstrated the specific release of the cytotoxic drug doxorubicin upon reaction in a mammalian cell culture context, resulting in a decrease in cell viability.
Additionally, we have also used 3-bromo-1,2,4,5-tetrazine to synthetize an amino-Tz containing non-natural amino acid and used it to achieve protein labelling through its genetic incorporation by amber codon suppression in Escherichia coli. The resulting site-selectively labelled proteins can also trigger fast, high yielding CtR reactions.
To summarize, we have successfully applied a new compound, 3-bromo-1,2,4,5-tetrazine, as a reagent to achieve either chemoselective or site selective protein labelling. We have applied the bioconjugated proteins to demonstrate their potential use for targeted drug delivery in a relevant cellular model, opening new therapeutically useful methodologies.

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(1) IRB Barcelona, Spain

Modulation of nuclear receptors through ligand architecture

PHOTO: Rens de Vries

Authors: Rens de Vries (1), Femke Meijer (1), Luc Brunsveld (1)

Nuclear receptors (NRs) have been one of the primary drug targets over the last decades for their ability to regulate gene expression. The traditional approach of modulating NRs is to design small synthetic molecules that interact with the ligand-binding domain (LBD) of the NR. Ligands can thereby either enhance or inhibit gene transcription. Apart from the effects on transcription, recent research shows that minor changes in the ligand scaffold can have a significant impact on the behavior of the NR. In this research, we show how small-molecules can change both the dimerization behavior of NRs and the recruitment of allosteric modulators.
The Retinoic X Receptor α (RXRα) is known as a master regulator among NRs through its ability to heterodimerize with, and thereby modulate, other NRs. We show, using a novel NanoBIT complexation assay, that small directed changes in the RXR ligand scaffold can lead to selective formation of specific hetero- and homodimers. Using our structural data and focused compound library, a model was developed to help to understand this effect of the ligand. This information can serve as a blueprint to design small-molecules that selectively target specific NRs via RXR. This makes RXR as an exciting and versatile target for NR modulation, especially when classical modulation of the partner NR is not possible.
Recently, small-molecules have been found to bind to allosteric sites of NRs. Allosteric ligands are of interest since they do not compete with the endogenous ligand of the NR and often shown an increased selectivity towards their target. We show, using X-ray crystallography and biochemical assays, that there is communication between orthosteric and allosteric ligands in the RAR-related orphan receptor γ t (RORγt). We successfully solved eleven new ternary crystal structures of RORγt in the presence of both orthosteric and allosteric ligands. These structures mechanistically show how binding of the orthosteric ligand leads to positive cooperative binding of the allosteric ligand.

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(1) Eindhoven University of Technology, The Netherlands

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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