Using chemical biology to expand the druggable proteome

Gerard Drewes
Head of Science, GSK Cellzome, Germany

In 2020 the EMBL Resource Development team and  industry partners of the EMBL Corporate Partnership Programme will bring together academic and industrial scientists with interests in chemical biology, chemogenomic libraries, pharmacology, medicinal chemistry and bioinformatics for the EMBL Conference: Expanding the Druggable Proteome with Chemical Biology (5-7 February 2020).

We spoke to co-organiser Gerard Drews from GSK Cellzome about how chemical biology is helping to expand the druggable proteome.

How would you define the “druggable proteome”?

This is the fraction of our >20,000 human proteins that can be functionally modulated by a drug. Drugs can be small molecules or large molecules such as therapeutic antibodies. Estimates of how many proteins are “tractable” vary widely, I think there may be around 5,000. Only a subset of these 5,000 would be “druggable” which means that modulating them with a drug will also have a therapeutic benefit.

How are advances in chemical biology helping to expand the druggable proteome?

Small molecules are still the main modality for intracellular targets. Deep pockets, typical for enzymes, are more easily tractable than shallow pockets typical for protein-protein interactions. Chemical biology has developed tools to explore different types of pockets. I am excited in particular by the potential of DNA-encoded libraries, and small fragment approaches with covalent modes of action. Some of these compounds will just be “binders” but these can be made into target degraders as PROTACs.

How can these advances help our understanding of disease biology?

If we had more chemical probes, we could use these in a standardised, controlled way to interrogate target function in cell-based models, organoids, and in some cases animal models. Yes, we have gene editing now, but that is not the same as pharmacological modulation.

We also need in vitro models that translate better to in vivo. Our old immortalised cell lines won’t do, we are going to need more work in primary cells, organoids, etc.

What are the main challenges facing scientists in this field?

Lack of standardised probe sets. Bad probe compounds, e.g. with bad selectivity, are still used and wrong conclusions drawn.

Lack of translational in vitro models.

Why is it important to bring industry and academia together to discuss this topic?

Academia brings creativity, agility, fast progress of new ideas and concepts, thinking out of the box.

Industry sometimes lacks these but knows how to develop a compound into a drug, which requires a host of technologies not readily available to academia. Also, industry requires a new generation of drug targets with better validation, and historically targets are often discovered in academia. Once a target hypothesis exists, academics and industry should ideally collaborate to figure out how to drug it.

What will be the main highlight of this conference?

I see many but still hope to be surprised!

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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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If there is no record of it, did it really happen?

World Day for Audiovisual Heritage #WDAVH, #audiovisualheritage

EMBL Archivist and guest blogger Anne-Flore Laloë, PHOTO: EMBL Photolab

Is there a sound from your childhood that just carries you back? For me, one of those is the opening credits of the Tintin animated show. That’s why I’m really grateful that I can click on a link and find it online and travel back in space and time pretty much at will.

As an archivist, though, I am acutely aware of the work that goes behind maintaining access to the world’s audiovisual heritage for future generations. Think about all those films, sound recordings, radio and TV programmes that are created everyday and capture unique records of activities, events and exchanges. But these exist in many formats, from wax cylinders to Super 8 films, .mp3 files or VHS tapes, and require specific hardware (such as VCRs, projectors, etc…) or software (like MPlayer, QuickTime media player) that can render the recordings.

In the course of its activities, and in particular its training activities undertaken by the EMBL Course and Conference Office, some audiovisual material might be created, most likely recordings of talks. This is a great way to create a trace of the meeting that can complement abstract books in an engaging format. It then also makes it easy to share these recordings and help disseminate knowledge further when some of these are made available for all to see through various channels, such at the EMBL YouTube “Keynotes @ EMBL” playlist. Even if you weren’t at the event, you can join in long after they have ended.

Nowadays, these videos are likely born-digital, straight into a format that you can watch on your laptop. But in earlier times, this is what you might have created:

Or even, earlier, this:

 

Luckily, when such things end up with me in the EMBL Archive, I can contact my colleagues in the EMBL Photolab, our in-house AV department to create digital files of these. They have the equipment that helps migrate the contents of these films into digital formats.

But whether these are born-digital or migrated, they all need to be preserved to ensure ongoing access to them. Because indeed, nothing is ever preserved – it is only ever being preserved.

Unfortunately, though, it happens that things are lost… With these discs, I have not been so fortunate and the video content contained on this CRVdisc could not be retrieved.

So, next time you are at a conference, and there’s a film crew, or when you are being interviewed on the radio – think about these traces you are leaving behind, that will traverse time so that future generations can look at your work and hear your voice in new formats, on machines we can’t yet fathom, and through these, make a connection with you as an individual presenter.

Links:

EMBL Archive: www.embl.org/archive
UN World Day for Audiovisual Heritage: https://www.un.org/en/events/audiovisualday/

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Meet the EMBL Events Team: María

We are happy to announce the start of a new series where you will get to know the people who make our events possible. They are extraordinary people who work hard so you can worrilessly enjoy the events you attend at EMBL. They are the superheroes behind the show who keep everything running smoothly, but they are also people like you and me who, after a long day at work, want to put up their feet and enjoy Netflix.

So let’s get started! Meet María Bacadare – course organiser and occasional conference organiser. She is from Venezuela, always has a smile on her face and is constantly running around (seriously María, be careful!).

María Bacadare PHOTO: Carolina Cuadras/EMBL

At EMBL since:
2014 – 2017 EMBL-EBI
2017 – present EMBL Heidelberg

Number of organised events:
2014 – 2017 EMBL- EBI: 38
2017 – present: 32

Favourite place in Heidelberg:

I love to walk around the Philosophenweg as it is very relaxing and you can get a super nice view of Heidelberg from there. My favourite part is the ice cream you can get on the way down at Amami Gelato!

First thing you do before an event starts and first thing you do after it finishes:

On the first day COFFEE! Coffee keeps me going with the running up and down the building to make sure everyone is fine and has found their way to the training labs/auditorium.

Once everyone has left the building the fun part starts with the tidying up of the rooms, taking down the signage and so on to start getting ready for the next meeting… but not before walking the participants/speakers down to the bus to wave goodbye!

If you weren’t an event organiser what would you be?

I would definitely be working at a bank and spending hours on excel sheets.

What is the strangest/funniest thing that has ever happened at an event?

The fun never ends in the ATC! We’ve sometimes found ourselves running down the helices or down the hill to get participants to the bus on time. But I think the funniest thing that ever happened on one of my shifts was the time a participant thought he had locked himself in the toilet as the sensor lights went off, and we could hear him screaming for help at the registration desk. We had to calm him down and ask him to wave his arms in the air to activate the lights. He was fine and we were all laughing afterwards.

If you were a superhero what power would you like to have?

I wish I could fly so I could be home with my family more often.

Favourite recipe:

Arepas! Easy, simple and delicious and not a single Venezuelan can live without them.

Upcoming events in 2020 María is organising: 

EMBL Course: Analysis and Integration of Transcriptome and Proteome Data. 2 – 7 February 2020, EMBL Heidelberg, Germany

EMBO|EMBL Symposium: The Organism and its Environment. 1 – 4 March 2020, EMBL Heidelberg, Germany

EMBO Practical Course: Microbial Metagenomics: A 360º Approach. 20 – 27 April 2020, EMBL Heidelberg, Germany

EMBL Course: Hands-on Flow Cytometry – Learning by Doing! 25 – 29 May 2020, EMBL Heidelberg, Germany

EMBO Practical Course: Molecular Geobiology. 19 – 24 July 2020, EMBL Heidelberg, Germany

EMBL Course: Cryo-Electron Microscopy and 3D Image Processing. 23 – 31 August 2020, EMBL Heidelberg, Germany

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Cooking for EMBL Events

Head of the EMBL Canteen and Cafeteria Michael Hansen (front, in grey) with his dedicated team. PHOTO: Marietta Schupp/EMBL

Anyone who has ever set foot in the EMBL Canteen is sure to go away wanting more. It’s no coincidence that the canteen has a reputation for serving some of the best food in the Heidelberg area.

So what is their secret?

Head chef Michael Hansen’s team of 29 (23 people in the canteen and 6 in the cafeteria) work tirelessly to cater for over 800 members of staff daily and over 6000 conference and course participants annually. Besides the great dedication of his staff – which involves regular evening and weekend shifts – he places great emphasis on the quality and freshness of the groceries they use.

“We buy our meat, fruit, vegetables, bread and eggs from local suppliers. For us it is important that the groceries have the shortest route so that they are as fresh as possible when they get to us. Our furthest supplier is 90 km away. For food that is not produced in Germany, such as olive oil, we do have to order from abroad, but we do that directly with the producers without going through a distributor.”

Everything is then freshly prepared and cooked before it is served, with close attention paid to nutritional value. This is especially important for the EMBL kindergarten, which caters for over 100 children of staff.

In 2018, the EMBL Canteen cooked for 6430 course and conference participants, and for this purpose used:

  • 32 crates of salad
  • 160 kg onions/garlic (imagine how many tears must have been shed!)
  • 225 kg fish
  • 225 kg potatoes
  • 290 kg meat
  • 803 kg fruit
  • 935 kg vegan/vegetarian dishes
  • 1,607 kg vegetables
  • 1,376,020 l coffee was served

“In the EMBL spirit, the canteen team is truly international, employing people from 12 nations who, despite their differences, have one thing in common – their love for cooking!  One of the reasons I became a cook is because of food’s power to unite people. And here I see this every day. Preparing one meal requires real team work. Everybody gets together and takes one step of the process so that all is done in the most efficient way, but still has great taste.”

Here is one of the canteen’s most popular recipes, named after Thomas Graf, EMBL Alumnus (1983 – 1998) and currently Senior Scientist at the Centre for Genomics Regulation in Barcelona, Spain:

Thomas Graf potatoes

1kg potatoes

100 ml oyster sauce

1 clove of garlic (pressed)

1 tsp honey

Pinch of salt

Black pepper

1 tbsp oil

Wash the potatoes and cut them into wedges without peeling them. Add all the ingredients and mix well. Preheat the oven to 180°C, place the potatoes on a baking sheet and bake for 40 min.


PHOTO: Marietta Schupp/EMBL
PHOTO: Marietta Schupp/EMBL
PHOTO: Marietta Schupp/EMBL
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