Visions: Matthias Wilmanns, Head of the European Molecular Biology Laboratory (EMBL) Hamburg

On how the European Molecular Biology Laboratory (EMBL) Hamburg is getting ready for the next Revolution in Resolution!  

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Portrait of Prof. Matthias Wilmanns

Matthias Wilmanns has been the Head of the Hamburg Unit of the European Molecular Biology Laboratory (EMBL), Hamburg, Germany, since 1997. He also holds a professorship at the Medical Faculty of the University of Hamburg, Clinical Center Hamburg-Eppendorf (UKE). He operates an active research group at EMBL focused mainly on large protein translocation systems by an integrated structural biology approach, complemented by functional experiments.

The EMBL site in Hamburg (Germany) is as old as the European Molecular Biology Laboratory, commonly known as EMBL. The site, initially called “Outstation”, was established together with the EMBL’s main site in Heidelberg in 1974, as the first International Laboratory supported initially by 11 European member states to focus on cutting edge research in molecular biology. EMBL Hamburg was added to EMBL in its phase of inception, reflecting the enormous potential expected at the time for making use of synchrotron radiation for future structural biology applications.

Synchrotron radiation from Hamburg – initially only produced as spin-off for high-energy physics experiments by the German Synchrotron DESY – was first pioneered by Ken Holmes and colleagues for muscle fibre diffraction studies. During the following decades EMBL Hamburg became a leading provider of highly specialized synchrotron end-stations, mainly for applications in X-ray crystallography to determine structures of biological molecules and complexes at atomic or near-atomic resolution. Until the early years of this millennium, the EMBL Hamburg beamlines used synchrotron radiation from the DORIS storage ring and, since then, from the much more state-of-the-art PETRA III storage ring. Most of the available beamline measurement time was given to hundreds of external research groups and thousands of projects over the years, the vast majority of them from different European countries. This remains our present model of operation and will continue in the future as well.

In the meantime, related and even larger user infrastructures have been established around the world. One of them is the European Synchrotron Radiation Facility (ESRF) situated in Grenoble (France), which is – similar to EMBL – supported by European member states. The Protein Data Bank (PDB) now hosts far more than 100,000 of these X-ray structures, which were mostly determined using synchrotron radiation in recent years.

Seminal research highlights in the field have been honoured by more than ten Nobel prizes. One of the recipients, in 2009, is Ada Yonath, together with Venkatraman Ramakrishnan and Thomas Steitz, for her seminal work on the first high-resolution structure of the ribosome. For this work Ada spent most of her time in Hamburg, where she had one of her laboratories, and used on-site synchrotron infrastructures as well as from other parts of the world. Access to the very best infrastructures was one of the keys for her success.

Cutting-edge technology to cut through complexity 

From its early beginnings, more than half a century ago, structural biology has continuously been undergoing dynamic developments by making use of the newest, most cutting-edge technologies. Especially due to innovative detector developments, recently single particle cryo-electron microscopy has opened unprecedented opportunities to determine high-resolution structures of some of the largest and most complex protein assemblies found in living systems. Werner Kühlbrandt, an EMBL alumnus, called this “The Revolution of Resolution” a few years ago. The most amazing additions can be now found on a weekly basis in scientific top journals.

The next step, looking at the structures within the cellular environment “in situ” by electron tomography, has been established more recently in a few laboratories, including EMBL, bringing closer our aspiration to directly visualize molecular structures in cells. In Hamburg, opportunities for an on-site “Revolution of Resolution” have become a reality by the establishment of new research infrastructures, such as the European X-ray Free Electron Laser, and by a state-of-art cryo-electron microscopy facility for both single particle analysis and electron tomography applications, at the recently opened Centre for Structural Systems Biology (CSSB). This centre hosts ten research partners, including EMBL.

In parallel, EMBL Hamburg has expanded its portfolio towards a truly integrated structural platform, which also hosts a leading beamline for small angle X-ray scattering (SAXS) to determine proteins shapes directly in solution, and the provision of state-of-the-art computational tools to obtain structural models from heterogeneous experimental data sets by integrative modelling.

Looking at structure in action

Our future vision goes far beyond our present opportunities. Central to our wishes is the imaging of the structures of biological macromolecules at high resolution within their living environment such as cells, organoids, organs and complete organisms. At the same time, we aim to capture their structural dynamics when being in action. To approach this most efficiently, EMBL Hamburg aspires to participate with an expanded portfolio at the next update of the present synchrotron in Hamburg PETRA IV, which is expected to provide a so-called diffraction-limited synchrotron source. With this approach, literally the only factor that will limit the future resolution will be the sample material. EMBL Hamburg has made a proposal that both builds on its track record, mainly in the fields of X-ray crystallography and small angle X-ray scattering, but also plans to move into new imaging applications.

Based on results from various recent pilot projects, we believe that there is an unexplored power of X-rays for imaging cellular and organismal structures, which can be implemented by a number of different technical modalities. The main advantages will be in the ability of hard X-rays for in-depth penetration of thick cellular specimens and opportunities for high-throughput by very rapid measurement times. With this technique we could gain unprecedented insight into even the most complex tissues, to address fundamental questions in biology that were impossible to address at a resolution achievable by X-ray imaging before.

Finally, we have enormous opportunities to synergize our capabilities in Hamburg with complementary skills and structural biology infrastructures at other EMBL sites, taking advantage of our internationality and support from 27 member states across Europe. This specifically applies to cooperation with platforms in structural biology at EMBL Heidelberg, with a new Imaging Centre to be opened later this year, as well as with the EMBL sites in Grenoble, on the campus of the ESRF, and the EMBL-EBI near Cambridge, the latter being a major provider of scientific data infrastructures and services.

Taking together all the scientific expertise and infrastructures we already have and we are planning to establish during the coming years, we are confident to contribute to a new golden era in structural biology, ultimately allowing our dreams to get closer to becoming a new reality, which is to visualize life in action at molecular and even atomic resolution.

Fundamentally responsive to societal challenges

What are the key challenges in the future? Much more than in the past, our research community is expected to position itself and to respond to major societal challenges, such as climate change and new waves of life-threatening global pandemics, with innovative research solutions. During the ongoing COVID-19 crisis the structural biology community, including EMBL researchers from its different structural biology sites, has impressively used the strength of its methods portfolio to unravel key underlying infection mechanisms at an amazing level of molecular and even atomic detail.

In addition, we have made our facilities and infrastructures available to researchers worldwide, which included engagement with industry users developing COVID-19 vaccines, solving high-resolution structures of viral targets in the presence of human host receptors, and repurposing available drug libraries for screening against these viral targets. These interactions testify to how fundamental research and concrete applications can cross-stimulate each other.

My own wish for the future is to maintain and further develop our unique EMBL research culture by keeping an open mind by using cutting edge research tools for finding solutions for some of the major global challenges we increasingly face. All of us need to advocate for the way in which science offers forward-looking solutions to counterbalance a false believe in conspiracies and doubts about the uncontested value of evidence-based arguments.

Matthias Wilmanns

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