CSSB: A new approach to infectious disease
On the DESY campus in Hamburg, the Centre for Structural Systems Biology (CSSB) is ready to make its mark as the new kid on the block and tackle some of the most important questions relating to how infections take hold in our bodies
Around a quarter of all deaths every year worldwide can be attributed to infectious diseases. Malaria alone results in half a million deaths per year. Other infectious diseases can be even more devastating: tuberculosis claims the lives of around 1.8 million and HIV around 1 million people per annum. A lack of vaccines and increasing resistance of pathogens to antibiotics and anti-viral drugs, mean that the battle to reduce deaths and cut instances of infectious disease is becoming ever more intense.
“Infectious disease is one of the greatest challenges the world faces today,” says Matthias Wilmanns, Head of EMBL Hamburg and Centre for Structural Systems Biology (CSSB) scientific director. “From multidrug resistant bugs in our hospitals, to tropical diseases, there is so much we don’t know about how pathogens such as viruses and bacteria infect humans.”
Taking further steps towards understanding how pathogens hijack cellular machinery and wreak havoc on human health needs large collaboration efforts. Wilmanns and colleagues wanted to take this a step further by bringing together computational, structural and wet lab researchers in a single building with access to state-of-the-art infrastructures. The opening of the CSSB building in June was the realisation of a vision first set out a decade ago.
CSSB is a collaboration of presently nine academic partners from North Germany, each active in different areas of infection biology research. The partners are represented by one or more research groups within the new building on the DESY campus in Hamburg, and together they will use a combination of structural and systems biology approaches to unravel the fundamental mechanisms of how pathogens infect their hosts. “It is not enough to understand the structure of the miniscule tools that a pathogen uses to infect its host, for example,” says Wilmanns. “In order to eventually inform the development of urgently needed new drugs, we need to understand how the tools are built, what other molecules are required to build it and how they all interact with each other. We need to throw all the knowledge and know-how we have together to understand this whole process.”
One of EMBL’s representatives within the CSSB is group leader Christian Löw. He was among the first to move into the new building after its inauguration in June. His cosy office on the second floor of the building looks out to a patch of woodland at the heart of the DESY campus. Löw has been heavily involved in shaping the concept and structure of CSSB since he joined EMBL three years ago, an experience he has very much appreciated. Now it’s time to focus on the science.
“CSSB is unique in that researchers have access to a simply breath-taking range of different techniques to study the structural details of molecules and cells at different scales of resolution,” Löw continues. “We have the tools to zoom in to the position of an individual atom within a cellular protein using X-ray crystallography and electron microscopy. We are also able to zoom out and see how components interact within cells and organisms using the latest fluorescence microscopy methods. We want to piece all this information together to get a complete picture of what happens during infection across time and resolution scales.”
CSSB will use bioinformatics analyses to interpret those snapshots within the context of how infections operate within a host. And the new building is perfectly situated to make use of the immense research infrastructures on its doorstep. “The parallel X-ray beams provided by the EMBL beamlines at the PETRA III synchrotron on campus are extremely intense and precise – ideal for studying tiny delicate crystals of large proteins,” explains Wilmanns. “The development of the CSSB will enable structural biologists to further focus their collective expertise in order to get the most out of these incredible infrastructures.”
The building will also host four core facilities using state-of-the-art technologies and equipment. Protein characterisation and crystallisation facilities at EMBL next door have been expanded and upgraded in order to serve both EMBL and CSSB. An advanced light and microscopy facility will be run in cooperation with leading microscope manufacturer Leica microsystems. A protein production facility is in the process of being set up. In addition, an in-house electron-microscopy facility will also be available, with four microscopes set to come online before the end of the year.
Löw is fascinated by membrane transporters. These large protein complexes sit astride the cell membrane and regulate the traffic passing in and out of the cell – letting important nutrients in and keeping nasty invaders out. Their size and shape mean they are tricky to study using methods such as X-ray crystallography alone. Löw has spent the last few years optimising methods for handling these proteins for crystallography experiments. “Now we understand how to work with these proteins we will help other CSSB groups optimise their protocols as well as widening our horizons to look at how they are regulated and interact within the cell,” he explains. Working together with CSSB group leader Tim Gilberger of the Bernhard-Nocht-Institute for Tropical Medicine, Löw plans to investigate a membrane complex that allows the malaria parasite to invade the red blood cells of a human host.
“This membrane complex is fascinating,” Löw explains. “It sits across multiple layers of the pathogen cell membrane and is very large. To visualise its atomic structure in high-resolution, we will use multiple techniques including crystallography and electron microscopy supported by Kay Grünewald of the Heinrich Pette Institute. The membrane complex is crucial for the survival of the malaria parasite, so a complete understanding of its structure and biology would enable us to design small molecules to block it, thereby halting the disease,” says Löw.
Even before groups moved into the building, interdisciplinary collaboration within the network developed during the CSSB’s formation started bearing fruit. Thomas Marlovits, CSSB group leader from the University Hospital Hamburg Eppendorf, uses a range of structural biology methods to study groups of proteins called secretion systems that certain types of bacteria such as Salmonella and E.coli use to infect their host. Wilmanns teamed up with Marlovits to study a secretion system found in the tuberculosis pathogen Mycobacterium. Using a combination of small-angle X-ray scattering and electron microscopy techniques complemented by biochemical and biophysical studies, the groups were able to reveal the unusual shape of the system and the unexpected position of the complex within the Mycobacterium cell membrane. “The results advance our knowledge of how tuberculosis pathogens function,” says Wilmanns. “It shows how powerful interdisciplinary studies can be for infection research.”
See the full list of partners on the CSSB website
In addition to space for research groups from the CSSB partners, around one fifth of the building is reserved for a ‘research hotel.’ Through the initiative, the CSSB provides young group leaders – irrespective of their research organisation – lab and work spaces including access to the core facilities and integration into the CSSB network for an average stay of five years. “Making the transition from postdoc to group leader is not easy,” says Löw. “Like at EMBL, the CSSB’s research hotel allows young scientists to focus on their science and group members without worrying about financing lab equipment at the same time,” he adds. Applicants are selected on the grounds of scientific excellence and how their research interests complement the CSSB research portfolio.
A short walk down the hall from Löw, EMBL’s Jan Kosinski has just moved into his office as the latest recruit to the research hotel. “I was really attracted by CSSB’s vision of integrating structure and systems biology approaches, because this is exactly what I want to do in my own research,” he says. Kosinski’s expertise is in combining and integrating data from different structural biology methods to develop models of molecules otherwise too large to determine with experimental methods alone. His work is a clear fit for the CSSB. As a postdoc at EMBL in Heidelberg Kosinski used a collection of different structural data to model the atomic structure of one of the biggest molecule components of the cell. “The nuclear pore complex is an important gateway to the cell nucleus, regulating which molecules can pass in and out,” explains Kosinski. “We want to know how it does this and how pathogens manage to pass through it.”
At the CSSB Kosinski will continue to integrate various data sources to model difficult to study molecules. He’s also excited about applying his methods to modelling entire infection pathways of, for example, the influenza virus, the malaria parasite together with Tim Gilberger and the herpesvirus in collaboration with Kay Grünewald. For this he plans to integrate not only various structural information but also systems biology ‘big data’ from high-throughput experiments such as protein-protein interaction or RNA interference screens. Kosinski only joined CSSB a few weeks ago, but has wasted no time getting started. “The CSSB has opened up a whole new range of collaboration opportunities,” he says.
Kosinski and Löw are keen to put the very special workspace at the CSSB through its paces and get everyone mixing and talking. “We have introduced communal coffee breaks and we plan joint seminar series, a graduate school for CSSB’s PhD students, as well as an opening symposium,” says Löw.
Communal kitchens, open plan office spaces, shared labs and a large modern lecture theatre – it is clear that the CSSB is a communicative and welcoming space. “It was always important for us to have a physical, rather than a virtual, place to work together,” says Wilmanns. “Good communication between groups, as well as to the outside community, was an important part of our vision from the beginning. We hope this common space will act as an incubator, fuelling innovations that build on our combined expertise and lead to knowledge that will pave the way for drugs and therapies in the fight against infectious diseases.”
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