After weeks of no or only strongly restricted access for our researchers to the laboratories we´ve restarted science to the new “normal”. Besides being back at the bench and computer, researchers at the Integrative Research Institute (IRI) for the Life Sciences have partly redirected their work and joined forces to help tackle the new challenges caused by the novel coronavirus SARS-CoV-2. Here we inform about our activities relating to the ongoing pandemic.
IRI Life Sciences belongs to Humboldt-Universität zu Berlin (HU). We advance research and quality by drawing on complementary expertise and open scientific exchange with shared resources among HU, Charité - Universitätsmedizin Berlin and the Berlin Institute for Medical Systems Biology (BIMSB) of Max Delbrück Center for Molecular Medicine (MDC). We have started pooling the resources of all involved researchers, bringing them together to investigate the virus and its effects to human cells.
Under the lead of IRI-spokesperson Prof. Dr. Markus Landthaler, professor for RNA biology at Humboldt-Universität and research group leader at the Berlin Institute for Medical Systems Biology (BIMSB)/Max Delbrück Center for Molecular Medicine (MDC), several research groups from MDC in collaboration with the group of Prof. Dr. Christian Drosten (head of virology at Charité - Universitätsmedizin Berlin) studied the RNA profile in SARS-CoV-2 infected human lung cell lines. By using bulk and single-cell transcriptomics, the study provided a rich dataset to analyze host cell expression changes in response to the viral infection and allowed to characterize the heterogeneity of the infection in different human cell lines.
Furthermore, the study identified the Heat-Shock-Protein-90 (HSP90) to be relevant for the infection, as inhibition of HSP90 resulted in a reduction of viral replication and of the expression of pro-inflammatory cytokine. Both effects, reducing the viral replication AND pro-inflammatory immune response is of clinical relevance, since the latter is known to be involved in the ARDS (Acute Respiratory Distress Syndrome) pathogenicity in lung infections. Further studies in primary lung cells and lung tissues are important to validate those findings and pave the way for a therapeutic intervention for SARS-CoV-2 infections.
MDC is at the forefront of using single-cell analysis approaches for diverse research questions. In the face of the global SARS-CoV-2 pandemic, researchers at MDC contributed their expertise in single-cell analysis methods to study the molecular mechanisms underlying the infection with SARS-CoV-2. As every organ the lung consists of a variety of cell types, each of them responding differently to changes in environmental conditions like for example infections. Single-cell analysis allows the characterization of the heterogeneous response of each cell type over the course of infection which may be hidden at the population level.
First author of the new study Dr. Emanuel Wyler, senior postdoc at Markus Landthaler’s group, explains the advantages of single cell studies over bulk sequencing analysis for scientific insights with the image of a fruit smoothie: “If I put ten types of fruit into a blender, I can roughly taste what is in it - blackberries, for example. With single-cell RNA sequencing, we don't get a smoothie, but a fruit salad. I can see the blackberries at a glance and tell exactly how many there are.”
Moreover, research on viruses are not new to Emanuel Wyler. For years he studied the herpes simplex viruses - the annoying cause of cold sores. In a study published in October 2019 in Nature Communications, Emanuel Wyler and colleagues used single-cell sequencing to look at herpes simplex virus infection in human skin cells (Wyler et al., Nat Commun 10, 4878). Two years earlier, they investigated manipulation of host cell transcription by the same virus (Wyler et al., Genome Biol 18, 209).
Wyler, Landthaler et al., Transcriptomic profiling of SARS-CoV-2 infected human cell lines identifies HSP90 as target for COVID-19 therapy. iScience. 2021 Feb 6:102151. doi: 10.1016/j.isci.2021.102151.
“If I put ten types of fruit into a blender, I can roughly taste what is in it - blackberries, for example. With single-cell RNA sequencing, we don't get a smoothie, but a fruit salad. I can see the blackberries at a glance and tell exactly how many there are.”
Together with the local water supply company, Berliner Wasserbetriebe (BWB), the research of Prof. Dr. Markus Landthaler (professor for RNA biology at Humboldt-Universität and research group leader at the Berlin Institute for Medical Systems Biology (BIMSB)/MDC) analyse wastewater to detect SARS-CoV-2 virus particles.“
We read very precisely what concentration the virus has in the wastewater as well as what variants are present“ Landthaler says. The virus concentration in wastewater corresponds closely to the incidence curve and regular sewage monitoring can serve as an early warning system to predict a few days prior to official announcements whether the incidence will increase or decrease.
What Berlin wastewater reveals about the coronavirus
The biophysicist Prof. Dr. Andreas Herrmann, professor for molecular biophysics at the Institute of Biology at HU and the founding spokesperson of IRI Life Sciences (2013-2017), aims to develop multivalent inhibitors preventing the binding of SARS-CoV-2 to its cellular receptor. In a joint project, Andreas Herrmann and life sciences colleagues from Berlin develop a drug that prevents coronaviruses from binding to host cells located in the throat and subsequent airways, thus preventing infection. The idea is that the inhibitor makes use of the trivalent receptors on the surface of the virus, referred to as the S-spike protein. In the case of infection, viruses hook to the ACE2 receptor on the surface of cells of the lung tissue.
In the project, nanoparticles covered with multiple ligands mimicking the ACE2 receptor are designed. Binding of those nanoparticles to the viral S-spike proteins prevent their attachment to the host cell and thus the infection. The project is part of the 'Corona Virus Pre-Exploration Project' funded by the Berlin University Alliance (within the Grand Challenge Initiative Global Health) and involves Prof. Dr. Christian Hackenberger (professor for chemical biology at HU and research group leader at Leibniz-Forschungsinstitut für Molekulare Pharmakologie) and Dr. Daniel Lauster, postdoc at Prof. Dr. Rainer Haag's group (co-speaker of the initiative) at Freie Universität Berlin.
Current antiviral drugs are only partially effective because they only attack the virus when it has already infected the host cells. It would be desirable and far more effective to inhibit virus entry and thereby preventing virus replication and cellular damage. Andreas Herrmann studied virus-host interactions, especially virus entry his whole academic life. He is part of a multidisciplinary team in Berlin which just recently successfully showed this new approach with influenza viruses.
Under the lead of Christian Hackenberger they developed a chemically modified phage capsid based on an empty and thus non-infectious envelope of a phage virus, which wraps the influenza viruses in such a way that they can practically no longer infect the lung cells (Lauster et al., Nat Nanotechnol. 2020 May;15(5):373-379). “This is exactly the concept we would like to transfer to the coronavirus” says Andreas Herrmann, convinced by the great potential of structurally adaptable virus binders as new therapy options.
“This is exactly the concept we would like to transfer to the coronavirus.”
Epidemiologist Prof. Dr. Dirk Brockmann is IRI member and professor at the Institute for Theoretical Biology at HU. He also leads the research department Epidemiological Modeling of Infectious Diseases at the Robert Koch Institute (RKI). Dirk Brockmann is a specialist in the field of complexity research and currently one of the most sought-after scientists in Germany when it comes to the spread of the coronavirus.
He was significantly involved in the development of the corona data donation app of RKI. Data from fitness trackers and smart watches, so-called wearables, can provide indications of symptoms of a COVID-19 infection. With the help of the app, citizens can make this data available to the RKI. The algorithms behind the corona data donation recognize symptoms that are associated with coronavirus infection. These include, for example, an increased resting heart rate and altered sleep and activity patterns. Together with data from other sources, e.g. the official reporting data, the wearables data help the scientists to better understand the spread of the coronavirus.
Dirk Brockmann and his team’s new idea is to create a "fever chart" for Germany. After careful processing, donated data is incorporated into a map that visually depicts the distribution of potentially infected persons down to the level of the postcode. This then is “an indication that there might be a new hotspot in certain places,” Dirk Brockmann says. The map will be regularly updated and published on the website of RKI.
Dirk Brockmann pioneered the field of computational epidemiology with the development of large-scale computational frameworks for the description and prediction of disease dynamics on large geographical scales. Right at the beginning of the current pandemic, Dirk Brockmann and his team analyzed mobility data and simulated the spread of the coronavirus. He played a major role in the development of the corona data donation app of the RKI. The app has rapidly become one of the largest voluntary data collection apps with more than half a million citizens donating their data.
The basis of epidemiological modelling is the evaluation of data related to the mobility of people and the amount of their contacts. Never before have people travelled more, never before have they had more contacts, and never before have they revealed more of themselves than in today's digitalized society. It is also clear that they never left more data traces. Modelers like Dirk Brockmann make use of these. They are interested in processes that can be identified from patterns of transport and movement, such as international air traffic with millions of travellers every day. Also on board: viruses and bacteria, which in turn are objects of interest to epidemiologists.
Another rich data pool are social networks with all their posts, tweets (I got Corona) or hashtags (#Corona) and also frequently used keywords at Google. However, most important are individual data, i.e. data that smartphones and fitness trackers collect from us. As these are very sensitive, it is particularly important for science that those data are encrypted and transmitted pseudonymously.
Corona Data Donation - Blog
Covid-19 Mobility Project
Re: Schneller als das Virus - Der digitale Wettlauf gegen Corona (arte.tv)
A map that visually depicts the distribution of potentially infected persons is “an indication that there might be a new hotspot in certain places.”
Vaccination against COVID-19 with mRNA vaccines from BioNTech/Pfizer and Moderna has been introduced into a large number of countries. Based on acute supply deficits in early 2021, authorities decided to stretch the vaccine, for instance by delaying the second dose.
A quantitative epidemiological assessment of risks and benefits of non-standard vaccination protocols remains elusive. Therefore, researchers in the team of Prof. Dr. Dirk Brockmann evaluated and compared different vaccination strategies of COVID-19 mRNA-vaccines in high-risk groups in Germany. They developed a stochastic epidemiological model that integrates specific vaccine rollout protocols into a risk-group structured infectious disease dynamical model.
Using the situation and conditions in Germany as a reference system, the researchers showed that delaying the second vaccine dose is expected to prevent deaths in the four to five digit range, should the incidence resurge. According to their study (published as preprint), this considerable public health benefit relies on the fact that both mRNA vaccines provide substantial protection against severe COVID-19 and death beginning 12 to 14 days after the first dose.
Preprint out: Potential benefits of delaying the second mRNA COVID-19 vaccine dose
The global pandemic caused by the new coronavirus draws the attention everywhere to sciences. Everyday new findings about the coronavirus - its biology, the effects of infection and the search for treatment and a vaccine can be read not only in scientific literature. To follow the rapidly growing knowledge about SARS-CoV-2 spread and the COVID-19 disease spectrum and evaluate them is already challenging for established scientists in different research fields.
A new Master course offered by IRI members from the Institute of Biology at HU takes this rare opportunity to teach the next generation of young scientists in molecular life sciences “am täglichen Erlebten”. Besides introducing the students to the scientific background of e.g. virology, innate immune responses to viral infections, epidemiology and vaccine development, the course aims to teach the students to scientifically evaluate new insights about the coronavirus and put them into context.
SARS-Cov-2 pandemic: Pathophysiology, epidemiology and cell biology
(MSc 'SARS-CoV-2' - online course (summer semester 2020) - lectures, literature review & 1-day symposium)
Originally, the participants wanted to discuss their study work in a symposium at the end of the summer semester 2020. However, corona-related restrictions at Humboldt-Universität thwarted plans for a face-to-face indoor event with all participants. The organizers made a virtue of this and invited the participants to a voluntary event in the open air instead. “I was impressed by the enthusiasm and scientific independence of the students, which they demonstrated in producing a literary work on such a rapidly changing topic” says Juliane Lippmann, one of the organizers of the course.
The course was offered to HU Master students in molecular life sciences as a response to the rapidly expanding knowledge base on the SARS-CoV-2 pandemic. Overall, participants praised
- how quickly and yet well it was put together,
- how much they benefited from the interdisciplinary selection of topics covered by the module and
- first-hand scientific expertise shared by the module organizers.
The course will be continued in the winter semester 2020/21. It will also be more interactive, for example, a journal club will be set up to discuss seminar-related scientific papers. Interested students find the course on Humboldt-Universität's Moodle-Platform or should write to juliane.lippmann(at)hu-berlin.de for further information.
“I was impressed by the enthusiasm and scientific independence of the students, which they demonstrated in producing a literary work on such a rapidly changing topic.”
IRTG 2290: Crossing Boundaries: Molecular Interaction in Malaria
The IRTG 2290 is a member program of the Graduate School at the IRI Life Sciences. The Berlin-Canberra alliance addresses fundamental issues in malaria. Molecular insights into Plasmodium infections can generate novel evidence-based strategies to develop curative and prophylactic drugs, and immunization strategies that elicit lasting protection against the disease.
IRTG 2403: Dissecting and Reengineering the Regulatory Genome
In an alliance between Berlin institutions and Duke University, the international training research group aims to teach the next generation of researchers in quantitative understanding of genome function and gene regulation in the context of biological systems.
RTG 2424: Computational Methods in Oncolocy – Towards Personalized Medicine in Cancer Research
As part of this research program, a new generation of researchers will be developing computer-based tools for use in cancer research. Until a few years ago, the analysis of tumor samples was based on visible tissue characteristics. Today, state-of-the-art high-throughput technologies enable scientists to obtain the detailed molecular profile of a specific cancer. These technologies produce vast volumes of data. Collating and interpreting these complex data sets represents a major challenge – one which requires innovative, computer-based technologies and mathematical models.
The need for information and knowledge about the novel coronavirus SARS-CoV-2 is still huge. Even for scientists it isn´t easy to keep up with new findings and putting them into context. To meet the demand of scientists and non-scientists to understand current public discussions, IRI Life Sciences offers a new weekly science format within the new social app called Clubhouse. At the moment, sessions take place on Thursdays.
With "Betreutes Lesen auf Clubhouse (Clubhouse Reading Circle)" Benedikt Beckmann, group leader of molecular infection biology at IRI Life Sciences, Emanuel Wyler, senior postdoc in the group of IRI Life Sciences' spokesperson Markus Landthaler from Max Delbrück Center for Molecular Medicine and Geraldine Nouailles from Charité – Universitätsmedizin started discussing individual corona studies publicly on Clubhouse in February 2021. They also give insights into their own research and experiences with the new coronavirus and answer questions from the participants.
Scientists discuss corona studies live on Clubhouse
Beckmann Lab: Betreutes Lesen auf Clubhouse (in German)
Every week scientists discuss coronavirus studies, provide background information and answer questions from participants live on Clubhouse.
All buildings are closed to the public, courses continued to be held online, and presence exams are only possible subject to the rules of distance and hygiene. And how is research at Humboldt-Universität? On June 18, 2020 we talked about how research has been slowly returning from the pandemic-related standstill.
“We are currently back to 50 percent,” said Dr. Benedikt Beckmann, group leader of molecular infection biology at IRI Life Sciences on HU Campus Nord. What he hadn't expected during the corona period: the cooperation has become surprisingly close in a scientific environment where there is a lot of competition. “I already have the hope that this will remain, that it could catch on,” said Benedikt Beckmann.
During the lockdown phase, we opened our empty laboratories for the photographers Wiebke Kahn and Andreas Maria Kahn. The 3D exhibition "Corona Laboratories" (curated by Fabian Kruse) at the arts festival "48h Neukölln" from 19 to 21 June 2020 showed a series of photographs taken in different laboratories at our IRI research building on HU Campus Nord. In dialogue with the researchers, the artistic concepts integrated spatial architecture, experimental setups and everyday objects.