Cell culture model: several compounds stop SARS-CoV-2 virus
FRANKFURT. A team of biochemists and virologists at Goethe University and the Frankfurt University Hospital were able to observe how human cells change upon infection with SARS-CoV-2, the virus causing COVID-19 in people. The scientists tested a series of compounds in laboratory models and found some which slowed down or stopped virus reproduction. These results now enable the search for an active substance to be narrowed down to a small number of already approved drugs. (Nature DOI: 10.1038/s41586-020-2332-7). Based on these findings, a US company reports that it is preparing clinical trials. A Canadian company is also starting a clinical study with a different substance.
Since the start of February, the Medical Virology of the Frankfurt University Hospital has been in possession of a SARS-CoV-2 infection cell culture system. The Frankfurt scientists in Professor Sandra Ciesek's team succeeded in cultivating the virus in colon cells from swabs taken from two infected individuals returning from Wuhan (Hoehl et al. NEJM 2020).
Using a technique developed at the Institute for Biochemistry II at Goethe University Frankfurt, researchers from both institutions were together able to show how a SARS-CoV-2 infection changes the human host cells. The scientists used a particular form of mass spectrometry called the mePROD method, which they had developed only a few months previously. This method makes it possible to determine the amount and synthesis rate of thousands of proteins within a cell.
The findings paint a picture of the progression of a SARS-CoV-2 infection: whilst many viruses shut down the host's protein production to the benefit of viral proteins, SARS-CoV-2 only slightly influences the protein production of the host cell, with the viral proteins appearing to be produced in competition to host cell proteins. Instead, a SARS-CoV-2 infection leads to an increased protein synthesis machinery in the cell. The researchers suspected this was a weak spot of the virus and were indeed able to significantly reduce virus reproduction using something known as translation inhibitors, which shut down protein production.
Twenty-four hours after infection, the virus causes distinct changes to the composition of the host proteome: while cholesterol metabolism is reduced, activities in carbohydrate metabolism and in modification of RNA as protein precursors increase. In line with this, the scientists were successful in stopping virus reproduction in cultivated cells by applying inhibitors of these processes. Similar success was achieved by using a substance that inhibits the production of building blocks for the viral genome.
The findings have already created a stir on the other side of the Atlantic: in keeping with common practise since the beginning of the corona crisis, the Frankfurt researchers made these findings immediately available on a preprint server and on the website of the Institute for Biochemistry II (http://pqc.biochem2.de#coronavirus). Professor Ivan Dikic, Director of the Institute, comments: “Both the culture of 'open science', in which we share our scientific findings as quickly as possible, and the interdisciplinary collaboration between biochemists and virologists contributed to this success. This project started not even three months ago, and has already revealed new therapeutic approaches to COVID-19."
Professor Sandra Ciesek, Director of the Institute for Medical Virology at the University Hospital Frankfurt, explains: “In a unique situation like this we also have to take new paths in research. An already existing cooperation between the Cinatl and Münch laboratories made it possible to quickly focus the research on SARS-CoV-2. The findings so far are a wonderful affirmation of this approach of cross-disciplinary collaborations."
Among the substances that stopped viral reproduction in the cell culture system was 2-Deoxy-D-Glucose (2-DG), which interferes directly with the carbohydrate metabolism necessary for viral reproduction. The US company Moleculin Biotech possesses a substance called WP1122, a prodrug similar to 2-DG. Recently, Moleculin Biotech announced that they are preparing a clinical trial with this substance based on the results from Frankfurt. https://www.moleculin.com/covid-19/.
Based on another one of the substances tested in Frankfurt, Ribavirin, the Canadian company Bausch Health Americas is starting a clinical study with 50 participants: https://clinicaltrials.gov/ct2/show/NCT04356677?term=04356677&draw=2&rank=1
Dr Christian Münch, Head of the Protein Quality Control Group at the Institute for Biochemistry II and lead author, comments: “Thanks to the mePROD-technology we developed, we were for the first time able to trace the cellular changes upon infection over time and with high detail in our laboratory. We were obviously aware of the potential scope of our findings. However, they are based on a cell culture system and require further testing. The fact that our findings may now immediately trigger further in vivo studies with the purpose of drug development is definitely a great stroke of luck." Beyond this, there are also other potentially interesting candidates among the inhibitors tested, says Münch, some of which have already been approved for other indications.
Professor Jindrich Cinatl from the Institute of Medical Virology and lead author explains: “The successful use of substances that are components of already approved drugs to combat SARS-CoV-2 is a great opportunity in the fight against the virus. These substances are already well characterised, and we know how they are tolerated by patients. This is why there is currently a global search for these types of substances. In the race against time, our work can now make an important contribution as to which directions promise the fastest success."
Publication: SARS-CoV-2 infected host cell proteomics reveal potential therapy targets. Denisa Bojkova, Kevin Klann, Benjamin Koch, Marek Widera, David Krause, Sandra Ciesek, Jindrich Cinatl, Christian Münch. Nature DOI: 10.1038/s41586-020-2332-7, https://www.nature.com/articles/s41586-020-2332-7 (active starting 10am London time (BST), 5am US Eastern Time)
downloaded here: http://www.uni-frankfurt.de/88340061
Captions: Dr. Christian Münch (Credit: Uwe Dettmar for Goethe University Frankfurt)
Prof. Dr. rer. nat. Jindrich Cinatl (Credit: University Hospital Frankfurt)
More about the mePROD method: Biochemistry researchers at Goethe University develop a new proteomics procedure https://aktuelles.uni-frankfurt.de/englisch/biochemistry-researchers-at-goethe-university-develop-new-protoeomics-procedure/
Professor Dr. rer. nat. Jindrich Cinatl, Head of the Research Group Cinatl, Institute for Medical Virology, University Hospital Frankfurt am Main, Tel. +49 69 6301-6409, E-mail: email@example.com,
Christian Münch, Head of the Group Protein Quality Control, Institute for Biochemistry II, Goethe University Frankfurt am Main Tel: +49 69 6301 6599, E-Mail: firstname.lastname@example.org,
Heat-loving bacteria use various tiny surface hairs for movement and DNA reception
FRANKFURT. Bacteria of the species Thermus thermophilus possess two types of extensions on their surface (pili) for the purpose of motion and for capturing and absorbing DNA from their environment. This has been discovered by researchers at Goethe University together with researchers in Great Britain. The discovery of the motion pilus helps to better understand the functionality of the DNA-capturing pilus functions. (Nature Communications, DOI 10.1038/s41467-020-15650-w)
The bacteria Thermus thermophilus likes it hot. It was first discovered in the hot springs at Izu in Japan, where it thrives at an optimal temperature of about 65 degrees Celsius. Like all bacteria, Thermus thermophilus has developed mechanisms to adjust to changing environmental conditions. The bacteria changes its genetic material by exchanging DNA with other bacteria, or absorbing DNA fragments from its environment. These might come from dead bacteria cells, plants or animals. The bacteria incorporate the DNA fragments into their genetic material and keep it if the DNA proves useful.
Microbiologists at Goethe University led by Professor Beate Averhoff from the Molecular Microbiology & Bioenergetics of the Department of Molecular Biosciences together with a team of scientists led by Dr Vicky Gold from the “Living Systems" Institute of the University of Exeter in Great Britain have now studied the tiny hairs (called pili) on the surface of the Thermus bacteria. The scientists discovered that there are two types of pili with different functions. High-resolution electron microscope images from Great Britain allow thick and thin pili to be distinguished, and the Frankfurt scientists used biochemical and molecular biological methods to demonstrate that the thick pili are for DNA capture, and the thin pili for moving on surfaces.
“We want to find out exactly how Thermus thermophilus absorbs DNA from its environment using its pili, as the precise mechanism is unknown," explains Professor Beate Averhoff from the Institute for Molecular Biosciences at Goethe University. “Through our most recent investigations we have learned that Thermus bacteria have distinct pili for motion. Therefore, the thick pili possibly serve the purpose of DNA absorption, which demonstrates how important this process is for the bacteria. In our structure analyses we also found an area on the thick pili where DNA could bind."
The interplay of electron microscopy and molecular biology also allowed the scientists to better understand the mechanics of the pili. For both motion and DNA absorption, pili have to be dynamic, i.e., able to be extended and retracted. “For the first time, the high resolution structure of both pili gave us insights not only into the structure of the pili, but also into the dynamics," Averhoff explains.
Since pili are widespread and in pathogenic bacteria are also responsible for attaching to the host, this may lead to new points of attack for preventing infectious processes.
Publication: Alexander Neuhaus, Muniyandi Selvaraj, Ralf Salzer, Julian D. Langer, Kerstin Kruse, Lennart Kirchner, Kelly Sanders, Bertram Daum, Beate Averhoff, Vicki A. M. Gold (2020). Cryo-electron microscopy reveals two distinct type-IV pili assembled by the same bacterium. Nature Communications, https://doi.org/10.1038/s41467-020-15650-w )
An image may be downloaded here: http://www.uni-frankfurt.de/88063448
Caption: Bacteria of the species Thermus thermophilus possess different tiny hairs (pili) which are used either to capture DNA or for motion. This has been discovered by scientists at Goethe University Frankfurt and the University of Exeter. Graphic: aduka, Agency Frankfurt am Main(www.aduka.de) for Goethe University Frankfurt.
Computer models of merging neutron stars predicts how to tell when this happens
FRANKFURT. According to modern particle physics, matter produced when neutron stars merge is so dense that it could exist in a state of dissolved elementary particles. This state of matter, called quark-gluon plasma, might produce a specific signature in gravitational waves. Physicists at Goethe University Frankfurt and the Frankfurt Institute for Advanced Studies have now calculated this process using supercomputers. (Physical Review Letters, DOI 10.1103/PhysRevLett.124.171103)
Neutron stars are among the densest objects in the universe. If our Sun, with its radius of 700,000 kilometres were a neutron star, its mass would be condensed into an almost perfect sphere with a radius of around 12 kilometres. When two neutron stars collide and merge into a hyper-massive neutron star, the matter in the core of the new object becomes incredibly hot and dense. According to physical calculations, these conditions could result in hadrons such as neutrons and protons, which are the particles normally found in our daily experience, dissolving into their components of quarks and gluons and thus producing a quark-gluon plasma.
In 2017 it was discovered for the first time that merging neutron stars send out a gravitational wave signal that can be detected on Earth. The signal not only provides information on the nature of gravity, but also on the behaviour of matter under extreme conditions. When these gravitational waves were first discovered in 2017, however, they were not recorded beyond the merging point.
This is where the work of the Frankfurt physicists begins. They simulated merging neutron stars and the product of the merger to explore the conditions under which a transition from hadrons to a quark-gluon plasma would take place and how this would affect the corresponding gravitational wave. The result: in a specific, late phase of the life of the merged object a phase transition to the quark-gluon plasma took place and left a clear and characteristic signature on the gravitational-wave signal.
Professor Luciano Rezzolla from Goethe University is convinced: “Compared to previous simulations, we have discovered a new signature in the gravitational waves that is significantly clearer to detect. If this signature occurs in the gravitational waves that we will receive from future neutron-star mergers, we would have a clear evidence for the creation of quark-gluon plasma in the present universe."
Publication: Post-merger gravitational wave signatures of phase transitions in binary mergers. Lukas R. Weih, Matthias Hanauske, Luciano Rezzolla, Physical Review Letters Physical Review Letters DOI 10.1103/PhysRevLett.124.171103 https://link.aps.org/doi/10.1103/PhysRevLett.124.171103
Visualisation of merging neutron stars: https://www.youtube.com/watch?v=rj-r-YA9d6E&t=1s
This simulation shows the density of the
ordinary matter (mostly neutrons) in red-yellow. Shortly after the two stars
merge the extremely dense centre turns green, depicting the formation of the
Pictures may be downloaded here: http://www.uni-frankfurt.de/87973606
Caption Montage: Montage of the computer simulation of two merging neutron stars that blends over with an image from heavy-ion collisions to highlight the connection of astrophysics with nuclear physics. Credit: Lukas R. Weih & Luciano Rezzolla (Goethe University Frankfurt) (right half of the image from cms.cern)
Caption Simulation: Shortly after two neutron stars merge a quark gluon plasma forms in the centre of the new object. Red yellow: ordinary matter, mostly neutrons. Credit: Lukas R. Weih & Luciano Rezzolla (Goethe University Frankfurt)
Further information: Goethe University Frankfurt, Prof. Dr. Luciano Rezzolla, Chair of Theoretical Astrophysics, Institute for Theoretical Physics, +49-69-79847871/47879, email@example.com, https://astro.uni-frankfurt.de/rezzolla/
Psychologists at Goethe University Frankfurt research the short-term memory of visual impressions
FRANKFURT. When we look at the same object in quick succession, our second glance always reflects a slightly falsified image of the object. Guided by various object characteristics such as motion direction, colour and spatial position, our short-term memory makes systematic mistakes. Apparently, these mistakes help us to stabilise the continually changing impressions of our environment. This has been discovered by scientists at the Institute of Medical Psychology at Goethe University. (Nature Communications, DOI 10.1038/s41467-020-15874-w)
This is, however, not at all true. Our short-term memory deceives us. When looking to the left the second time, our eyes see something completely different: the bicycle and the car do not have the same colour anymore because they are just now passing through the shadow of a tree, they are no longer in the same location, and the car is perhaps moving more slowly. The fact that we nonetheless immediately recognise the bicycle and the car is due to the fact that the memory of the first leftward look biases the second one.
Scientists at Goethe University, led by psychologist Christoph Bledowski and doctoral student Cora Fischer reconstructed the traffic situation – very abstractly – in the laboratory: student participants were told to remember the motion direction of green or red dots moving across a monitor. During each trial, the test person saw two moving dot fields in short succession and had to subsequently report the motion direction of one of these dot fields. In additional tests, both dot fields were shown simultaneously next to each other. The test persons all completed numerous successive trials.
The Frankfurt scientists were very interested in the mistakes made by the test persons and how these mistakes were systematically connected in successive trials. If for example the observed dots moved in the direction of 10 degrees and in the following trial in the direction of 20 degrees, most people reported 16 to 18 degrees for the second trial. However, if 0 degrees were correct for the following trial, they reported 2 to 4 degrees for the second trial. The direction of the previous trial therefore distorted the perception of the following one – “not very much, but systematically," says Christoph Bledowski. He and his team extended previous studies by investigating the influence of contextual information of the dot fields like colour, spatial position (right or left) and sequence (shown first or second). “In this way we more closely approximate real situations, in which we acquire different types of visual information from objects," Bledowski explains. This contextual information, especially space and sequence, contribute significantly to the distortion of successive perception in short-term memory. First author Cora Fischer says: “The contextual information helps us to differentiate among different objects and consequently to integrate information of the same object through time."
What does this mean for our traffic situation? “Initially, it doesn't sound good if our short-term memory reflects something different from what we physically see," says Bledowski. “But if our short-term memory were unable to do this, we would see a completely new traffic situation when we looked to the left a second time. That would be quite confusing, because a different car and a different cyclist would have suddenly appeared out of nowhere. The slight 'blurring' of our perception by memory ultimately leads us to perceive our environment, whose appearance is constantly changing due to motion and light changes, as stable. In this process, the current perception of the car, for example, is only affected by the previous perception of the car, but not by the perception of the cyclist."
Publication: Context information supports serial dependence of multiple visual objects across memory episodes. Cora Fischer, Stefan Czoschke, Benjamin Peters, Benjamin Rahm, Jochen Kaiser, Christoph Bledowski. Nat. Commun. 11, 1932 (2020). https://doi.org/10.1038/s41467-020-15874-w
Frankfurt researchers solve puzzle of Compton scattering – new approach for testing theories in quantum mechanics