Multifaceted and up-to-date – Coronavirus research in the SNI networkSNI INSight August 2020
The SARS-CoV-2 coronavirus has been occupying all of our minds over the past weeks and months. No one imagined that the world could change so radically in such a short space of time. At the start of the pandemic, we didn’t know much about the virus. Thanks to the tremendous dedication of researchers around the world, we now understand much more about how the virus spreads, how we can detect it, what the consequences of infection are and how we can keep infection rates as low as possible. Members of the SNI network are also involved in research on the virus – some through projects they initiated themselves, and others through experiments that began earlier but whose results can be applied to coronavirus research. Here we provide a brief overview of some of the projects.
New approaches in diagnostics
Rapid detection of the novel coronavirus SARS-CoV-2 is a significant part of the fight. Only if we know quickly whether a patient is infected, can the massive spread be reduced by measures such as quarantine. Information about whether someone has already been exposed to the virus and whether the body has produced specific antibodies that protect against reinfection is also important. In order to expand testing capabilities, several research groups from the SNI network are working on the development of new test systems.
Detecting the virus in different media
Together with their interdisciplinary teams, Professor Sai Reddy (Department of Biosystems Science and Engineering, ETH Zurich in Basel, D-BSSE) and Professor Michael Nash (Department of Chemistry, University of Basel and D-BSSE) aim to develop a new diagnostic test for COVID-19 infections.
This new test is based on high-throughput sequencing of SARS-CoV-2 and utilizes an approach called “molecular barcoding” to test many patients in parallel. Using this method, about 5,000 individual patient samples could be tested for SARS-CoV-2 at once. The researchers are also developing a high-throughput serological platform for detecting antibodies against SARS-CoV-2. Patients who have survived an infection with the virus and have these antibodies in their blood are likely to be immune to new infections for a certain period of time. Professor Reddy is leading this project, which is funded by the Botnar Research Center for Child Health (BRCCH).
Dr. Sören Fricke (CSEM Muttenz) is also involved in a BRCCH-funded diagnostics project. He is working in a team led by Professor Daniel Paris (Swiss Tropical and Public Health Institute, TPH). Their aim is to develop a simple, low-cost assay for detecting SARS-CoV-2 antibodies in saliva.
In a first step, the team is currently proving that the saliva contains a sufficiently high concentration of antibodies. They will then begin developing a lateral flow assay, which works like a pregnancy test. CSEM will contribute to the project with developments in the area of cellulose pads, sample preparation and visuals, in order to optimize the test for saliva and for readability on smartphones.
The groups led by Professors Ernst Meyer and Christoph Gerber (both Departement of Physics, University of Basel) are investigating whether a mechanical sensor for the ultrasensitive detection of coronavirus could be used in public spaces and vehicles. Their approach involves applying short RNA fragments, which are complementary to specific RNA segments of the virus, to a cantilever. If these RNA fragments come into contact with virus RNA, it causes a hybridization reaction and creates mechanical stress. This bends the mechanical sensor, and the bending can be detected by an optical detection system. The method could be used to identify even very low virus concentrations.
Reaching the goal with a microfluidic system
Various groups in the SNI network are working on microfluidic systems and are investigating their use in COVID-19 research.
Thomas Mortelmans, a doctoral student at the SNI PhD School at PSI, is writing his doctoral dissertation on the development of a microfluidic system that can be used to sort cell organelles and other biological nanoobjects based on their size. He is now investigating whether the fluidic system can also be used for antibody testing. Functionalized nano- or microparticles (beads) bind specifically to the antibodies. These can then be purified and identified.
Dr. Yasin Ekinci, Dr. Celestino Padeste, Dr. Xiaodan Li (all PSI) and Dr. Thomas Braun (Biozentrum, University of Basel) are supervising Mortelmans’ doctoral dissertation.
Infection with SARS-CoV-2 causes the new respiratory disease COVID-19. According to the Robert Koch Institute, the disease can take different courses that vary enormously – from asymptomatic cases to severe pneumonia accompanied by respiratory failure. According to data from the German reporting system, about 17% of the cases reported in Germany by July 2020 required hospital treatment (source). In Switzerland and Lichtenstein the hospitalisation rate was around 12% (source).
Severe pneumonia causes an acute undersupply of oxygen, and the patient requires mechanical ventilation. The ventilator pushes oxygen into the lungs, and from there it enters the blood.
Dr. Sören Fricke (CSEM Muttenz) is involved in a BRCCH-funded project led by Professor Thomas Erb (University Children’s Hospital Basel, UKBB) that is seeking to make ventilation safer. The researchers are planning to integrate an innovative pressure sensor into low-cost ventilators. In doing so, they hope to improve ventilation and help overcome the global shortage of ventilators. Erb und Fricke are building on a joint project in which CSEM integrated a flexible, microstructured pressure sensor into a tube. The sensor measures the pressure closer to the respiratory organs, which makes it easier to avoid the sensitive tissue being damaged by the mechanical ventilation.
Production protocol for in-demand drug
A team working with Professor Jörg Huwyler and Dr. Tomaž Einfalt at the University of Basel’s Pharmazentrum has developed, produced and characterized a generic formulation of the drug hydroxychloroquine (HCQ). HCQ is a quinoline derivative used to treat malaria and rheumatic diseases. Recent reports that HCQ could be effective against SARS-CoV-2 have led to a rapid increase in global demand for the drug1. As a result, patients with rheumatic diseases being treated with HCQ were facing acute shortages of their medication. The scientists working at the Pharmazentrum hope that the published production protocol will help ensure that sufficient quantities of HCQ tablets can be produced.
Learning to understand the new virus
Overall, it is important that we gain a better understanding of SARS-CoV-2 so that we can effectively protect ourselves against infection and effectively treat infections.
InterAx Biotech AG, a startup from PSI and a long-term partner in the Nano Argovia Program, is working with the Hospital del Mar Medical Research Institute (IMIM) in Barcelona on identifying antiviral active substances. The researchers are looking for potential antiviral compounds in a virtual 3D-structure database using specific computational algorithms. They will then use an assay with a SARS-CoV-2 pseudovirus to test whether the compounds can prevent the virus entering the cells. The team is investigating two different ways of attacking the virus.
The group led by Professor Thomas Jung (Department of Physics, University of Basel and PSI) is planning to investigate whether the composition or consistency of a medium such as saliva or tears that contains the virus can prolong the survival of the virus. The current literature is contradictory. Some papers report that the virus can remain infectious on surfaces for up to three weeks.
Jung’s group is currently seeking partners to produce the SARS-CoV-2 spike protein and “dummy” viruses from artificial vesicles. The “dummy” viruses will be embedded in a matrix modeled on mucous. The researchers will then use various methods to investigate how different types of disinfection (UV light, alcohol, vinegar) and climate factors affect the destruction of the vesicles and the denaturation of the spike proteins. The work should help with planning effective and cost-efficient disinfection campaigns.
The group of Argovia Professor Roderick Lim is also interested in understanding SARS-CoV-2. The team has been working for many years on the transport of molecules into and out of the cell nucleus, which is regulated by nuclear pore complexes in the membrane of the cell nucleus.
Based on findings from SARS-CoV-1 studies, various viral proteins and proteases from SARS-CoV-2 are suspected of influencing the function of the nuclear pore complexes. It is not currently known whether and how SARS-CoV-2 damages these selective channels to disrupt the transport of vital proteins into the cell nucleus.
Using tests with antiviral compounds, the scientists plan to investigate whether it is possible to prevent potential damage that SARS-CoV-2 might inflict on the nuclear pore complexes and to sustain transport through the nuclear membrane.
SNI doctoral student Stefano di Leone is working on a project that will improve our understanding of how viruses can penetrate membranes. Biological membranes are formed from lipids and are typically between 3 and 5 nm thick.
Artificial planar membranes that spontaneously form from amphiphilic block copolymers in aqueous environments are a very good way of examining transport processes through the membrane. The artificial membranes are between 5 and 25 nm in diameter and are more stable than their natural counterparts.
When the amphiphilic block copolymers are mixed with lipids, membranes form with specific domains of polymers and lipids. Functional proteins can then be very immobilized in a highly targeted manner on either the lipid or the polymer domain. These model membranes can be used to investigate how the virus attaches itself to the host. It is also possible to test whether proteins that induce a specific reaction from the virus can be integrated into the membrane.
Di Leone’s work is being supervised by Professor Wolfgang Meier (Department of Chemistry, University of Basel) and Professor Uwe Pieles (FHNW School of Life Sciences).
“Our knowledge about SARS-CoV-2 will continue to grow in the coming weeks and months. We are very much looking forward to seeing the results that will come out of global studies and those being conducted within the SNI network.”
Professor Christian Schönenberger, SNI Director
1 A research group from the University of Basel and University Hospital in Basel recently published that the concentration of hydroxychloroquine in the lungs of Covid-19 patients is not sufficient to fight the virus (media release).