“We want to understand exactly the structure of Sars-CoV-2”

BerlinAn international research team led by structural biologist Andrea Thorn has been trying since the beginning of the pandemic to decipher individual protein components of Sars-CoV-2 as precisely as possible – among other things, so that drug developers around the world can search for remedies. But there is still a lot that remains to be clarified.

Berlin newspaper: Frau Thorn, wWhy is it so important to structurally examine the coronavirus?

Andrea Thorn: The coronavirus is made up of molecules. Understanding their structure exactly and having models of these molecules is necessary in order to find out how Sars-CoV-2 works in the first place: If, for example, the virus takes over a human cell and causes it to produce more viruses, then every single step has been taken made from a protein molecule. And disabling these protein molecules therefore means stopping the infection. But you can only do that if you know it very well: you have to understand the lock in order to be able to build a key. We are improving the molecular models of the coronavirus and making them publicly available online so that drug developers can specifically search for active ingredients that match the proteins and block them, for researchers at universities and also in the pharmaceutical industry.

Photo: Thomas Splettstößer/SciStyle/Coronavirus Structural Task Force

In the 3D illustration you can also see the sugar chains (gray) on the spikes (green). They make the surface of the virus slimy, making it harder for the immune system to recognize it.

Photo: Thomas Splettstößer/SciStyle/Coronavirus Structural Task Force

The Sars-CoV-2 genome is one of the longest known genomes in the viral world.

You head the “Coronavirus Structural Task Force”, an international network of experts in the field of structural biology. How did it come about?

In February 2020 I looked at molecular models of the Sars coronavirus, which had already triggered a pandemic in 2002 and is very similar to the new coronavirus, and found out that more biological knowledge can be extracted from the structures with today’s methods. With this knowledge, I started a month later, together with my work group and international colleagues, to systematically examine the structures from Sars and the new coronavirus. From then on we have grown steadily. Today we’re a pretty diverse group with 27 team members in nine time zones. That was quite unusual for a research project: no professor at the top, at the beginning without research funding – we are now funded by the Federal Ministry of Research – and all results go online immediately. But we were able to use our knowledge to fight the pandemic – and that was the reason we joined forces.

So the pharmaceutical companies don’t need approval from the task force?

No. We want drug developers from the Philippines to Brazil or India, all over the world, to have access to our data.

What does Sars-CoV-2 look like in simple terms?

The coronavirus is not completely round. It’s like a soap bubble in constant motion – wobbly, if you will. The outer layer is thin, soft and made up of fatty acids that are chemically similar to soap. Because of this, soap can completely dissolve the shell of the virus – provided that the hands are washed long enough. The outer layer is covered by so-called spines, which allow the virus to penetrate into lung cells, for example. But what you call a virus – that is actually just the form of transport, the “virion”. Inside, it carries genetic material for a total of 28 protein molecules, most of which are first built in the host cell in order to transform it into a virus production facility.

All this is difficult to imagine for laypeople.

Many people still believe that viruses cannot be made visible. They may even fail to realize that the colored images shown in the media are images of the virus. The virus and its danger are not visible. The people do not see the many dead, they do not see the completely overloaded intensive care units because there is a ban on visits. This is also one of the reasons why we also made and printed a 3D model of the virus so that we can make the danger a bit more tangible.

Photo: .Judith Flurer/RVZ/Coronavirus Structural Task Force

As accurate as possible: 3D model of Sars-Cov-2 on a scale of one to a million.

How do you decipher the molecular structures?

The entire virus is not measured, but individual molecules. Structural biologists are looking for one of the 28 different proteins that make up Sars-CoV-2, for example the spikes on the surface of the virus. The molecule is not dangerous on its own, which makes work a lot easier. Genetically modified bacteria produce many copies of this molecule. Then there are two options: Either we take the thinly applied sample, cool it down to very low temperatures and put it under an electron microscope. A so-called transmission image is created, a negative image of the virus protein. From these individual snapshots of the molecule you can make a three-dimensional picture and use it to build a model of the molecule.

The other option is to crystallize the egg white. The crystals are a tenth of a millimeter in size and consist of thousands of identical protein molecules. This crystal is then measured using X-rays at a so-called synchrotron, a particle accelerator, such as Bessy II in Berlin. These data also make it possible to build a three-dimensional model of the molecule from which the crystal was made.

Foto: Coronavirus Structural Task Force

To person

Andrea Thorn is a structural biologist at
Institute for Nanostructure and Solid State Physics at the University of Hamburg.

Thorn set up the “Coronavirus Structural Task Force”, which is funded by the Federal Ministry of Education and Research, shortly after the WHO declared the spread of the new coronavirus a pandemic.

What role does the task force take on in these research steps?

We review and improve the models that were generated with the measurement data. My team members sit in front of a 3D monitor wearing special glasses and look at every single atom. Sometimes we build the models from scratch. Of course, you don’t just have to orientate yourself on the measurement data, but also position the individual atoms in a chemically sensible way, at the correct distance from one another: It’s a bit like how computers play.

How long do the individual steps take?

The multiplication in the bacterium can take one to 36 months with the purification until it works. The egg whites crystallize in one to 24 months. The measurement in the synchrotron takes about three minutes. The data acquisition and the assembling of the structures with the special glasses take a week to four months.

That means your team is responsible for the 3D modeling of the structures?

I agree. With 10,000 or more atoms per molecule, mistakes can easily happen – especially under the pressure of a global pandemic. These mistakes can doom the development of a drug from the outset. That is why we have to find and fix the errors beforehand. This is also very important for the biological questions about the virus. We are not the pioneers who will measure the structures, nor are we the ones who will find the medicine. We can enable and facilitate it and ensure that everything that is possible is really extracted from the experimental data.

Photo: Janet Iwasa,/Universität Utah/Coronavirus Structural Task Force

With the help of the spike protein or the sting, the coronavirus binds to a receptor in the host cell. A chain reaction ensues: the membrane of the cell fuses with the envelope of the virus. It is unclear exactly how this mechanism works.

How big are the gaps in knowledge about Sars-CoV-2 today?

A lot has been discovered in the past year. Researchers around the world have worked together – so do we! But of the 28 molecules of the virus, only 17 have so far been successfully measured. And even about these 17 we know we don’t know enough. Its a lot to do.

Is there anything that amazed you in the course of your corona research?

At Sars, people got very sick very quickly and went to the hospital soon after their infection. Once they were hospitalized, they could no longer infect anyone – that is, the outbreak could be more easily contained. With the novel coronavirus, around 15 percent of people develop no or few symptoms, but are still contagious. So the coronavirus is particularly dangerous because it doesn’t make you sick that badly. That sounds paradoxical, but of course it means that many more people can become infected and, in the end, there are many more deaths.

What do you know about the molecular details of virus mutants, new virus variants?

So far there are not many structures – the determination takes a few weeks or months – but these structures can be simulated very easily on the computer, as only a few of the thousand atoms in the molecule change.

What would have happened if scientists hadn’t stopped researching the virus after the Sars pandemic from 2002 to 2004?

The studies never stopped entirely. There were researchers like the Lübeck biochemist Rolf Hilgenfeld, who did corona research for many years in a quiet little room – with one and a half positions and small budgets. We owe the knowledge at the beginning of the corona pandemic to them. But yes, after the Sars pandemic, research declined significantly and was no longer funded as much. With Sars-CoV-2 it becomes clearer than ever: It is worthwhile to invest in research projects in the long term, and indeed for longer than one legislative period. If Sars research had been carried out continuously, we would have had a lot more knowledge about coronaviruses at the beginning of the pandemic. That would have been a huge benefit and I hope we are better prepared for the next pandemic.

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