Interview: G. V. Shivashankar
Why Covid-19 hits older people especially hard
The older you are, the higher the risk of dying from a coronavirus infection. G. V. Shivashankar, a group leader at PSI and professor at ETH Zurich, now presents an unusual thesis in a publication in Nature Reviews: that the stiffness of cells might play a decisive role in the course of the disease. In this interview, he explains why.
Mr. Shivashankar, how stiff a lung tissue is might have an influence on how susceptible it is to the coronavirus. You and your collaborator Caroline Uhler from ETH Zurich wrote this in a comment in Nature Reviews. How did you arrive at that idea?
G. V. Shivashankar: Coronaviruses infect both younger and older people, but in aged patients, the virus has proven to be much more dangerous. So we were wondering: In what ways is old lung tissue different from younger tissue? One answer is that flexibility is different. Generally, the older a person is, the stiffer the lung tissue is.
How can that have an influence?
Various physical forces act on cells, such as pushing, pulling and tugging. Over the years, it has become clear that cells not only sense these physical forces, but also react to them. This means that a cell can sense tension and then pass this information on to the cell nucleus to regulate genes. As we age, the lung tissue becomes stiffer – and this has a dramatic effect on the way a cell functions in lung tissues.
In other words: Stiffer cells change the way they read their genetic material and translate this information into proteins?
Exactly. What we realized over the years is that the stiffness of a tissue induces dramatic changes in the way the DNA and the cytoskeleton are set up inside a cell. Let me explain: All cells in our body have a certain shape. It's like a tent held up by poles. In the case of cells, the cytoskeleton does a similar job of providing support. It is a complex network of interlinking protein fibres. Recent research, including our own, has revealed important links between the cytoskeleton on the one hand and the shape and size of the cell nucleus on the other hand.
How can the cytoskeleton affect what happens inside the cell nucleus?
If the entire genetic material of a human cell, which is stored in the form of extremely long molecular chains in the cell nucleus, were stretched out on the ground, the cumulative length of these chains would be a couple of metres. This long thread has to be packed into the small cell nucleus. The cytoskeletal fibres apply forces on the nucleus, helping to maintain this tight packing. They also help in opening and closing this huge amount of material – for example, when the genetic material, that is, the DNA, is being read to produce proteins.
Why is all that so important when coronaviruses come into play?
Coronaviruses hijack the cells' immune system in order to be able to reproduce. When a virus infects a cell, it uses the signalling pathways of the host cell – complex networks of molecules through which different parts of a cell communicate with each other. The virus uses this communication system to get cells to replicate the virus's genome. Simultaneously, the virus dampens the cell's immune response. We were intrigued to find out that coronaviruses interact with exactly the same signalling pathways during infection that are turned on in cells when they become stiffer.
So you hypothesise that the virus can therefore reproduce better in aged cells?
Yes. Our hypothesis is that the virus infects both old and young people in the same way, but that once in the cell, the virus can interact more effectively with the signalling pathway in older cells. This is why we believe the virus can replicate and reproduce better in aged people.
Increasingly, however, there are reports that young people too become seriously ill and even die from Covid-19. Doesn't that contradict your hypothesis?
Well, every cell is a little different because the microenvironment in which it lives is not a homogenous one. It is quite plausible that even in younger people there are pockets of lung tissue that are stiffer due to a previous illness, for example. Everyone is different. Some people have stronger lungs, others weaker. But in an aging person, in any case, the proportion of stiffer lung tissue is much higher.
How do you want to test your hypothesis?
When we get lung tissue from people who have died of Covid-19, we want to use high-resolution imaging to examine that tissue at the level of individual cells. Then we want to analyse which cells contain more viruses and which less. We will examine the state of cells with more versus less viruses and create a kind of map: How is each cell’s nucleus set up, how is the cytoskeleton structured, and how the signalling pathways? Such an analysis will reveal whether cells in stiffer tissues are infected by a larger number of viruses.
Assuming your hypothesis is correct – how could that contribute to the fight against the Covid-19 pandemic?
If the coronavirus really takes advantage of the tissue's stiffness and the corresponding signalling pathways within cells, this could help in finding a treatment. There are already many approved substances that target these pathways. We could then test these drugs to see if they block virus replication.
How exactly do you want to investigate this?
We plan to create tissue cultures in the Petri dish that mimic the lung tissue. Such cultures are called organoids, and have become a common, popular laboratory technique. In such cultures, we can tune the stiffness of the tissue; we can produce "younger" softer organoids and "older" stiffer ones. We then want to infect these tissues with coronavirus particles and rapidly screen drugs. Using bioimaging, genomic analyses and machine learning, we want to find out which protein-protein interactions the virus is hijacking – this will help us to find a drug that stops the virus from multiplying.
Since these drugs are already approved and available, wouldn't it be easier to test them directly on patients?
There are hundreds of drugs that target the corresponding signalling pathways in the cell. And maybe you don't need a single drug, but a combination of them. We also don't know what concentrations would be best. Some drugs have already been used in the clinic on corona patients who were in very critical condition, but intelligent screening, such as we suggest, would allow the method of treatment to be carefully analysed and selected.
Will the infrastructure at PSI be useful for your research?
Definitely. PSI has a number of facilities that are unique in the world. The Swiss Light Source SLS in particular is a very important element in our project. To use tissue cultures in a way most likely to succeed, we need excellent bioimaging to examine cells, DNA structures and viruses inside the cells with high resolution.
The Biology and Chemistry Division at PSI is also a leader when it comes to analysing protein structures and investigating the relationships between the structure and function of a protein – that expertise will be invaluable in this project. The excellent microfabrication facilities at PSI to create organoids and new diagnostic platforms for such studies will be indispensable. Strong computational programs at PSI, integrating data science, are just as crucial.
Is it a special characteristic of coronaviruses to exploit the stiffer mechanics of a cell, or could this also apply to other viruses? The flu, for example, also hits older people much harder than younger people.
Yes, I think the idea that tissue stiffness changes with age may play an important role for many diseases. In fact, we have a large program to look at tumour samples in our laboratory. Cancer begins with a single cell that grows into a tumour – so here too, the mechanical state of the microenvironment is critical. We are currently starting to discuss collaborations to pursue those studies with the Centre for Radiopharmaceutical Sciences and the Centre for Proton Therapy at PSI. And there are many other age-related diseases, such as neurodegeneration, in which tissue stiffness could play a role. Understanding exactly what happens in older, stiffer tissues, how the mechanics of a tissue can interact with gene regulation, is still underappreciated but gradually becoming an important aspect in the study of many diseases. I am most excited to carry out this research at PSI.
Interview: Paul Scherrer Institute/Brigitte Osterath