A crisis calls for community: how three Oncode Investigators help find solutions for COVID-19

Bianca-Olivia Nita

For more than half a year now, finding solutions to solve the current COVID-19 crisis is a priority - not only for the Netherlands, but for the entire world. With labs closed and the entire country in lockdown, the urgency and the pressure became almost tangible. In the midst of the chaos, Oncode Investigators Marvin Tanenbaum, Hans Clevers (both Hubrecht Institute) and Lude Franke (UMC Groningen) decided to put their knowledge and skills to good use. For Tanenbaum contributing meant a step out of the box. For Clevers, it was a logical continuation of the work he had been doing for decades. And for Franke, the crisis brought an opportunity. And what all three of them found in these last months was not only new ideas and solutions, but also a sense of community and meaning, and a renewed clarity about the importance of basic science.

The phone calls

In the first week of the lockdown, Marvin Tanenbaum was at home. ‘I was watching TV and I was getting really frustrated. They were saying that not enough tests could be done because of the problems with the test. And as a molecular biologist, it felt so strange to be at home. I thought – shouldn’t I be contributing something to this crisis? We have all this expertise in the Netherlands, why are we all sitting at home?’ He started making phone calls. He called his colleagues at the Hubrecht Institute, Oncode Investigators Geert Kops, Alexander van Oudenaarden and Wouter de Laat, who would soon team up with Tanenbaum. They all agreed the situation called for action and for finding a way to have a quicker, easier and cheaper way to do the test. ‘We saw that several of our colleagues abroad had similar initiatives and that a lot of innovation was happening around the world, including in diagnostics. And that motivated us,’ says Tanenbaum.

Hans Clevers had a different kind of idea. Well known for developing mini organs called ‘organoids’, which revolutionized the study of cancer, Clevers wondered how organoids could be used to understand the virus better. ‘The virus responsible for COVID-19 causes pneumonia, but there were lots of signs that the virus was not only in the lungs, but possibly in the gastrointestinal system as well. This was important as some patients only had gastrointestinal issues and were not diagnosed as COVID-19 patients, and they should have been. Looking into the way the virus infects the gut is also relevant to understand if the virus can spread through faecal routes and not only through the air, ending up for example in the sewage system’ says Clevers. ‘I thought of this on the 15th of March and thought – why don’t we start working with a lab that has the virus. I called a virology lab in Rotterdam, then an electron microscopy lab in Maastricht, and we immediately started collaborating’.

In the north of the Netherlands, Lude Franke and his colleagues had just recently completed the generation and quality control phase of genotype data for Lifelines, a large database gathering biomedical information of 167,000 people living in the three northern provinces of the country. Franke is a geneticist and had been working on this project for years. ‘In a sense that genotype data we had gathered was waiting to be used for a good purpose’ he says. ‘I was on the bike going to the supermarket, when I realized that we could get in touch with the participants of the Lifelines biobank and ask them whether they had symptoms or had been diagnosed with COVID-19. Next, I started making phone calls to colleagues.’

Marvin Tanenbaum (photo by: Marloes Verweij)

Insights, knowledge and solutions

These phone calls were the beginning of three projects. For Tanenbaum and De Laat, talking to others and taking a closer look at what was being done at the time, made clear what the challenges were. ‘We found out when we visited one of the diagnostics labs at UMC Utrecht that the molecular biology behind the tests was quite robust and didn’t need much adaptation, but the whole logistics and automation around it was not built to do large scale population screenings. And this was something we wanted to change’. Together with his colleagues, he got in contact with Genmab, one of the largest biotech companies in Europe, which has a lot of experience in automation. ‘We decided to team up with them and build a new platform from scratch that can do high throughput instead of single patient centred diagnostics,’ says Tanenbaum.

If there is a crisis like this, the scientists are the ones that can find solutions. - Marvin Tanenbaum

In the meantime, Clevers and his team moved forward as well. ‘We did one huge experiment that worked – we took lung and gut organoids and infected them with the COVID-19 virus, looking at how the virus infected them and how it proliferated. The results were spectacular. The virus is extremely good at multiplying in the lungs, but it looked like it was much better at multiplying in the gut,’ says Clevers. ‘We immediately wrote a paper, while replicating the experiment and submitted it to Science. After you finish a study, it usually takes at least a year to have it published. Now the project took six weeks from start, through two rounds of review, to publication: The paper was online on May 1st’.

Three weeks after Lude Franke’s first phone call to his colleagues, the first questionnaire was sent out to the 167,000 participants in the Lifeline project. The questionnaire inquired about disease symptoms. But that was just the beginning. ‘We immediately realized we could also ask about their social feelings and understand what the pandemic is doing to them. Questions like: how do you feel? Are you nervous? Are you afraid that you might lose your job? Is it easy to stick to the 1.5 meters rule?’ says Franke. And soon the answers started coming in. With more than 300.000 questions filled and millions of answers given, the questionnaire started to reveal a larger picture. From it, Franke and his colleagues developed the Corona Barometer (coronabarometer.nl). And they didn’t stop there.

Hans Clevers (photo by: Thijs Rooimans)

The next steps

The New England Journal of Medicine has recently published an important research paper on genome wide association analysis, which may allow for the identification of potential genetic factors involved in the development of COVID-19. The study looks at Italian and Spanish cohorts, where the virus was severe. Franke explains: ‘The main authors started from cohorts of patients that were severely ill and then they started generating DNA. For us it was the other way around. We already had the DNA information, but we didn’t know who was ill and who wasn’t. They collected DNA for the patients that were severely ill, generated DNA data, and did a genetic study on those cohorts. And they used our data to replicate their findings. And they do replicate. This paper is indicating that there is a role for genetic variation as well. There is for instance one locus on chromosome 3 that is having quite substantial effect on increasing the risk of getting a severe COVID-19 infection.’

And there is more to come. ‘We collaborate with different groups now, both nationally and internationally, and we will do a new analysis. We hope to find many more places in the DNA. We cannot predict whether an individual will get a severe form of COVID-19. That is because, as we know from other illnesses, that it is determined by a combination of environmental risk factors in conjunction with genetic risk factors. I suspect that for COVID-19 environmental factors play a major role that determine severity. There is, of course a role for genetic factors as well, but not as important. What we do is use the sets of data we generate and those we also get from the public domain to make inferences about what the genetic risk factors we identify disrupt. We aim to understand what kind of genes are altered, what kind of cell types are affected, and what kind of biological processes they can disrupt. And we will apply the same techniques, the same datasets and the same expertise to understand those risk factors for the severe form of COVID-19 and what they do in the body. We will investigate the kind of biological processes they are affecting, into what cell types those effects appear, and start putting together a coherent story. By finding places in the genome for COVID-19, we might also be able to pinpoint what process is playing a crucial role in causing a severe infection. And maybe we can then identify existing drugs that are already known to correct those particular biological processes, and that could be repurposed for treating COVID-19 patients,’ explains Franke.

In the meantime, Clevers and his collaborators have submitted a new paper for publication. The manuscript looks in greater detail at what happens to the gut once infected with the COVID-19 virus. And while he waits for a response, he is supervising a laboratory in Shanghai. Biomaterials from China cannot be exported and the bats that must be studied are species only found in China. ‘We now work on setting up a laboratory there, because only there we can work with these bats and study COVID-19 and other corona viruses,’ says Clevers.

For Tanenbaum and De Laat’s project, the urgency meant working on several issues in parallel. The swab for the individual tests for example, used a long stick and a big tube. For an automated process an alternative needed to be found. They had to fit into a 96-tube format box. ‘Once the box arrives at the laboratory, the whole box goes into the machine, immediately. Using very high throughput robotics you can increase the capacity of the whole procedure enormously. We are now thinking 20-fold higher,’ says Tanenbaum.At the same time the price of testing can go down a lot. ‘There is very little human involvement, and we can produce the test ‘kits’ ourselves from individual reagents. The boxes are smaller, and everything is done by a robot, and less enzymes and reagents are being used. The price of one test could go down by as much as 90%’ he adds.

By finding places in the genome for COVID-19, we might also be able to pinpoint what process is playing a crucial role in causing a severe infection. And maybe we can then identify existing drugs that are already known to correct those particular biological processes, and that could be repurposed for treating COVID-19 patients. - Lude Franke

As the project moved forward, a consortium was starting to take shape. Besides Genmab, Tanenbaum and De Laat partnered with Bodegro, a company of laboratory IT specialists, which had been working on COVID-19 diagnosis for several months. They also got in contact with scientists at PAMM, a first line medical diagnostics lab. The Hubrecht Institute, KNAW and Friends of the Hubrecht helped the project financially. Then Oncode Institute made a crucial decision. ‘We had been doing experiments for two months. But nothing could be done without the custom robot that we needed and had to design ourselves. And to buy it we needed 1 million euros and that is where Oncode came in’ explains Tanenbaum. Joining the fight against the COVID-19 virus, Oncode Institute decided to buy the robot and make it accessible for Tanenbaum and De Laat’s initiative during the crisis. ‘That was the big breakthrough’ says Tanenbaum. ‘Oncode stepped in and helped support the project financially and with expertise.’

Lude Franke (photo by: Evert Doorn)

The lessons in community building

For these researchers, their projects meant facing new challenges and the chance to help society. But they were also a showcase for the power of joining hands for a greater goal. ‘What I saw is that whatever competitive feelings there were in the past, the kind that sometimes get in the way of collaboration, had totally evaporated. Everyone wanted to contribute, and no one started negotiating - what is my part of this, how much should I do, will I be an author on the paper and so on,’ says Clevers.

For Franke’s team, working on the COVID-19 project was a remedy for loneliness. ‘The young people in my team often felt lonely. This was something reflected in the results of our survey also, that loneliness was an issue particularly for people under 30, living alone. The young people in my team working on the COVID-19 project told me that this work gave them energy and meaning, because they felt they were working on something immediately relevant. This project helped a lot’ says Franke.

The Dutch approach to science right now is to only invest and pursue the issues that are commercially interesting. Because of this, every curiosity of a researcher becomes a hobby to fit within the limitations of the grants available. - Hans Clevers

With Oncode’s help, the much-needed robot for Tanenbaum and De Laat's project will be delivered in less than three months. For Oncode, the investment goes beyond the project, to hopefully facilitate the continuation of cancer research and cancer patient care in hospitals if a second wave of the virus hits later in the year. While waiting for the delivery of the robot, the last molecular biology tests are being done, the IT system built and the space for it created within PAMM. This means once the robot arrives, we hope to quickly generate a proof-of-principle that could provide a fast, high-capacity and cost-effective alternative for large-scale COVID-19 testing. When looking back at how far they’ve come, Tanenbaum finds that solving big problems is a matter of people working together. ‘When you look at the COVID-19 crisis – and my guess is that this would be the same for most biomedical crises - and at a community like Oncode that is so diverse, you realise that we have the core expertise for whatever situation may appear. For this particular case we definitely had the expertise. It was just a matter of mobilizing people. What surprised me is that no one from the government contacted us for help. We have these fantastic institutes and scientists with a lot of knowledge and expertise. They supported our efforts at later stages, but they didn’t get us involved initially, to ask our opinion or to request us to find solutions to make things better. The lesson to take is that we have to take initiative, get involved and not wait to be asked for help, because that might never happen.’

Investing in basic science

When asked about the need to invest more in basic science, Franke suggests the scientific community should make a point by showing the value of their work in quantifiable ways. ‘We can be optimistic and hope that the COVID-19 crisis will just lead to more funding for basic research, but I doubt that will happen easily. The problem is that we, as scientists, never point to the value of our work from a quantitative perspective and show how the money invested in our work yields return. We could do that, but we are somehow afraid. I believe we should show how one euro invested saves 10 euros in this crisis. I never saw estimates of this kind. And now is the time to spend on science, because we need a vaccine and we need to do more research to understand the virus’ he says.

Tanenbaum believes their project clearly illustrates the value of science and the importance of scientists joining hands. ’If there is a crisis like this, the scientists are the ones that can find solutions. And it is clear from our initiative that we do have a good understanding of the basic principles, we know how to find the right mix of people and how to find an expert in every little niche we need. None of the people initially involved are experts in diagnostics, but all had many years of experience - developing a certain molecular biology assay, for example, or developing a certain robot. And this experience provides the ability to come up with something innovative, quickly. I absolutely believe that basic science and basic scientists play an important role in a situation when innovation is needed. Having these scientists is critical, because they will solve biomedical problems if no solution is available when a crisis happens’ he adds.

For Clevers, the crisis clearly points at the importance of research. ‘We are all biomedical researchers and what we want in the end is to contribute to mankind. And this is a very good example of a huge disaster where science plays a crucial role,’ he says. He warns against focusing only on the things that seem immediately important. ‘The Dutch approach to science right now is to only invest and pursue the issues that are commercially interesting. Because of this, every curiosity of a researcher becomes a hobby to fit within the limitations of the grants available. And a good example against this approach of only focusing on what is commercially interesting at a given time, is the example of retroviruses, which before HIV were considered totally irrelevant. If we had ignored these viruses because we thought they were irrelevant, we would have known nothing about them and by that about HIV. Also – in the past, corona viruses were known but they were not dangerous at the time. But later, thanks to the fact that we did conduct a certain level of basic research on what seemed a totally unimportant type of virus, when SARS appeared, we knew about these viruses. And now because of SARS and later because of MERS, we learned even more. And still we were totally unprepared when this current crisis unfolded. So why don’t we invest and make vaccines for all known Corona viruses now? At the end of this pandemic we could have all the vaccines we’d ever need for all known Corona viruses, at a fraction of the cost’.

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