First of all, what is your background?

I started with psychology and within that I ended up doing two majors: clinical psychology and the more biological side of psychology. I found both interesting. Then I did a master's in medical anthropology because I also enjoy travelling. Then I obtained a PhD in statistical genetics: a field that investigates to what extent differences between people are determined by our gene pool. It is a field in which there have been spectacular developments in recent decades and in which what we do now was science fiction 20 years ago. My current research is at the intersection of genetics and neuroscience: I investigate the genetic basis of brain disorders such as schizophrenia, depression, insomnia, and Alzheimer's disease.

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Can you tell us some more about the development of your field?

When I did my PhD 20 years ago, the Human Genome Project had mapped all the genetic variants of human DNA for the first time. This was a landmark for genetics. It led to a lot of research in which genetic variation could be linked to differences between people. Such as the difference in certain traits or in the risk of a certain disease. This also brought to light how genetically complex certain conditions such as schizophrenia, depression and Alzheimer's disease are. Most rare diseases affected by one or just a few risk genes have now been mapped, but the development of complex conditions such as psychiatric diseases often involves thousands of genes. This complicates follow-up research into how these genes affect the disease.

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Regular newspaper headlines read: 'Six new schizophrenia genes discovered', or 'Extra Alzheimer's gene found'. Where does that research stand now?

The rapid identification of genes that may play a role in the development of brain disorders does not yet mean we know exactly what goes wrong in brain cells. We know, for example, that certain variants of genes are more common in people suffering from depression, schizophrenia and addiction. We now want to go a step further and show whether those genes are causally involved, and if so, how those genes cause some people to get depression and not others. Or why one person suffers addiction and another does not. Simply put, we know the beginning piece - the DNA abnormalities - and the end piece - the symptoms of a disease. But the part in between is missing: what happens at the cellular level in the brain?

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How exactly do you do the research?

My team conducts research using databases aggregating genetic information from millions of people. By analysing this data, it is possible to map very precisely which genes are involved in brain disorders. The kind of datasets we work with is a spreadsheet with some 10 million columns (the DNA letters) and 100 thousand rows (people who have donated their DNA). In recent decades, the computing power of computers has increased exponentially allowing analysis of ever larger DNA collections. Today, we use a supercomputer to process this data.

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How do you reliably determine the genetic origin of mental disorders?

First, we look purely statistically at the differences in DNA between healthy people and people with conditions such as schizophrenia or depression. Is there a genetic variant that occurs more or less often in the sick people than in the healthy ones? On the computer, we run millions of tests and then often hundreds or thousands of genetic variants roll out of them, all showing a statistical association with the disease. For example, I was involved as a research leader in a large genetic study on schizophrenia. We found hundreds of risk genes for the development of schizophrenia. These genes normally ensure that brain cells exchange information efficiently. Changes in genes could probably contribute to the onset of the mental disorder. As a next step, we now want to find out exactly how these genes combine to cause schizophrenic symptoms. So the question is what exactly happens at the cellular level. To unravel those underlying biological processes in the cell, we geneticists work together with neurobiologists.

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Why is this move from genetics to neurobiology so important?

Every cell in your body contains genes. That genetic information contains the blueprint for proteins that allow cells to perform their functions. If there is a flaw in one or more genes, certain proteins may not be made or may be made incorrectly. Sometimes this leads to disease, although this need not always be the case. Statistical genetics can detect in which part of the DNA there is a genetic error, but cannot explain how such a genetic error leads to the absence or malfunctioning of a protein, and how this then leads to disease. Neurobiology can figure out which biological processes in the brain are disturbed and whether they can be repaired, for instance with drugs. Only when we understand those biological mechanisms can we develop targeted therapies that act on the right system in the brain.

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Do views on those therapies drive your fundamental research?

Firstly, I want to be able to put the genetic puzzle pieces together and gain biological understanding of a disease. In addition, I want to be able to predict who will get sick and who will not. For cardiovascular diseases or breast cancer, for example, genetic information can already reasonably predict whether someone has an increased risk of becoming ill. For the mental disorders I am researching, this is currently more difficult because they are influenced by so many genes and variants. Developing new methods for this, combining data and running analyses is what I find most interesting as a scientist. At the same time, developing drugs for mental disorders is also important. Within our team, we therefore have a think tank that identifies potential leads for new therapies. That can be valuable information for the pharmaceutical industry to take forward.

Why do you like working with other disciplines?

I now have enough overview of my own field to be able to ask: what do I need from other fields? I now work with an interdisciplinary team of mathematicians, biologists, bioinformaticians, psychologists and stem cell biologists. Talking to researchers from other fields is not always easy because sometimes you literally use a different language, or the same words mean slightly different things. But I have been working with neuroscientists for ten years now so we have come to understand each other a lot better.

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How do you make sure you ask the right questions?

Crucial to innovation in science is to keep asking yourself: do I still have the right research goals? And is the way I am trying to achieve them still the best route? It is important to keep a close eye on whether you are still on the right path and which way the research should go. Sometimes I come to the conclusion that we need to involve a new field in a project. Reading up on a new field takes time but also provides many new insights. So it can be constructive to realise what you don't yet know. You have to keep cultivating that curiosity as a scientist.

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Is that also the strength of unfettered fundamental science?

Absolutely. As scientists, we work within a certain paradigm of frames of mind that have become self-evident. You have to constantly question whether those assumptions are still correct and consciously look for the blind spots. To make room for new ideas, you have to occasionally dare to say: I don't really understand this, it doesn't actually fit. It is precisely where things fray that you can push the boundaries. If an authority in the field presents something, it should not be assumed in advance that it will be correct. That doesn't help science move forward. That's why I always tell new students who join the group: ask questions about everything you notice that we pretend is normal. Staying open to new perspectives keeps us on our toes. Only if you dare to think outside the paradigm can you really push boundaries in science.

As a senior scientist, you also contribute by educating people. Is that important to you?

When I do something, I want to give it my full attention, so I personally supervise a maximum of three PhD students at a time. I am always very grateful for their dedication in the four years they work with us and I encourage them to remain critical. There is hierarchy in science but it should not stop junior researchers from thinking for themselves. It's no use if you all train clones. Instead, they are supposed to rise above you. When PhD students publish a nice paper, I like to push them to the fore, for instance by tweeting about them or having them speak at a congress. Often, they are then quickly picked off and recruited by other groups. Of course, I regret losing people again but for their academic development it is important to let them fly the nest. In the end, I am proud when they end up with a good position elsewhere.

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You were on the Biomedical Sciences advisory committee of the Ammodo Science Award for fundamental research. How do you decide which candidate the award is well spent on?

We looked for driven and innovative researchers. I think it is important that scientists follow their own path and dare to go off the beaten track. I find that important when hiring PhD students myself. Someone can be incredibly smart and ambitious, but that sense of wonder and willingness to dive into something completely makes all the difference. I have that myself: if I am enthusiastic about something, I can lose myself in it. At a given moment, you're ten hours in, you haven't eaten but you've done loads of work because you've read everything there is to read. Those moments make science worthwhile for me. I also hope to see that in the laureates: is this someone who really goes for it and can push science forward?

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What is your dream for the future?

I would love it if, in 10 or 15 years' time, we better understand at least one brain disorder and preferably also treat it better. That we can say: this is going wrong at DNA level, that is why this is not working as well in the brain, and that is why these people are becoming ill. I think that is the most important thing, that we ultimately translate our fundamental insights into solving diseases.

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Published on 8 March 2021.

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Photos: Florian Braakman