There are approximately 1,000 nuclear pore complexes in the nuclear envelope of a human cell. They are ‘transport machines’ and form the sites for entry and exit from the nucleus. Veenhoff explains why this is a pivotal task: ‘The nucleus contains the human cell’s genetic information, also known as DNA. In the nucleus, DNA is transcribed into RNA, which in turn is translated into proteins, i.e. the building blocks of the cells in a human body. The nuclear pore complexes must first help properly made RNA to leave the nucleus. However, they prevent defective RNA from leaving the nucleus by keeping the gate closed.’
Also, a signal indicating that new cells are required, for instance, needs to enter the nucleus. The nuclear pore complexes ensure that this message is being transferred. They therefore play a pivotal role. Veenhoff says: ‘I am still amazed that the cell nuclei of all plants, animals and humans contain nuclear pore complexes. This means that in biology, there is only one way of regulating the entry and exit of all these molecules.’
Veenhoff was involved in the development of the first map of the nuclear pore complex. ‘It consists of 500 proteins’, she says. ‘We explored how these are bound to each other and jointly form the nuclear pore complex. Imagine a doughnut with strands of spaghetti sticking in to the centre. These strands form a selective filter for transport. You may also compare nuclear pore complexes to waving sea anemone tentacles.’
Veenhoff and her fellow researchers not only study nuclear pore complexes, but also the ageing process. ‘We noticed that damaged nuclear pore complexes are absent in young cells. In contrast, old cells have fewer nuclear pore complexes, some of which are clearly damaged and not functioning properly. Nothing out of the ordinary, you would say, because there are so many things that could go wrong with ageing. What strikes us is the absence of damaged complexes in young cells, which means that they are being repaired. Therefore, there must be mechanisms to check for defects and take the necessary actions. What is the nature of these mechanisms and what does the repair process of nuclear pore complexes look like? We know, for instance, that the ‘spaghetti strands’ tend to stick together, which causes them to lose their function. So how can we ensure that the inner side remains intact and continues to work properly? That is what we would like to find out.’
‘Rightly so, people always want to know what the point of all this is’, Veenhoff laughs. ‘The questions that I ask are very basic. For many reasons, I am a huge supporter of curiosity-driven research. Although you never know exactly how the knowledge you gained can be applied, you are more likely to acquire applicable knowledge from basic research than from strategic or applied research focusing on one question or problem. Curiosity-driven research allows you to remain open-minded about potential applications.’
This curiosity driven approach has also led to the discovery of the connection between nuclear pore complexes and neurodegenerative diseases, according to Veenhoff. ‘It is obvious, for instance, that certain parts of the nuclear pore complexes can help to reduce toxicity caused by proteins associated with ALS and Huntington’s disease. Cells from ALS patients that are forced to produce huge amounts of a certain protein of the nuclear pore complex will become much healthier. This cannot be explained yet, but it is a very exciting finding.’
Veenhoff also keeps another possible application in the back of her mind: the fight against viruses, such as the coronavirus SARS-CoV-2 causing COVID-19. ‘At a certain point in time, parts of the virus must pass through the nuclear pore complex to initiate or stop processes within the cell’, Veenhoff says. ‘Viruses have become very good at manipulating the transport system. They can, for instance, avoid transport of certain signals to activate the immune system. You do not stand a chance if these signals cannot enter the nucleus. Although this is not the aim of my study, we do consider whether we can be useful in this matter.’
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