‘When Nynke asked me in 2014 whether she could do a sabbatical in my lab, we had never met each other before’, says John Diffley, professor at the Francis Crick Institute in London. ‘Of course, I knew who she was – after all, she has made incredibly important contributions to biophysics. She was looking to take a different direction with her research and wanted to know more about the DNA copying systems we’d set up in our biochemistry lab.

During such a sabbatical, visitors often hide away in their office to answer emails, and they mainly come to enjoy the nightlife. However, Nynke came to the lab each day to learn how to purify various proteins and how to perform copying reactions with these. She now uses the same type of reactions in her own lab to study how DNA replication works at the single-molecule level.’

Diffley’s anecdote characterises the brand-new Spinoza laureate. ‘Nynke is driven by substantive questions’, says fellow Spinoza laureate Marileen Dogterom, chair of the Department of Bionanoscience at TU Delft. ‘She’s always looking for new subjects to sink her teeth into. Her sabbatical in the UK is a superb example of that. She used it to deliberately shift her research away from interactions between a single protein with a single DNA or RNA molecule towards experiments with more complex systems that can consist of up to twenty proteins. She reads up on the subject, does such a sabbatical, learns new things, and comes up with a decisive plan.’

Back to more biological research

‘For several years, I’d focused on developing new technologies, and I wanted to go back to biological research again’, says Dekker about that decision. The biophysicist wanted to focus on DNA replication in eukaryotic systems – systems in which the cells contain nuclei. John Diffley’s group provided her with the necessary knowledge for this. ‘I went there together with my analyst to learn how to purify the twenty different proteins needed for the replication’, says Dekker. ‘But to be honest, it was more like I was his assistant, and I mainly learned how much patience you need for all that purification.’

Nynke Dekker studied physics and applied mathematics at Yale University and gained a doctorate from Harvard University on the magnetic manipulation of caesium atoms on a chip. After that, she wanted to broaden her horizons. ‘Although I found atomic physics quite interesting, it was too predictable for me. You could very neatly calculate what should happen. Then you spent years doing experiments, only to come up with an outcome that wasn’t in the slightest bit surprising. Back then, an awful lot was happening in biology. For example, the human genome project and DNA sequencing techniques were making considerable advances. From a practical point of view, biophysics is in some ways rather similar to atomic physics because you also use lasers, mirrors and magnetic fields. Only the system you’re studying is different.’

Pulling and rotating DNA molecules

Before she delved into this new discipline, Dekker visited several highly promising groups in this young field. Ultimately, she was attracted to the group of David Bensimon at the École Normale Supérieure in Paris. ‘Nynke contacted us and asked whether a postdoc position was available. She had experience with the magnetic manipulation of objects and, back then, we had just developed magnetic tweezers with which we could pull and rotate DNA molecules. When she came to us, Nynke knew nothing about biophysics or magnetic tweezers, but she rapidly mastered both. Later she improved those magnetic tweezers in her own group, for example by adding possibilities to measure the torque (rotational force). She has done fantastic work using these techniques, such as her work on topoisomerase, a protein controls the torsion in the DNA molecule. In that research, she has not only demonstrated how that enzyme uncoils DNA, but also how a certain type of chemotherapy blocks this protein and therefore kills cancer cells. I think showing how a drug works at the molecular level is her finest contribution.’

Helping the discipline advance

When Dekker is asked what she is most proud of, then her answer is the new technologies she has developed. ‘Our magnetic tweezers are now being used by others to make new biological observations that are genuinely increasing our knowledge.’ And although she acquired international fame with her work on topoisomerases, she is personally perhaps even more satisfied with her studies into polymerases, the proteins that play a crucial role when a virus copies its RNA. ‘It took us five years before we got that to work’, she sighs. ‘And it has always been difficult to acquire funding for that type of research, which is why it’s never been a large part of my group. However, I’m really pleased that we persisted with this work because now we can rapidly characterise antiviral inhibitors. And that could prove very useful in a world that’s been turned upside down by COVID-19.’

More focus

After several years focusing on the interactions between a single protein and a single RNA or DNA molecule, she found the work less satisfying. ‘Within the field, we’d been hopping between subjects for some time. I missed the depth and wanted to create more focus.’ This musing led to her sabbatical at John Diffley’s lab, which in turn resulted in the plan that yielded her an ERC Advanced Grant of 2.5 million euros. Since 2018, this has allowed her to investigate the replication of DNA in a context that is as natural as possible. ‘When a cell divides, several protein complexes are transferred from the original DNA molecule to the daughter molecules. At the molecular level, we want to figure out which of those so-called nucleosomes ends up on which daughter molecule, because the allocation between old versus new nucleosome complexes on the daughter DNAs has an impact on the signalling function of nucleosomes.’

Dekker wants to use the Spinoza Prize to add an extra dimension to this research. ‘Now we’re mainly examining the interactions between molecules which ensure that the DNA is copied. However, in future research we could make the link to the repair of DNA damage, or examine how different components of the DNA replication machinery influence each other.’ Bensimon and Diffley have high expectations of this research: ‘We roughly know how DNA replication works in bulk reactions, but at the molecular level we still know little about the regulation and replication of our genetic material. That molecular understanding is a holy grail in our discipline, and Nynke can make important advances in this regard.’

This is a publication by NWO.