“We are trying to understand how small biological machines work”
With a little imagination, DNA looks a lot like twisted rope: a long, flexible chain of twisted strands. You can grab a rope, stretch it, and flip it. It is also possible with a strand of DNA, although this strand is a billion times smaller. It’s a work. You also need a mini tweezer for this mini string.
Such meticulous work is the specialty of Nynke Dekker (1971), professor of molecular biophysics at the Kavli Institute of Nanosciences at TU Delft. She herself constructs the complex equipment to capture the individual DNA molecules. She will receive at the end of May the dutch physics prize, due to its innovative way of researching at the nanoscale. “Mechanical engineers understand big machines,” says Dekker. “We are trying to understand how small biological machines work. Everything is possible in biology, I understood it now.
What excites you about this field?
“At the beginning of this century, scientists gained more and more control over biological molecules, and you could do more and more precise tests. I thought it would be fantastic as a physicist to be part of this movement. Physicists were an independent thing back then, nerds building their new instruments. But in the end we turned out to be useful and then we were partly absorbed by biology.
“That’s also what makes this field fun, that it’s so interdisciplinary. In addition to physicists for instruments, we need biochemists for protein purification and characterization and programmers for data analysis. In this way, a team can achieve what no individual could achieve alone. New developments are emerging in this field, such as super-resolution microscopy or new DNA sequencing methods.
Because it’s a crucial biological process, we’re curious to know how it works at the nanoscale.
Molecular biophysics is a mouthful. What do you do as a molecular biophysicist?
“Actually, two things: we are designing instruments with which we can observe individual molecules. We then use it to study what these molecules do. We actually ask biological questions, which we answer from a physical point of view. My interest lies in DNA replication, DNA copying. The underlying mechanism has been studied for some time from biochemistry: which proteins are involved? From a biophysical perspective, you take a look under the hood. How do all these proteins move? »
Why do you want to know in such detail how DNA replication works?
“If the replisome, the protein complex that regulates DNA replication, is not assembled correctly or is shifting, then the DNA is not being copied correctly. Then you have a problem. As it is a crucial biological process, we are curious to know how it works at the nanoscale. Because we measure each individual replicame, we can get a picture of the whole replication mechanism at work, with very high resolution.
How do you do that, measurements on individual molecules?
“We measure the number of proteins, their speed and where they move. This can be done, for example, by sticking light tags on your proteins. With a fluorescence microscope, you can follow their movement on DNA, you film them at the nanometric scale.
“We also measure forces. What is the influence of the shape of DNA, ie length or twist, on the functioning of a protein? Take, for example, a protein motor that travels on DNA. It exerts a force on the strand. If you also exert a force in the opposite direction on the DNA, you can measure the power of this protein. We do this with magnetic tweezers, among other things.
We design our instruments according to our own wishes, so that we can measure exactly what we want to measure
Dekker walks towards the laboratory, down a wide staircase and through white hallways. “I sometimes get lost here, because I’m not here often. I spend more time in my office. A door leads to a room with no daylight. A large glass box, closed by a curtain, stands on a solid table. It contains an arrangement that has many similarities to a microscope. Where a lens normally sits, there are magnets.
“It’s actually quite simple. There’s DNA on a plate under those magnets. You stick one end of the strand on the glass plate, the other on a magnetic ball. The magnets above attract these spheres, which exerts a force on the DNA. With a motor, we can move the magnets up and down and spin them, causing the DNA to stretch or rotate. This in turn influences the functioning of proteins.
It seems that this configuration was self-built.
“Beats. We used to build all the instruments ourselves, now I estimate 60%. We design our instruments according to our own wishes, so that we can measure exactly what we want to measure. Initially, it took months to design the magnetic tweezers. Now it’s more of a Lego construction kit. We’ll be building one in a few weeks.
“We have used them more recently in our virus research. They only need one replicating protein, the polymerase, which makes experiments relatively simple. We have studied how virus inhibitors impede such a polymerase at the molecular level, allowing us to identify the weak point of a replication mechanism. Based on this idea, other scientists can design inhibitors to reduce a virus population.
I’m not an engineer who understands how the latest coffee maker works
“We have seven of these magnetic tweezers here, but ironically we don’t use any at the moment. Indeed, in recent years, we have mainly studied the replisome of cell-nuclear cells. It does not consist of one protein, but of at least fifteen. It often goes wrong with this setup: with this setup, you can’t see if the replisome is assembled correctly. A protein can still stick in the picture, so the experiment will no longer be of any use to you.
“That’s why we now work more with fluorescence microscopy. We recently used it to map the workings of helicase: a protein complex that unpacks DNA so it can be copied. Our ultimate goal is to understand how the replisome works as a whole. You need complex techniques for this. This is why we will soon be integrating fluorescence microscopy into magnetic tweezers.
Do you find “normal” scale machines as interesting as nanoscale machines?
“No, I’m not an engineer trying to find out how the latest coffee machine works. I have always had a fascination for children. I can’t give a rational reason for this, but on such a small scale a machine seems more manageable. »
A version of this article also appeared in the May 8, 2023 newspaper.
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