With a little imagination, DNA looks a lot like a twisted rope: a long, flexible string of twisted strands. You can grab a rope, stretch it and turn it around. This is also possible with a DNA strand, although this string is a billion times smaller. It’s a piece of work. You also need mini tweezers for this mini string.
Such meticulous work is the specialty of Nynke Dekker (1971), professor of molecular biophysics at TU Delft’s Kavli Institute of Nanoscience. She builds the complicated equipment for grasping individual DNA molecules herself. She will receive at the end of May the Dutch Physics Prize, because of its innovative way of researching at the nanoscale. “Mechanical engineers understand large machines,” says Dekker. “We try to understand how small biological machines work. Everything is possible in biology, I have figured that out by now.”
What fascinates you in 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 that 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 is also what makes this field fun, that it is so interdisciplinary. In addition to the physicists for the instruments, we need biochemists for the purification and characterization of proteins and programmers for the data analysis. In this way, a team can achieve what no individual could achieve alone. New developments are emerging from this field, such as super-resolution microscopy or new DNA sequencing methods.”
Because it’s such a crucial biological process, we’re curious about how it works at the nanoscale
Molecular biophysics is a mouthful. What do you do as a molecular biophysicist?
“Actually two things: we design instruments with which we can look at individual molecules. We then use it to investigate what those molecules do. We actually ask biological questions, which we answer from a physics perspective. My interest lies in DNA replication, copying DNA. The mechanism behind it has been studied for some time from biochemistry: which proteins are involved? From a biophysics perspective, you take a look under the hood. How do all those proteins move?”
Why do you want to know in so much detail how DNA replication works?
“If the replisome, the protein complex that regulates DNA replication, is not properly assembled or moves, then the DNA is not copied correctly. Then you have a problem. Because it’s such a crucial biological process, we’re curious about how it works at the nanoscale. Because we measure each individual replisome, we can get a picture of the entire replication mechanism at work, with a very high resolution.”
How do you do that, measurements on individual molecules?
“We measure the numbers of the proteins, their speed and where they move. This can be done, for example, by sticking luminous labels to your proteins. With a fluorescence microscope you can follow how they move over the DNA, you film them at the nanoscale.
“We also measure forces. What is the influence of the shape of the DNA, i.e. the length or the twist, on how a protein works? Take, for example, a protein motor that moves over the DNA. It exerts a force on the strand. If you also exert a force in the opposite direction on the DNA, you can measure how powerful that protein is. 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 lab, down a wide staircase and through white corridors. “I sometimes get lost here, because I’m not here that often. I spend more time in my office.” A door leads to a room without daylight. A large glass box, enclosed by a curtain, stands on a sturdy table. It contains an arrangement that shows many similarities with a microscope. Where normally a lens is, there are magnets.
“It’s actually quite simple. There is DNA on a plate under those magnets. You stick one end of the strand to the glass plate, the other to a magnetic ball. The magnets above attract those spheres, which exerts force on the DNA. With a motor we can move the magnets up and down and rotate, causing the DNA to stretch or rotate. That in turn influences the functioning of proteins.”
It looks like this setup was self-built.
“Beats. We used to build all the instruments ourselves, now I estimate 60 percent. 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. It is now more of a Lego building kit. We’ll build one in a few weeks.
“We used them most recently in our virus research. They only need one replication protein, polymerase, which makes the experiments relatively simple. We have investigated how virus inhibitors hinder such a polymerase at the molecular level, allowing us to pinpoint the weak spot in a replication mechanism. Based on this insight, other scientists can design inhibitors to reduce a virus population.
I’m not an engineer figuring out how the very latest coffee maker works
“We have seven of those magnetic tweezers here, but ironically we don’t use any at the moment. This is because in recent years we have mainly studied the replisome of cells with a cell nucleus. It does not consist of one protein, but at least fifteen. This often goes wrong with this set-up: with this set-up you cannot see whether the replisome is being put together correctly. A protein can always stick to the picture, then the experiment will no longer be of any use to you.
“That is why we now work more with fluorescence microscopy. We recently used this to map the functioning of helicase: a protein complex that unzips DNA so that it can be copied. Our ultimate goal is to understand how the replisome functions as a whole. You need complex techniques for that. That is why we will soon be integrating fluorescence microscopy into the magnetic tweezers.”
Do you find machines on the ‘normal’ scale just as interesting as machines on the nanoscale?
“No, I’m not an engineer figuring out how the very latest coffee machine works. I’ve always had a fascination with the small. I can’t give a rational reason for that, but on such a small scale, a machine feels more manageable.”