May 29, 2023

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We're trying to understand how little biological machines work

We’re trying to understand how little biological machines work

With a little imagination, DNA is a lot like a twisted rope: a long, flexible string of twisted strands. You can grab, stretch and rotate a rope. This is also possible with a DNA strand, although this strand is a billion times smaller. It’s part of the job. You also need small tweezers for this little chain.

Such delicate work is the specialty of Nynke Dekker (1971), professor of molecular biophysics at the Kavli Institute for Nanoscience at TU Delft. She makes the intricate equipment to capture individual DNA molecules herself. You will receive it at the end of May Dutch Physics Prize, because of his innovative method of research on the nanoscale. “Mechanical engineers understand big machines,” Decker says. We are trying to understand how small biological machines work. Anything is possible in biology, I’ve now discovered it.”

What fascinates you in this field?

“At the beginning of this century, scientists are gaining more and more control over biological molecules, and you can do more and more rigorous tests. I thought it would be cool as a physicist to be part of that movement. Physicists were a separate thing at the time, obsessed with building their new tools. But in the end we turned out to be useful, and then we partly plunged into biology.

“This is also what makes this field so interesting, it is so interdisciplinary. In addition to hardware physicists, we need biochemists to purify and characterize proteins and programmers to analyze data. In this way, a team can achieve what no one individual can achieve alone. New developments emerge from this field, such as super-resolution microscopy or new DNA sequencing methods.”

Since it is such a critical biological process, we are interested in how it works at the nanoscale

Molecular biophysics is the pinnacle. What do you do as a molecular biophysicist?

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Actually two things: we design tools with which we can look at individual molecules. Then we use it to learn what these molecules do. We are actually asking biological questions, which we answer from a physical perspective. My interest lies in DNA replication, DNA transcription. The mechanism behind it has been studied for some time from biochemistry: what proteins are involved? From a biophysics perspective, take a look under the hood. How do all these proteins move? “

Why do you want to know in detail how DNA cloning works?

“If the protein complex that regulates DNA replication is not assembled or transported properly, then the DNA is not transcribed properly. Then you have a problem. Because it is such a critical biological process, we are interested in how it works on a nanoscale. Since we measure each individual individual We can get a picture of the entire transcriptional machinery in action, at very high resolution.”

How do you do that, measurements on individual particles?

We measure the number of proteins, their speed and where they are moving. This can be done, for example, by sticking luminous stickers on your proteins. Using a fluorescent microscope, you can follow how they move on the DNA, and you image them at the nanoscale.

“We also measure forces. What effect does the shape of the DNA, that is, the length or the twist, have on how the protein works? Take for example a protein motor moving 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 strong that protein is. We do this using magnetic tweezers, among other things.”

We design our instruments according to our own desires, so that we can measure exactly what we want to measure

Decker walks towards the lab, down a wide staircase and through white corridors. “Sometimes I get lost here, because I’m not here much. I spend more time in my office.” A door leading to a room without daylight. A large glass box surrounded by a curtain stands on a sturdy table. It has an arrangement that shows many similarities to a microscope. Where the lens is normally, there is a magnet.

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“It’s actually very simple. There’s DNA on a plate under those magnets. You stick one end of the string to the platen of glass, and the other to a magnetic bobbin. The magnets above attract those spheres, which creates a force on the DNA. Using the motor we can move the magnet up.” And down and rotate, which causes the DNA to stretch or rotate. This, in turn, affects the functioning of the proteins.”

This setup appears to be self-built.

“Beats. We used to build all the tools ourselves, now I’d estimate 60 percent. We design our tools according to our own desires, so we can measure exactly what we want to measure. In the beginning, it took months to design the magnetic tweezers. Now it’s more of a Lego building set. We’re going to build one.” within a few weeks.

We have been using it recently in our virus research. They only need one replication protein, polymerase, which makes experiments relatively simple. We investigated how virus inhibitors impede such polymerase at the molecular level, allowing us to identify a weak point in the replication machinery. Based on this insight, other scientists could design inhibitors to reduce the number of viruses.

I’m not an engineer. Find out how the latest coffee maker works

“We have seven of those magnetic tweezers here, but ironically we don’t use any of them right now. That’s because in recent years we’ve mainly studied cell regeneration with the cell nucleus. It’s not made up of one protein, but at least fifteen. It often goes wrong. In this setting: With this setting, you can’t know if the items are grouped correctly.Protein can always stick to the picture, so the experience won’t work for you anymore.

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This is why we are now working more with fluorescence microscopy. We recently used this to map the action of the helix: a protein complex that uncompresses DNA so that it can be copied. Our ultimate goal is to understand how compensation works as a whole. You need sophisticated techniques for that. That is why we will soon be incorporating fluorescence microscopy into magnetic tweezers.”

Do you find machines on the “ordinary” scale as interesting as machines on the nanoscale?

“No, I’m not an engineer who has figured out how the latest coffee machine works. I’ve always been fascinated by the small. I can’t give a logical reason for that, but on this small scale the machine seems more manageable.”