'By cleverly combining new techniques for analysing DNA at the level of individual molecules, we can achieve real breakthroughs in research into conditions such as dementia,' predicts Professor John van Noort. Together with four leading biophysics research groups, he has written a review article in Science.
'Individually, we can already analyse DNA on a large scale at the level of single molecules,' says John van Noort, Professor of Biophysics, enthusiastically. 'With this Science article, we place our techniques in a broader context and describe opportunities for future research. This is part of a much bigger picture.'
Analysing DNA at the level of single molecules
Using the latest single-molecule analysis techniques - such as the SPARXS-technique developed by Van Noort and Joo in 2024 - scientists can study hundreds of thousands of individual DNA molecules in a relatively short time. For example, by applying tiny forces to a DNA molecule using magnets inside a microscope, so-called magnetic tweezers, and then measuring how the molecule responds. Van Noort's colleagues at the Universities of Uppsala and Oxford have developed similar techniques like SPARXS.
In biology, observing molecules directly is an essential step. Cells are highly dynamic systems in which many processes take place at the same time. To understand exactly what happens, and why, researchers need to map these events molecule by molecule.
Building bridges to other disciplines
'Looking at just one type of DNA molecule is no longer enough. Until now, our experiments mainly showed that our techniques work under laboratory conditions. But today, we are studying diverse collections of DNA molecules as they occur in real biological systems,' Van Noort explains. 'DNA molecules inside the cell nucleus behave in very different ways, and it is precisely this diversity that we now want to understand.'
To achieve this, the researchers have combined their single-molecule analysis techniques with another modern method: next-generation DNA sequencing. Their aim is to uncover how differences in the physical properties of DNA molecules arise, and how these differences affect processes such as the binding of proteins to DNA. This is important, as the researchers suspect that such variations influence vital processes within the cell.
Van Noort sees many opportunities to expand this research further: 'The structure and function of RNA and proteins also depend on the exact sequence of their building blocks.'
Taking the technology worldwide
To speed up progress globally, Van Noort has been working for years to make his technology accessible to other scientists. His microscope has already been installed at universities around the world, including in Singapore, Shenzhen, Gettysburg and Warsaw.
'Closer to home, in Leiden, we will soon be launching 4ces, a spin-out company together with CEO Hidde-Jan Lenstra. Through this company, we want to make our magnetic-tweezers technology and its applications available to an even wider audience.'
Public-private collaboration with Leiden-based company 1NA
Van Noort is also collaborating with the Leiden bedrijf 1NA, led by Eugene Ostrofet, which also specialises in single-molecule research. In a new joint project, they are studying how medicines influence the way DNA is folded and packaged inside the cell, a process involving structures known as histones.
'Small differences in this process can cause certain genes to switch on or off at the wrong moment. Such errors can ultimately contribute to diseases such as dementia, cancer or disorders of the immune system,' Van Noort says. 'By studying at the molecular level how medicines alter the way DNA is packaged, we may be able to treat these diseases more effectively in the future.'
Article in Science
'From sequence to function: Bridging single-molecule kinetics and molecular diversity'
A. N. Kapanidis (Oxford), L. Muras , K. Sreenivasa , J. Hazra , J. van Noort (LEI), Chirlmin Joo (Delft), S. Deindl (Uppsala)
