The research themes of the group are currently focused on unraveling the mechanics and dynamics of biological systems using an array of experimental techniques such as AFM, optical tweezers and (single-molecule) fluorescence. By investigating increasingly complex biological processes, we aim to link single molecule research with experimental systems biology. Most of our biophysical questions are solved in collaboration with biochemists, biologists, theoretical physicists and physicians.
There are four major themes in my group:
Combing STED with Optical Tweezers (Nature Methods, 2013)
DNA organization – DNA inside organisms is organized by multitudes of proteins in structures called chromosomes. It is extremely challenging to get data of the dynamics of these proteins which often bind non-specifically to DNA. We forged breakthroughs by developing a new instrument (Noom et al., Nature Methods, 2007) that was able to measure the location, binding forces and dynamics of individual proteins (Dame et al., Nature, 2006; Farge et al., Nature Communication, 2012; Laurens et al., Nature Communcation, 2012). From this data we could reveal the physical properties that emerged from arrays of these proteins interacting with multiple DNA strands (Noom et al., Current Biology, 2007). Moreover, we solved with a string of papers a long standing controversy about the physical nature of DNA under tension (van Mameren et al., PNAS, 2009; Gross et al., Nature Physics, 2011; King et al., PNAS, 2013).
DNA repair & recombination - is essential for maintaining genome integrity. Yet, the molecular mechanism of this process remains elusive. By combining fluorescence microscopy and optical manipulation (van Mameren et al, Biophysical J., 2006) we demonstrated that it became possible to control, visualize and dissect key steps in the recombination reaction down to the single molecule (van Mameren et al., Nature, 2009; Candelli et al., PNAS, 2013). Our lastest project has been on XLF-XRCC4 two essential proteins involved in repairing human DNA. Using a four optical tweezers combined with fluorescence we showed that these proteins form a mobile connection between broken DNA fragments (Brouwer et al., Nature, 2016).
Tetris made with a time-shared optical tweezers, constructed in our lab a while back by Joost van Mameren
Technique development – in my group has resulted in an easy to use multi-beam optical trap capable of handling multiple DNA molecules (Noom et al., Nature Methods, 2007; Brouwer et al., Nature 2016), and in instruments that integrates optical trapping with the capability to visualize (single) fluorescent molecules on DNA (van Mameren et al., NAR, 2008; van Mameren et al., Nature, 2009). This combination of technologies we expanded further by introducing super-resolution detection in the optical trap (Heller et al., Nature Methods, 2013). Another key innovation is our invention of a new class of biophysical instrumentation, Acoustic Force Spectroscopy (Nat Meth 2015), which is making a big impact with research groups worldwide implementing this technology. Many of these instruments are now commercial available via LUMICKS.
Bursting virus (Nature Chemistry, 2013)
Physics of viruses – Viruses are the simplest, smallest and often most rugged forms of life. The protective nanometer-scale proteinaceous shells (capsids) of viruses are particularly striking examples of biological materials evolution. These highly regular, self-assembled, nanometer sized containers are minimalistic in design, but combine complex passive and active functions. Besides chemical and physical protection, they are involved in the selective packing and injection of the viral genetic material. These objects illustrate an interesting array of basic physical principles which we wish to experimentally explore. Using atomic force microscopy, optical tweezers and fluorescence techniques we are studying the physical properties of viral capsids.
This animation shows a nanoindentation experiment on a single virus by Atomic Force Microscopy (AFM). It is based on research by Gijs Wuite and Wouter Roos of the Vrije Universiteit Amsterdam.