Thorsten-Lars Schmidt
*** Now hiring ***
Currently, I am looking for students or postdocs
- Student worker: to set up the lab (payment: 10 h / week). A little experience in molecular biology / biochemistry would be optimal.
- Summer research projects: Minimum duration 2-3 months, 20 h / week
- PhD projects: Several projects are available for students from various backgrounds Physics, Chemisty (Polymer chemistry or Biochemistry), and Biology (molecular)
- Postdoc: Opportunity for a fully funded postdoctoral research position for researchers with experience setting up a TIRF microscope. Experience in single-particle tracking, microfluidics and a little cell biology would be a plus.
If you are interested to join my lab, please send me your cv and give me a short overview over your previous research experience.
Research
Why building with DNA?
DNA is a unique polymer. It is the information storage molecule of all known life forms, and can be used to build up almost arbitrary structures and patterns out of DNA. These structures can be functionalized with a large variety of inorganic nanoparticles, small molecules or large biomolecules such as proteins and antibodies. Our group is leveraging this programmability to engineer nanoarchitectures and tools for applications in Biophysics, Molecular Biology, Nanophotonics and Nanomedicine. Moreover, we are developing scalable “next-generation DNA synthesis” methods.
DNA-encircled lipid bilayers
Lipid bilayers and lipid-associated proteins play a crucial role in biology. As in vivo studies and manipulation of single molecules are inherently difficult, several membrane-mimetic systems have been developed to enable investigation of lipidic phases, lipid-protein interactions, membrane protein function and membrane structure in vitro. We leverage the unique programmability of DNA nanotechnology to create DNA-encircled bilayers (DEBs). DEBs provide an unprecedented control over size and allows the orthogonal functionalizations and arrangement of engineered membrane nanoparticles.[Nanoscale 2018].
Outlook: We want to use DEBs as a tool for biophysical investigation of lipid phases and lipid-associated proteins and complexes including structure determination of membrane proteins. Moreover, we explore lipid-DNA interactions further and will use DNA structures anchored to supported lipid bilayers to investigate interactions of molecules with cells.
DNA-based plasmonic devices
The field of plasmonics exploits the interaction of light with nanoscale metallic structures to confine, guide and manipulate light on scales below the diffraction limit. Plasmonic structures exhibit significant potential for applications including quantum optics, sensing, and short-distance optical communication (a). Towards this goal, we demonstrated the precise, robust, and high-yield assembly of gold nanoparticles on DNA origami templates (b). [ACS Nano 2016].
More recently, we realized energy propagation through such a self-assembled waveguide to a fluorescent nanodiamond and out coupling of energy. We analyzed the waveguiding at a single-device level by electron energy loss spectroscopy (c) and cathodoluminescence imaging spectroscopy. Our work visually demonstrates the realization of nanometer-precise light manipulation and energy conversion. [Nano Lett. 2018].
Finally, these closely spaced gold nanoparticles create a strong plasmonic hotspot for the sensing of molecules. [Nano Lett. 2019].
Triangulated DNA origami and nanomechanical actuators
In the macroscopic world, stiff and material-efficient structures such as construction cranes and high voltage transmission towers are usually built from triangulated wireframe structures. We extended the DNA origami concept to generate a series of triangulated trusses. These provide defined cavities that we seek to fill with functional elements. [Nano Lett. 2016].
By introducing single-stranded regions edges of the wireframe trusses, the structures are heavily deformed due to the entropic spring forces contracting the single-stranded region. The gaps can be filled by a gap filling polymerase (such as the T4 polymerase) or the addition of the missing oligonucleotides, thus creating a nanomechanical actuator. [ACS Nano 2018].
Outlook: This principle shall be the basis for stimuli-responsive mechanical nano devices in photonics or for applications in molecular biology. Moreover, we wish to determine biophysical properties such as their bending and torsional stiffness with super-resolution microscopy.
Nanomedicine
An important goal in nanomedicine is the synthesis of smart designer nanoparticles, which show a lower renal clearance compared to conventional drugs and increase specificity to malignant cells. Cancer stem cells (CSCs) are responsible for drug resistance, tumor recurrence, and metastasis in several cancer types, making their eradication a primary objective in cancer therapy. In a collaboration project lead by Dr. Goncalves-Schmidt, gold nanorods were functionalized with nestin-binding peptides that specifically recognize Glioblastoma multiforme stem cells for photothermal therapy. [Acta Biomaterialia 2017] and [Biomat. Sci. 2018].
Outlook: Building up on our experience with gold nanoparticle based cell uptake, we will develop sophisticated and more complex functionalized DNA structures for drug delivery or as diagnostic and therapeutic devices.
Stabilizing DNA structures for nanomedicine
A main drawback of structural DNA nanotechnology is the instability of structures in biological environments. We developed a protection strategy based on block copolymer micellization which stabilizes DNA structures in biological or low-salt environments. [Angew. Chem. 2017].
Outlook: We will use this protection to enhance DNA-based nanomedicines.
“Next-generation” DNA synthesis methods
Synthetic oligonucleotides (short single-stranded DNA) and genes (long double-stranded DNA) are the main cost factor for many studies in DNA nanotechnology, genetics and synthetic biology. Inexpensive chip-synthesized oligonucleotide libraries can contain hundreds of thousands of distinct sequences, however only at sub-femtomole quantities per strand. We developed a selective oligonucleotide amplification method based on rolling circle amplification (RCA) with a 10-1000-fold cost-reduction compared to synthetic oligonucleotides or competing amplification methods such as PCR. [Nat. Commun. 2015].
Outlook: We have recently extended our method for de novo gene synthesis. This will allow us to design custom scaffolds, and testing design principles that influence the folding kinetics and yields.
Other future directions
More multi-disciplinary projects are being followed at the interface of Physics, Biology, Chemistry and nanoscale Engineering. For example, we want to learn about the mechanobiology of cell-cell contacts. Please inquire.
Further Reading
For more information, I recommend this 3-hour lecture (iBiology) by William Shih:
https://www.youtube.com/watch?v=Ek-FDPymyyg
https://www.youtube.com/watch?v=noWkRxKYBhU
https://www.youtube.com/watch?v=5cmg1oa4-fg
or a current review on structural DNA nanoetchnology such as: DNA Origami: Scaffolds for Creating Higher Order Structures.
Assistant Professor
Kent