Researchers at ETH Zurich have developed a molecule that uses fluorescent lights to indicate where new tissue is being created in the body. The molecule not only helps to make tumors visible, but could also play an important role in research into wound healing disorders.
The most common proteins in our body are collagens. They make up around a third of all proteins and network to form stable fibers. Skin, tendons, cartilage, bones and connective tissue are made of it. Researchers at ETH Zurich have now developed a multi-component molecule that interacts with collagen and can be used to make visible where tissue is newly formed in the body.
An increased formation of new collagen fibers occurs, for example, during wound healing, but also when tumors grow. As part of this new formation, the thread-like collagen molecules network to form the stable fibers. This requires an enzyme called LOX. It oxidizes certain places in the collagen molecules. These chemically altered areas then react with their own kind on other collagen strands and connect to them.
Sensor and functional peptide
The researchers, led by Helma Wennemers, professor at the Laboratory for Organic Chemistry at ETH Zurich, developed a sensor molecule with inducible fluorescence. It does not in itself fluoresce. It only begins to fluoresce after it has reacted with the LOX enzyme. The sensor molecule is therefore a marker for LOX activity. The scientists then linked this molecule with a short, thread-like peptide that is similar to collagen. The researchers have equipped this peptide with a so-called reactive group that only reacts with oxidized collagen.
In collaboration with researchers from Sabine Werner’s group, professor of cell biology, the scientists carried out experiments on mice, into which they injected the multicomponent molecule into the skin, as well as in vitro experiments with tissue sections. They were able to show that the molecule is stored in collagen fibers where new tissue is currently forming. And it fluoresces when the new tissue formation is initiated and the enzyme LOX is formed in the process. “Thanks to the modular structure and the three components – sensor, peptide and reactive group – our system is extremely specific and precise,” says Matthew Aronoff. He is a senior scientist in Wennemer’s group and lead author of the study.
For cancer medicine and wound healing
Because new tissue is formed primarily at the tumor margins as tumors grow, the new molecule can be used to make the edges of the tumor visible when examining biopsies, for example. “One of our visions is that surgeons will one day be able to use this molecule directly on the operating table while removing a tumor,” says ETH Professor Wennemers. The molecule would show the surgeon the edge of the tumor and help remove the entire tumor.
Other possible applications of the new marker molecule relate to wound healing, such as research into tissue formation in principle or healing disorders in diabetes and other diseases. Corresponding questions are also to be investigated as part of the interdisciplinary skin research project Skintegrity, in which ETH Zurich is involved.
The scientists have applied for a patent for the system. They are currently exploring various options for bringing it to market maturity or further developing it for additional applications.
For this research work, which has now been published for the first time in a specialist journal, the researchers received the Spark Award from ETH Zurich last year. More information in this video:
Featured image: Fluorescence microscopy image of the tumor margin. The tumor margin is colored blue with the new marker molecule; there is tumor tissue at the top left. Green: collagen, red: cell nuclei. (Image: ETH Zurich / Matthew Aronoff)
Aronoff MR, Hiebert P, Hentzen NB, Werner S, Wennemers H: Imaging and targeting LOX-mediated tissue remodeling with a reactive collagen peptide. Nature Chemical Biology, July 12, 2021, doi: 10.1038 / s41589-021-00830-6
Provided by ETH Zurich