Click chemistry: “Living cells are our test tubes”

“Whereas classical chemistry works with test tubes and round-bottomed flasks, we go a step further: living cells are our test tubes,” explains Professor Andrea Rentmeister, who has been Chair of Organic and Biological Chemistry at LMU’s Faculty of Chemistry and Pharmacy since the start of 2024. Her work operates at the boundaries of chemistry and biology – with the goal of decoding and actively controlling fundamental processes in the cell. “We’re trying to change biomolecules such as mRNA using chemical and biological methods, so that we can better analyze them or improve their properties.”

When you look inside a cell, you do not see much at first. But if you attach synthetic labels to certain biomolecules, you can observe them better under the microscope. With chemical modifications, moreover, you can change the function of biomolecules – by switching their activity on or off, for example, using light-dependent markers.

Customized molecules

However, this is easier said than done. “In a cell, there are countless components that can react with each other,” explains the chemist. “If I add a new molecule, I have to consider that some other molecule could react with it – and that’s extremely complex.” The solution is a technique known as click chemistry or bioorthogonal chemistry. This involves developing so-called bioorthogonal groups, which, all going well, react exclusively with each other and with nothing else in the cell. “Bioorthogonal chemistry opens up an entirely new dimension,” says Rentmeister. “You build a molecular lock, so to speak, and a matching key. The two click with each other, but don’t react with anything else.”

As part of her doctoral thesis, Rentmeister carried out research into RNA in connection with in-vitro evolution – “a fascinating process that involves ‘breeding’ molecules with desirable properties.” Later, in California, she researched under Frances H. Arnold, who received a Nobel Prize in 2018 for her work on the directed evolution of proteins. In her own work, Rentmeister tried to connect the RNA and the protein levels. “Naturally enough, I didn’t want to just emulate my boss, but also do my own thing. My work centered around changing proteins so they can be used to modify RNA.”

Over time, she increasingly incorporated chemical approaches into her research. After her postdoc period in California, Rentmeister was Junior Professor at the University of Hamburg. Then, before her appointment at LMU, she spent several years in the Institute of Biochemistry at the University of Münster, where she was Professor of Biological Chemistry and Biomolecular Label Chemistry.

Basic research with huge potential

Andrea Rentmeister sees herself as a basic researcher. Her primary goal is to decode fundamental chemical and biological realities. At the same time, her work has great potential for practical applications – for example, in mRNA-based cancer therapy. Her methods could make it possible one day to selectively obtain effects in specific cells without affecting other cells, which would considerably increase the safety and efficacy of mRNA-based therapies. But there is still a long way to go before such treatments are a reality, cautions Rentmeister. “Currently, we’re working on establishing such principles in model organisms like the zebrafish to test their feasibility.”

When we ask the chemist which topic she is most excited about at the moment, she finds it hard to pick: “All my projects are my favorites!” Currently, her energies are particularly devoted to the cell-selective activation of translation, “a topic we’re addressing as part of a new German Research Foundation (DFG) project.” In addition, she’s doing intensive research in the fields of epigenetics and epitranscriptomics – that is to say, modifications of DNA and RNA that influence the activity and regulation of genes. “Our goal is to take molecules that used to be hard to capture in biology and make them accessible and analyzable.” Again, chemical tools are very much part of her toolkit here.

Ideas do not fall from the sky

Has she ever had something like a eureka moment? Yes, says the chemist, from time to time, although brainwaves do not appear from nowhere: “Chance favors the prepared mind, as Louis Pasteur put it. You work on a topic intensively over a long period and then – usually at a moment when you’re not expecting it – you get an insight. Although the eureka moment feels sudden and unexpected, it has actually matured in the mind over years of research.”

Another vital factor is having the right work environment. The Faculty of Chemistry and Pharmacy at LMU offers ideal conditions for her endeavors. At the adjacent Gene Center Munich and the surrounding institutes, there is a plethora of research groups that focus on nucleic acids. In her specialist area, she explains, the density of excellent researchers with different professional backgrounds is particularly high here. “When chatting to people in the office kitchen, you discover things that are not in print, gain new perspectives and impressions, and sometimes even get exciting new research ideas.”