“Whenever I approach someone, it's like, 'Sure, we can do this.'”

Milena Schuhmacher. Credit: Alain Herzog (EPFL)

Milena Schuhmacher. Credit: Alain Herzog (EPFL)

Milena Schuhmacher is a Scholar of the EPFL Life Sciences Independent Research (ELISIR) program. Once an opera singer aspirant, her research now focuses on the “secret life” of lipids in the cell.

As the EPFL Life Sciences Independent Research (ELISIR) program enters its fifth year, we meet one of its recent scholars, Dr Milena Schuhmacher, who joined in 2022 from the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden. Schuhmacher’s research takes a chemical biology approach to opening “the door to investigate the so far mostly invisible and thus secret work of lipids.”

What led you to science?

I actually wanted to be an opera singer! I even passed the exam in Germany, and I love the opera, the theater stage, all that. But I also wanted something with more stability, so I turned to science — which none of the people who knew me in school would’ve ever thought about me! I started off as a chemist, studying at Heidelberg for both my bachelor’s and master’s degrees. I’ve always been interested in interdisciplinary research, which is why I chose to study chemistry as a starting point to enter the field of chemical biology. However, my studies were very chemistry-focused and lacked bio influences. So, I challenged myself to find my way into interdisciplinary research by doing my bachelor’s thesis in a structural biology lab and spending almost a year abroad in New Zealand at the University of Auckland. During my time there, I took part in the master’s curriculum and completed two research internships – one focused on peptide synthesis with Margaret Brimble and another focused on virion capsids using electron microscopy.

Which one do you prefer? Biology or chemistry?

I find both biology and chemistry interesting, but I think biology questions are more relevant to humankind. Chemistry can be incredibly useful in answering these questions, though. The Nobel Prize in Chemistry was recently awarded for click chemistry and biorthogonal chemistry, which is a great example of how chemistry can be applied in life systems. I’ve always been interested in chemistry as long as I could use it to answer biological questions or make something applied, like a drug. I enjoy the physical work in the lab too, working with glassware and actually making something. In the end, I did my master’s thesis at EMBL in the lab of Carsten Schultz, a famous chemical biologist, because I’m always trying to find connections between chemistry and other disciplines.

So now you work on cell membranes. What led you there?

During my bachelor’s thesis, I was tasked with purifying a membrane protein from the bacterial flagellum. It was a challenging project that taught me critical thinking and skepticism. I became interested in microbiology and structural biology from that experience. Later, I joined Carsten Schultz’s lab at EMBL, where I worked on insulin secretion and beta cells in the pancreas. I established optogenetic tools to modify the lipid composition of the plasma membrane, which was a novel approach at the time. I learned a lot of biology working in that chemical biology lab with a biologist supervisor, including cell culture, imaging techniques, and cloning.

Afterward, I joined André Nadler’s lab at the Max Planck Institute in Dresden, where I found the perfect opportunity to use chemistry to answer biological questions. Although I had considered going into structural biology, I realized that using chemistry to answer biological questions was the right path for me.

You’ve written before that there’s a lack of tools for research on lipids. Does your research at EPFL focus on developing such tools or are you using tools you developed before to discover things?

It’s actually a bit of both. I think this is one of the major problems for chemical biology because they develop a lot of tools, but then they don’t do the actual biology with them because that’s not what they’re equipped for. But then the biologists are very hesitant to use something that is not shown to them hands-on. So I’m trying to bridge this by having a lab that’s both chemistry and biology.

We’re using tools that have been previously developed or that I have developed during my PhD, and we are going to use them on biological questions, but we are of course also thinking about the missing parts, the toolbox and how we can fill them. And I’m of course pushing that forward as much as I can. So it’s both method development and actually asking biology questions and trying to answer them.

Can you describe one of these tools?

During my PhD, I developed a method to measure rate and binding constants for individual lipid species in living cells, something that wasn’t possible before. Lipids are very small molecules compared to proteins, and attaching a big fluorophore to a lipid can change its behavior, making it difficult to distinguish between the fluorophore and the lipid. So, I developed a method using a photo-activation or a ‘photo-caging’ approach to study an unlabeled lipid as it would be synthesized by the cell. This involves attaching a photolabile protection group to the head group of the lipid to mask it biologically until it is cleaved off using light of a specific wavelength. We can load it on cells or bring it to different subcellular organelles, and as soon as we release the photocage from the lipid, the experiment begins.

Investigating individual lipid species wasn’t possible previously, but is very important since we have over 40,000 lipid species, twice the amount of coding genes in the genome. The cell goes to such lengths to make this plethora of lipids, and as a chemist, I believe that their structural differences and can lead to differential signaling outcomes. My work showed differential behavior of individual lipids in the cell membrane, with different rate constants for the dynamics of the lipid in the membrane and for the binding of an effective protein. Small changes in the lipid’s side chains, such as a couple of double bonds, can make a big difference.

What do you think about the ELISIR program?

I think it is a fantastic opportunity. It’s like a short track: if you already have a good idea after your PhD, you can actually just dive right into it, set up your own lab, realize your own ideas. It is an absolutely unique opportunity in Europe. And also, especially at a university like EPFL where you have literally everything. Everything is here and there’s an expert for everything. And people are very friendly and very welcoming. So whenever I approach someone, it’s like, “Sure, we can do this”.

Also the ELISIR scholars are a really nice community. I’m the fifth ELISIR, and I’ve come into a really welcoming environment. And I’ve had a lot of support, especially in the beginning when I didn’t know my way around because nothing prepares you for setting up a lab. And that was really helpful. I came here and found this perfect network where we all support each other.

What do you hope to achieve in the time that you will be at EPFL?

I’d like to draw more attention to lipids because I have the feeling that a lot of researchers find working with lipids tedious. So I’d like to produce a methodology that makes lipids more approachable for people. And I also I have the feeling that cell membranes are still underestimated. The diversity we have in biological membranes, just lipid-wise is incredible but is very often overlooked. There’s still a lot to discover, but I feel like people stay away because it’s complicated and there is not so much methodology. So I’d like to push that a little forward. If things go well and we publish some nice papers, I’ll have the opportunity to stay in academia and then, of course, there’s a lot more methodological development about lipids that I’d like to follow up on, and thousands of biological questions.

The idea behind ELISIR is that nurturing top young scientists during their most creative years can usher in a new generation of leaders. The non-tenured position runs for three years with an optional renewal for another two, and offers a recent PhD graduate a full research budget, mentorship program, and the opportunity to work as independent principal investigator in an interdisciplinary institution with state-of-the-art infrastructure and core facilities.