Since May 2021, Dr. Natalie Köhler is the new CIBSS tenure-track professor for “Precision Targeting of Signalling Pathways” at the Medical Faculty of the University of Freiburg. There, she uses cutting-edge techniques to develop innovative approaches for blood cancer therapy. Her childhood dream to develop better therapies for leukaemia could soon become reality. In an interview with Mathilde Bessert-Nettelbeck from CIBSS she speaks about cancer cells and immune cells, new analysis methods, why collaborations matter in science, and how research from the lab is brought to the patient’s bedside.

So far, you have been working in oncology and haematology at the University Hospital. What is it that fascinates you about blood diseases, and especially blood cancers?

Natalie Köhler: I knew very early on that I wanted to work in oncology. There were cases of cancer in my immediate family and I really wanted to do something about it. That is why I chose to study Molecular Medicine at the University of Freiburg. During the first semesters of my studies, I started working as a student assistant in hematooncology – this is where my enthusiasm for leukaemia research began.

What exactly is leukaemia? 

It is a cancer of the blood cells. Cells of the hematopoietic system acquire mutations and begin to divide uncontrollably. In most cases of leukaemia, the number of white blood cells in the blood is greatly increased.

Do you have direct interactions with patients?

I myself am not in direct contact with patients, but I work with blood samples and bone marrow material from patients who are being treated at the Freiburg University Medical Center and other clinics. My group is in close contact with practicing physicians who treat patients and conduct clinical trials, and my research is strongly influenced by the clinical environment.

What signals are you researching in the context of these blood cancers?

Two signalling networks are particularly important in my research: oncogenic signalling, and signalling in immune cells, especially T cells. Oncogenic signalling encompasses the signalling pathways responsible for the malignant transformation of, for example, white blood cells or their precursor cells. Signalling within cells can change due to mutations in the DNA; in cancer cells, for example, this causes them to divide uncontrollably.

In particular, we are also investigating how oncogenic signalling manipulates the immune system. Our immune system can actually recognize and fight cancer cells. However, the tumour cells are able to inhibit these immune cells and evade destruction. Here, we aim to get a more precise picture of which signalling pathways are involved with respect to specific types of leukaemia.

On the other hand, we are also investigating immune signalling, specifically, how the immune system responds to cancer cells. How does it recognize cancer cells? How does it form an effective immune response to kill these cells? Which cells are involved and how?

This means that we are looking at both the signalling in leukaemia cells and the signalling pathways of the immune cells fighting against them. In addition, I am particularly interested in how these two signalling pathways influence each other.

What is "Precision Targeting"?

The precise manipulation of signalling pathways. This is also the ultimate goal of my research. We want to understand the mechanisms underlying the signalling pathways that promote cancer development. But then the next and important step is to help patients by influencing or inhibiting these signalling pathways. Of course, such therapeutic approaches must be very precise in order to minimize side effects.

Put simply, this is what precision targeting means: precise and targeted intervention in signalling pathways – by the means of drugs, for example – so that we can better combat blood cancers.

What applications do you have in mind?

Ideally, we want to find therapeutic options that inhibit the signalling pathways used by tumour cells to escape the immune system. One of the therapeutic approaches we are working on, for example, targets tyrosine kinase signalling: When this signalling chain is overactive – which it is in some tumour cells – it leads to the production of a molecule that inhibits an effective anti-tumour immune response. Meaning that the types of tumour cells that produce this oncogenic tyrosine kinase inhibit the immune response against them. Drugs against overactive tyrosine kinases indeed already exist, and our research can identify the patients who would particularly benefit from these drugs. Thus, our research results could directly benefit patients in the future. That is ultimately my long-term goal: the "translation" – meaning the transfer from basic research into clinical practice in order to directly help patients.

What do you want to achieve within CIBSS?

I am already collaborating with various CIBSS members, and we would like to deepen and expand these collaborations. I am also working on clinical studies of allogeneic stem cell transplantation, where stem cells from a foreign donor are transplanted into patients with leukaemia to replace their immune cells. The foreign immune cells should attack and destroy the tumour, but they also attack some of the patient's healthy tissues. This is a so-called “graft-versus-host” reaction, which can be fatal.

We are investigating how the transplanted T cells react to signals from the body's own cells and what signalling processes happen inside them. We are collaborating with the research group of CIBSS member PD Dr. Susana Minguet to better understand these signalling mechanisms. Susana Minguet is an expert in T cell receptor signalling and has already made important contributions to this project.

We are now starting studies in metabolic signalling as well – here we are also looking forward to collaborating with the metabolism experts in CIBSS. There are so many exciting approaches that could be used to identify the small metabolites in cancer and immune cells, so I am looking forward embarking on this new research direction in CIBSS. It is a great research environment for this.

What technology plays an important role in your research?

Our goal is to integrate data from different experimental models: results from human samples, but also from mouse models of leukaemia and immunological diseases, and of course from cell culture research. We do a lot of single-cell RNA sequencing, because this method can give us a detailed view at what is going on in a single cell. In classical analysis, data loses some of its power and accuracy when it comes to analysing complex and mixed cell populations all at once (in "bulk"). Therefore, we use single-cell RNA sequencing to analyse individual cancer cells and immune cells from mice and humans. Cancer cells can vary widely in their RNA sequence expression patterns. In the case of immune cells, we are looking specifically at T cells: there are very many subtypes with different RNA expression patterns. If we do not analyse the subtypes of T cells individually, we might miss some of the regulatory processes. Single-cell RNA sequencing reveals very subtle differences between populations and can identify very small, rare cell populations. When I started doing research, this was not yet possible, and I think it is a very promising method for the future‚that also gives new insight into signalling processes

As an alumnus of the University of Freiburg, would you recommend the Freiburg Molecular Medicine programme?

Yes, definitely. I was in one of the first classes of this programme in Freiburg. In my opinion, it prepared me very well for translational research because it builds a perfect bridge between human medicine and biology. Now I even teach within this programme myself, and some of the doctoral researchers and students in my lab have completed this programme as well.