Kirsten Falk working at the HPLC system, ca. 1990. Copyright Olaf Rötzschke

Kirsten Falk was a pioneer in the discovery of peptides presented by MHC molecules.

She started her studies in biochemistry at the University of Hannover, Germany, and continued at the University of Tübingen, together with her partner Olaf Rötzschke. During a lab rotation in 1988 she joined a new junior group at the Max-Planck-Institute for Biology, Department of Immunogenetics (Director Prof. Jan Klein), led by Hans-Georg Rammensee. She and her partner strove to be the first to isolate natural T-cell antigens directly from living cells.

The crystal structure of MHC class I molecules had just been reported, and showed a groove occupied by material not belonging to the MHC sequences. This material was assumed to be a mixture of the self-peptides constitutively presented by normal cells, but the exact nature of the peptides was unknown. By employing methods Kirsten had picked up a in a peptide chemistry group during a previous lab rotation, she and her partner indeed succeeded in solubilizing the cell-derived antigens and separating them on HPLC. Some of the fractions were specifically recognized by T cells, proving not only that minor histocompatibility antigens indeed are peptides derived from polymorphic or sex-specific proteins (PMID: 1695760) but also that the method makes it possible to isolate MHC-restricted peptides from cells and to functionally characterize them. Therefore, the next step was to try to identify MHC-restricted virus-derived peptides from virus-infected cells, which was also successful (PMID: 1700304). In the same issue of Nature, Grada van Bleek and Stan Nathenson demonstrated that such peptides could be isolated from purified MHC molecules of virus-infected cells.

The identification of such naturally processed MHC-restricted viral peptides and a comparison of their sequences led to the hypothesis that the presentation of peptides on MHC molecules follows allele-specific rules (PMID: 1713253). To prove this, Kirsten and Olaf isolated the peptides directly from purified MHC molecules and subjected this complex mixture directly to sequence analysis by classical Edman degradation. Organic chemist Prof. Günther Jung, at first reluctant regarding this “dirty” approach, agreed, and his PhD student Stefan Stevanović successfully performed this “pool sequencing”. Indeed, the results clearly showed that the peptides presented by a given MHC molecule must adhere to allele-specific motifs in order to be stably attached to the MHC molecule (PMID: 1709722). This was a breakthrough in the field, and was later classified as a hallmark paper (PMID: 16920905), which allowed the exact prediction of naturally MHC-presented peptides (PMID: 1718764). Moreover, the knowledge of the allele-specific MHC motifs started a new field in immunoinformatics, which has grown to become an immensely large body of data (https://www.iedb.org/).

It is remarkable that Kirsten did her experiments for this groundbreaking work mainly as an undergraduate student. She was a hardworking scientist, strongly focused on intelligent design and the performing of experiments. She would typically appear late in the lab but always stayed long into the night. Presenting her fantastic work, however, was not her favorite activity, which preferred to be done by Olaf. She also showed little interest in pursuing a standard academic career, preferring to continue conducting more experiments. Her publications and her legendary track record allowed her to complete her own PhD in less than six months. For her early achievements, she received the Otto-Westphal-Promotionspreis of the German Society for Immunology (DGfI) 1993 and the Walter and Christine Richtzenhain-Prize 1995. After completing the thesis, she did her postdoc in Jack Strominger’s lab at Harvard University, continuing to work on MHC peptide interaction but also moving to other fields related to T-cell biology and autoimmune reactions. Together with Olaf, she then led a research group at the Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany, where she continued studying MHC-peptide interaction as well as the function of regulatory T cells (Treg).

In 2008, her plan was to move to Singapore, where she had accepted a job offer from the Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), led by Profs. Paula Ricciardi Castagnoli and Philipp Kourilsky. However, before this move was possible, the tragedy of her life began. During a scientific visit in West Africa, she had an accident with her off-road vehicle, which resulted in a severe injury to her cervical spine. But despite the accident leaving her completely paralyzed, she developed a strong and admirable will to live. She spent her last 16 years in an apartment in Berlin, dependent on a nursing team but always keenly interested in science. She passed away peacefully on December 18, 2024, following an acute lung infection.