Phage-Encoded Twin Endolysins

Grantee: Thomas Sicheritz-Pontén, Professor, University of Copenhagen

Amount: DKK 3,999,597

Grant category: Serendipity Grants

Year: 2025

Geography: Denmark

Thomas Sicheritz-Pontén serendipitously found that ~15% of sequenced phages encode two adjacent, independently active endolysin genes, often with distinct catalytic and binding domains. In one example, each enzyme is active on its own, and modelling suggests they also form a complex. While developing a custom endolysin predictor incorporating gene neighbourhood context, he detected genomic patterns missed by other tools. Most studies focus on individual lysins or domains, overlooking adjacent full-length endolysin genes. His large-scale analysis of 21k phage genomes revealed this hidden trend and a possible unrecognised lysis strategy hiding in plain sight.

The project will begin with phage AA002, which infects Staphylococcus hominis, a contributor to human body odour. Thomas Sicheritz-Pontén will clone, express, and purify its two endolysins, assess their activity alone and in combination, and investigate synergy and complex formation. Structural modelling will provide mechanistic insight. In parallel, he will mine publicly available phage genomes to identify additional dual-endolysin systems and prioritise further candidates for testing on skin-associated bacteria under skin-like conditions.

This study will define a novel category of cooperative phage lytic enzymes, offering insights into phage genome organisation and enzyme evolution. Beyond fundamental discovery, these enzymes could serve as precise, microbiome-friendly actives for non-antibiotic applications such as next-generation deodorants.

SkinSense: Dissecting the Effect of Stretch-Mediated Tissue Expansion on Innervation

Grantee: Mariaceleste Aragona, PhD, Novo Nordisk Foundation Centre for Stem Cell Medicine

Amount: DKK 3,924,998

Grant category: Serendipity Grants

Year: 2025

Geography: Denmark

“Stretch-mediated tissue expansion” is used to grow extra skin during breast reconstruction. A mouse model mimicking this clinical process was used to unravel fibroblast-epithelial crosstalk supporting keratinocyte self-renewal. Unexpectedly, the research project found that stretching alters gene expression in Schwann cells, which support nerve function, and reduces touch sensitivity. However, how stretching impacts skin nerves and sensation remains unclear. In light of this serendipitous discovery, the project now plans to investigate how Schwann cells contribute to the regeneration and re-innervation of peripheral sensory neurons in stretched skin.

The new research project – SkinSense – will explore how stretching affects peripheral sensory neurons and Schwann cells, which are key to skin sensation. Single-cell transcriptomics and high-resolution imaging will be used to study how peripheral sensory neurons are affected in terms of structure, function, and repair. Based on these findings, gene therapy approaches using adeno-associated viruses will be tested to restore nerve function and recover skin sensation.

Loss of skin sensitivity after breast reconstruction can greatly affect the quality of life of women. Yet, the reasons behind this sensory loss are not well understood. SkinSense aims to uncover the biological causes of this dysfunction and test ways to restore sensation. This research could lead to new treatments that improve sensory outcomes for patients undergoing reconstructive surgery.

Targeted and localized skin inflammation as a potential immunotherapy against cancer

Grantee: Vasileios Bekiaris, Associate Professor, Technical University of Denmark

Amount: DKK 3,987,557

Grant category: Serendipity Grants

Year: 2023

Geography: Denmark

Vasileios Bekiaris will investigate how an observed adverse impact of a drug candidate in psoriasis may be converted to a potential treatment of cancer.

Vasileios Bekiaris and his team have been studying the mechanisms by which psoriasis is induced for several years, and their goal was to find ways to suppress it. They have discovered a molecule that is necessary for the generation and function of the immune cells responsible for causing psoriasis. Moreover, they have access to a drug that targets and neutralizes this molecule, and therefore they thought that it could potentially inhibit psoriasis. Contrary to what they expected, the drug induced inflammation and exacerbated psoriasis instead of treating it. It is known that for many cancers, inflammation promotes favourable protective immunity and helps the efficacy of immunotherapy. Using a mouse melanoma model, Vasileios Bekiaris and his team have managed to generate data suggesting that the pro-inflammatory drug could in fact suppress tumour growth.

Vasileios Bekiaris will therefore investigate the drug’s potential in cancer treatment and, if successful, may open possibilities for a new immunotherapy against skin cancers. Vasileios Bekiaris and his team also believe that this data will continue their contribution towards understanding how skin inflammation is mediated.

An unexpected link between age-associated B cells and CD8 T cells

Grantee: Søren Degn, Associate Professor, Aarhus University

Amount: DKK 3,337,538

Grant category: Serendipity Grants

Year: 2023

Geography: Denmark

Søren Degn will investigate a novel link between age-related B cells (ABCs) and cytotoxic CD8+ T cells.

Søren Degn and his team have discovered a new and unexpected link between a type of immune cells that normally produce antibodies (B cells) and a type of immune cells that are responsible for eliminating the body’s own cells when they are infected or become cancerous (CD8+ T cells). Their preliminary findings indicate that this link may play an important role when the immune system is erroneously activated, when an infection cannot be cleared, or when a cancer is established. It is not known which exact signals are responsible for the communication between these two cell types, and whether it occurs directly or via a third-party messenger. However, it is known that it occurs in the spleen, an important immune organ, which filters the blood and prevents infections, but also plays a critical role in autoimmune diseases.

The intention of Søren Degn is to understand the cellular and molecular mechanisms behind this novel link. An increased understanding may enable new therapeutic strategies in the future across a range of important diseases such as inflammatory skin disorders, autoimmune diseases, and cancer.