The Jahre Lectures 2025

Abstracts

"In vivo CRISPR engineering to reprogram human T cells"

William Nyberg

Karolinska Institutet, Stockholm, Sweden

Engineered T cells, reprogrammed to express chimeric antigen receptors (CAR) or T cell receptors (TCR), have transformed cancer treatment and are being explored as therapeutics for autoimmune disorders and infectious diseases. Enhancing T cell function through genome editing¡ªeither by disrupting endogenous genes or precisely inserting DNA payloads¡ªhas shown significant promise. However, the ex vivo manufacturing process is lengthy, costly, and requires pre-conditioning, limiting the accessibility of these therapies. In vivo generation of CAR-T cells could overcome these barriers. In this presentation, I will demonstrate that stable and cell-specific transgene expression can be achieved through in vivo site-specific integration of large DNA payloads. We developed a two-vector system to deliver CRISPR-Cas9 ribonucleoproteins (RNPs) and a DNA donor template, using enveloped delivery vehicles (EDVs) and adeno-associated virus (AAVs), respectively. By integrating a CAR transgene into a T cell-specific locus we generated therapeutic levels of CAR-T cells in a humanized mouse model in vivo. These findings offer a promising pathway to more efficient, precise, and widely accessible T cell therapies.

¡°Dynamic autophagy trajectories shape the aging brain¡±

Thomas McWilliams

University of Helsinki, Finland

Our cells and their components accumulate damage over a lifetime, gradually compromising tissue function and integrity. Autophagy (from the Greek for ¡°self-eating¡±) safeguards against this decline by capturing and delivering damaged components to lysosomes for degradation. Elegant biochemical studies have provided a rich molecular foundation, and emergent human cases have revealed its clinical significance. Yet how different autophagy pathways are orchestrated within complex mammalian tissues remains poorly understood. To develop precision therapies for neurological disease that target autophagy, we must first unravel its spatiotemporal and mechanistic logic across physiological contexts. Our work has revealed unexpected vistas of organelle destruction at single-cell resolution in vivo. We and others have provoked a reassessment in the field, showing that autophagy pathways are highly pervasive at steady state and follow dynamic, mechanistically diverse, and cell-specific trajectories across the lifespan. This framework reshapes our understanding of organelle homeostasis and tissue resilience, opening opportunities for the development of novel therapeutics and improved preclinical models for age-related neurological decline.

"Identification and fate-mapping of hematopoietic stem cells in normal and malignant blood cell production"

Sten Eirik Waelgaard Jacobsen 

Karolinska Institutet, Huddinge, Sweden

Normal hematopoietic stem cells (HSCs) possess two unique properties, multipotentiality (the ability of a single HSC to produce all types of blood and immune cells), and self-renewal a property critical for safe-guarding life-long blood cell replenishment, amounting to millions of blood cells per second and representing almost 90% of the daily turnover of cells in humans. The life-long self-renewal comes at the expense of each HSC accumulating approximately 15 DNA mutations per year, in contrast to short-lived progenitors and most mature blood cells. This, combined with the multistep malignant transformation process spanning over years or decades explains why HSCs although being exceptionally rare in the bone marrow, almost invariably represent the cells of origin for many types of hematological malignancies. In my Jahre Lecture I will summarize key findings from our HSC research the two last decades:

• the establishment of extensive HSC heterogeneity, including identification of HSCs that exclusively replenish the platelet lineage (essential for coagulation).
• the unraveling of novel lineage progenitors/differentiation pathways from HSCs to mature blood cell lineages, resulting in redrawing of the classical ¡°textbook¡± hematopoiesis map.
• the finding that the same mature blood cells (platelets) can be replenished through 2 alternative lineage-replenishment pathways, each initiated by a distinct population of HSCs.
• the identification, characterization and therapeutic surveillance and targeting of the stem cells in hematological malignancies.

The last part of my talk will focus on recent (unpublished) work in which naturally occurring mutations have enabled us to retrospectively as well as prospectively fate map the normal blood lineage contribution of HSCs in humans.